umu.sePublications
Change search
Refine search result
567891011 351 - 400 of 1698
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 351.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundgren, David
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The combined diagnostic value of faecal haemoglobin and calprotectin in colorectal cancerManuscript (preprint) (Other academic)
  • 352.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alexeyev, Oleg
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cancer-associated fecal microbial markers in colorectal cancer detection2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 12, p. 2528-2536Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harboring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a "high-risk" microbial pattern to other further diagnostic procedures such as colonoscopy.

  • 353.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Å.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 10, p. 2153-2163Article in journal (Refereed)
    Abstract [en]

    Background Mutations in KRAS, BRAF, PIK3CA and PTEN expression have been in focus to predict the effect of epidermal growth factor receptor-blocking therapy in colorectal cancer (CRC). Here, information on these four aberrations was collected and combined to a Quadruple index and used to evaluate the prognostic role of these factors in CRC. Patients We analysed the mutation status in KRAS, BRAF and PIK3CA and PTEN expression in two separate CRC cohorts, Northern Sweden Health Disease Study (NSHDS; n = 197) and Colorectal Cancer in Umea Study (CRUMS; n = 414). A Quadruple index was created, where Quadruple index positivity specifies cases with any aberration in KRAS, BRAF, PIK3CA or PTEN expression. Results Quadruple index positive tumours had a worse prognosis, significant in the NSHDS but not in the CRUMS cohort (NSHDS; P = 0.003 and CRUMS; P = 0.230) in univariate analyses but significance was lost in multivariate analyses. When analysing each gene separately, only BRAF was of prognostic significance in the NSHDS cohort (multivariate HR 2.00, 95% CI: 1.16-3.43) and KRAS was of prognostic significance in the CRUMS cohort (multivariate HR 1.48, 95% CI: 1.02-2.16). Aberrations in PIK3CA and PTEN did not add significant prognostic information. Conclusions Our results suggest that establishment of molecular subgroups based on KRAS and BRAF mutation status is important and should be considered in future prognostic studies in CRC.

  • 354. Ekman, Maria
    et al.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lee, So Young
    Edlund, Sofia
    Kozakai, Takaharu
    Thakur, Noopur
    Tran, Hoanh
    Qian, Jiang
    Groeden, Joanna
    Heldin, Carl-Henrik
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    APC and Smad7 link TGF beta type I receptors to the microtubule system to promote cell migration2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 11, p. 2109-2121Article in journal (Refereed)
    Abstract [en]

    Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3 beta (GSK-3 beta). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-beta (TGF beta) and is known to inhibit various TGF beta-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGF beta stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3 beta kinases to facilitate local TGF beta/p38-dependent inactivation of GSK-3 beta, accumulation of beta-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGF beta type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF beta.

  • 355. Ekman, Simon
    et al.
    Harmenberg, Johan
    Frödin, Jan-Erik
    Bergström, Stefan
    Wassberg, Cecilia
    Eksborg, Staffan
    Larsson, Olle
    Axelson, Magnus
    Jerling, Markus
    Abrahmsen, Lars
    Hedlund, Åsa
    Alvfors, Carina
    Ståhl, Birgitta
    Bergqvist, Michael
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 2, p. 140-148Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors.

    MATERIAL AND METHODS: This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing.

    RESULTS AND CONCLUSION: Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.

  • 356. Elena, J. W.
    et al.
    Steplowski, E.
    Yu, K.
    Hartge, P.
    Tobias, G. S.
    Brotzman, M. J.
    Chanock, S. J.
    Stolzenberg-Solomon, R. Z.
    Arslan, A. A.
    Bueno-De-Mesquita, H. B.
    Helzlsouer, K.
    Jacobs, E. J.
    Lacroix, A.
    Petersen, G.
    Zheng, W.
    Albanes, D.
    Allen, N. E.
    Amundadottir, L.
    Bao, Y.
    Boeing, H.
    Boutron-Ruault, M. -C
    Buring, J. E.
    Gaziano, J. M.
    Giovannucci, E. L.
    Duell, E. J.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Howard, B. V.
    Hunter, D. J.
    Hutchinson, A.
    Jacobs, K. B.
    Kooperberg, C.
    Kraft, P.
    Mendelsohn, J. B.
    Michaud, D. S.
    Palli, D.
    Phillips, L. S.
    Overvad, K.
    Patel, A. V.
    Sansbury, L.
    Shu, X. -O
    Simon, M. S.
    Slimani, N.
    Trichopoulos, D.
    Visvanathan, K.
    Virtamo, J.
    Wolpin, B. M.
    Zeleniuch-Jacquotte, A.
    Fuchs, C. S.
    Hoover, R. N.
    Gross, M.
    Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 1, p. 13-25Article in journal (Refereed)
    Abstract [en]

    Purpose: Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). Methods: The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. Results: Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). Conclusions: These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.

  • 357. Eliassen, A. Heather
    et al.
    Hendrickson, Sara J.
    Brinton, Louise A.
    Buring, Julie E.
    Campos, Hannia
    Dai, Qi
    Dorgan, Joanne F.
    Franke, Adrian A.
    Gao, Yu-tang
    Goodman, Marc T.
    Hallmans, Goeran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Helzlsouer, Kathy J.
    Hoffman-Bolton, Judy
    Hulten, Kerstin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sesso, Howard D.
    Sowell, Anne L.
    Tamimi, Rulla M.
    Toniolo, Paolo
    Wilkens, Lynne R.
    Winkvist, Anna
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Hankinson, Susan E.
    Circulating Carotenoids and Risk of Breast Cancer: Pooled Analysis of Eight Prospective Studies2012In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 104, no 24, p. 1905-1916Article in journal (Refereed)
    Abstract [en]

    Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Statistically significant inverse associations with breast cancer were observed for -carotene (top vs bottom quintile RR 0.87, 95% CI 0.71 to 1.05, Ptrend .04), -carotene (RR 0.83, 95% CI 0.70 to 0.98, Ptrend .02), luteinzeaxanthin (RR 0.84, 95% CI 0.70 to 1.01, Ptrend .05), lycopene (RR 0.78, 95% CI 0.62 to 0.99, Ptrend .02), and total carotenoids (RR 0.81, 95% CI 0.68 to 0.96, Ptrend .01). -Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER) than for ER tumors (eg, -carotene: ER: top vs bottom quintile RR 0.52, 95% CI 0.36 to 0.77, Ptrend .001; ER: RR 0.83, 95% CI 0.66 to 1.04, Ptrend .06; Pheterogeneity .01). This comprehensive prospective analysis suggests women with higher circulating levels of -carotene, -carotene, luteinzeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer. 

  • 358. Ellingson, Benjamin
    et al.
    Abrey, Lauren
    Garcia, Josep
    Chinot, Olivier
    Aftab, Dana
    Schwab, Gisela
    Revil, Cedric
    Saran, Frank
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm, Sweden.
    Hessel, Colin
    Harris, Robert
    Woodworth, Davis
    Leu, Kevin
    Lai, Albert
    Sahebjam, Solmaz
    Pope, Whitney
    Mason, Warren
    Wick, Wolfgang
    Wen, Patrick
    Cloughesy, Timothy
    RESIDUAL ENHANCING TUMOR VOLUME IS A STRONG PROGNOSTIC BIOMARKER FOR SURVIVAL IN BOTH NEWLY DIAGNOSED AND RECURRENT GBM REGARDLESS OF THERAPY: EVIDENCE FROM 1,535 PATIENTS IN SINGLE AND MULTICENTER TRIALS2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 131-131Article in journal (Refereed)
  • 359. Ellingson, Benjamin M.
    et al.
    Abrey, Lauren E.
    Garcia, Josep
    Chinot, Olivier
    Wick, Wolfgang
    Saran, Frank
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm, Sweden.
    Mason, Warren P.
    Harris, Robert J.
    Leu, Kevin
    Woodworth, Davis C.
    Mehta, Arnav
    Raymond, Catalina
    Chakhoyan, Ararat
    Pope, Whitney B.
    Cloughesy, Timothy F.
    Post-chemoradiation volumetric response predicts survival in newly diagnosed glioblastoma treated with radiation, temozolomide, and bevacizumab or placebo2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1525-1535Article in journal (Refereed)
    Abstract [en]

    Background. In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods. Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had > 4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results. A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions. The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

  • 360. Ellingson, Benjamin M.
    et al.
    Abrey, Lauren E.
    Nelson, Sarah J.
    Kaufmann, Timothy J.
    Garcia, Josep
    Chinot, Olivier
    Saran, Frank
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm.
    Mason, Warren P.
    Wick, Wolfgang
    Butowski, Nicholas
    Ligon, Keith L.
    Gerstner, Elizabeth R.
    Colman, Howard
    de Groot, John
    Chang, Susan
    Mellinghoff, Ingo
    Young, Robert J.
    Alexander, Brian M.
    Colen, Rivka
    Taylor, Jennie W.
    Arrillaga-Romany, Isabel
    Mehta, Arnav
    Huang, Raymond Y.
    Pope, Whitney B.
    Reardon, David
    Batchelor, Tracy
    Prados, Michael
    Galanis, Evanthia
    Wen, Patrick Y.
    Cloughesy, Timothy F.
    Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 9, p. 1240-1250Article in journal (Refereed)
    Abstract [en]

    Background. In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS). Methods. Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O-6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS. Results. A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status. Conclusion. Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

  • 361. Elmstedt, Sixten
    et al.
    Mogensen, Hanna
    Hallmans, Dan-Erik
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lundström, Staffan
    Lindskog, Magnus
    Cancer patients hospitalised in the last week of life risk insufficient care quality: a population-based study from the Swedish Register of Palliative Care2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 4, p. 432-438Article in journal (Refereed)
    Abstract [en]

    Background: One-quarter of all cancer deaths in Sweden occur in hospitals. If the place of death affects the quality of end-of-life (EOL) is largely unknown.

    Methods: This population-based, retrospective study included all adults cancer deaths reported to the Swedish Register of Palliative Care in 2011-2013 (N = 41,729). Hospital deaths were compared to deaths occurring in general or specialised palliative care, or in nursing homes with respect to care quality indicators in the last week of life. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with specialised palliative home care as reference.

    Results: Preferred place of death was unknown for 63% of hospitalised patients and consistent with the actual place of death in 25% compared to 97% in palliative home care. Hospitalised patients were less likely to be informed when death was imminent (OR: 0.3; CI: 0.28-0.33) as were their families (OR: 0.51; CI: 0.46-0.57). Validated screening tools were less often used in hospitals for assessment of pain (OR: 0.32; CI: 0.30-0.34) or other symptoms (OR: 0.31; CI: 0.28-0.34) despite similar levels of EOL symptoms. Prescriptions of as needed drugs against anxiety (OR: 0.27; CI: 0.24-0.30), nausea (OR: 0.19; CI: 0.17-0.21), or pulmonary secretions (OR: 0.29; CI: 0.26-0.32) were less prevalent in hospitals. Bereavement support was offered after 57% of hospital deaths compared to 87-97% in palliative care units and 72% in nursing homes.

    Conclusions: Dying in hospital was associated with inferior end-of-life care quality among cancer patients in Sweden.

  • 362. Eloranta, Sandra
    et al.
    Adolfsson, Jan
    Lambert, Paul C.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Akre, Olof
    Andersson, Therese M-L.
    Dickman, Paul W.
    How can we make cancer survival statistics more useful for patients and clinicians: an illustration using localized prostate cancer in Sweden2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 3, p. 505-515Article in journal (Refereed)
    Abstract [en]

    Studies of cancer patient survival typically report relative survival or cause-specific survival using data from patients diagnosed many years in the past. From a risk-communication perspective, such measures are suboptimal for several reasons; their interpretation is not transparent for non-specialists, competing causes of death are ignored and the estimates are unsuitable to predict the outcome of newly diagnosed patients. In this paper, we discuss the relative merits of recently developed alternatives to traditionally reported measures of cancer patient survival. In a relative survival framework, using a period approach, we estimated probabilities of death in the presence of competing risks. To illustrate the methods, we present estimates of survival among 23,353 initially untreated, or hormonally treated men with intermediate- or high-risk localized prostate cancer using Swedish population-based data. Among all groups of newly diagnosed patients, the probability of dying from prostate cancer, accounting for competing risks, was lower compared to the corresponding estimates where competing risks were ignored. Accounting for competing deaths was particularly important for patients aged more than 70 years at diagnosis in order to avoid overestimating the risk of dying from prostate cancer. We argue that period estimates of survival, accounting for competing risks, provide the tools to communicate the actual risk that cancer patients, diagnosed today, face to die from their disease. Such measures should offer a more useful basis for risk communication between patients and clinicians and we advocate their use as means to answer prognostic questions.

  • 363. Elsir, Tamador
    et al.
    Edqvist, Per-Henrik
    Carlson, Joseph
    Ribom, Dan
    Bergqvist, Michael
    Ekman, Simon
    Popova, Svetlana N
    Alafuzoff, Irina
    Ponten, Fredrik
    Nistér, Monica
    Smits, Anja
    A study of embryonic stem cell-related proteins in human astrocytomas: identification of Nanog as a predictor of survival.2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 5Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO Grade II) and 98 high-grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n = 42) with high levels of Nanog protein (p = 0.0067) and of Klf4 protein (p = 0.0368), in high-grade astrocytomas (n = 85) with high levels of Nanog (p = 0.0042), Klf4 (p = 0.0447), and c-Myc (p = 0.0078) and in glioblastomas only (n = 71) with high levels of Nanog (p = 0.0422) and of c-Myc (p = 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p = 0.0039), high-grade astrocytomas (p = 0.0124) and glioblastomas only (p = 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.

  • 364.
    Emilsson, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Svensk, Ann-Christine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindh, Jack
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Support group participation during the post-operative radiotherapy period increases levels of coping resources among women with breast cancer.2012In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 21, no 5, p. 591-598Article in journal (Refereed)
    Abstract [en]

    Support group participation during the post-operative radiotherapy period increases levels of coping resources among women with breast cancer Being diagnosed with breast cancer is a traumatic experience that can elevate levels of distress and cause depletion of coping resources in many of the disease's victims. This non-randomised case-control study among breast cancer patients undergoing radiotherapy indicates that participation in a support group that focuses on communication and mutual sharing between its member's has positive effects and increases levels of coping resources assessed with the Coping Resources Inventory (CRI). Results of the CRI showed a significant difference between the study group and control group in the social domain at the second occasion of measurement (P= 0.007) and in the emotional domain at the third occasion (P= 0.028). Within the study group, over time, increased levels of coping resources reached significant levels concerning the emotional domain at the second occasion (P= 0.025). Conversely, coping resources were decreased in the same domain within the control group over time, at the third occasion (P= 0.053). Additionally, anxiety and depression were assessed using the Hospital Anxiety and Depression Scale, showing no difference between the groups. This study shows that participation in a support group during post-operative radiotherapy can be socially and emotionally strengthening because of the opportunity for the patients to mutually share experiences.

  • 365.
    Eriksson, Björn
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Levan, Göran
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Establishment and characterization of a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia1999In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 27, no 4, p. 682-688Article in journal (Refereed)
    Abstract [en]

    In this study, a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia with an early onset and high incidence was established and characterized. All tumors analyzed were found to express the alpha,beta T-cell receptor, and the majority of them had a mature, CD3+CD4+CD8- immunophenotype. In a few cases, tumors with a more immature CD3+CD4+CD8+ phenotype were isolated. Expanded phenotyping using a broad panel of lymphocyte differentiation markers confirmed the mature T-cell phenotype of the tumors. Histologic and cell cycle analysis of the tumors revealed an aggressive lymphoblastic malignancy with a very high proliferation rate and widespread engagement of bone marrow and lymphoid as well as nonlymphoid organs. Thus, the TLL mouse strain represents a unique model for the analysis of the oncogenesis and progression of mature T-cell tumors and for the development of therapeutic measures to combat such tumors.

  • 366. Eriksson, H.
    et al.
    Lyth, J.
    Månsson-Brahme, E.
    Frohm-Nilsson, M.
    Ingvar, C.
    Lindholm, C.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stierner, U.
    Wagenius, G.
    Carstensen, J.
    Hansson, J.
    Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma: a nationwide population-based study in Sweden2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no 12, p. 2705-2716Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden.

    METHODS: We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010.

    RESULTS: The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55years, patients with truncal tumours and during the first 5years after diagnosis.

    CONCLUSION: Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies.

  • 367.
    Eriksson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kahari, Jenna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vestman, Amanda
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Mattias
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sandström, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Improved treatment of glioblastoma: changes in survival over two decades at a single regional Centre2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 3, p. 334-341Article in journal (Refereed)
    Abstract [en]

    Background: Glioblastoma (GBM) is an aggressive brain tumor with a short overall survival (OS) in general. The treatment of GBM has evolved over the last decades and is today multimodal including surgical resection followed by radiochemotherapy and adjuvant chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single regional center.

    Patients and methods: Survival was studied for 571 patients in our region diagnosed with GBM between 1995 and 2015. Samples from 244 patients out of those treated 2005-2015 have been included in a tissue/blood bank and a clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment.

    Results: The median OS for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995-1996 and 2010-2015, respectively (p<.05). The 2-year survival for the same time periods improved from 7% to 18% (p<.01). After introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased OS was noted and following implementation of intraoperative 5-aminolevulinic acid the number of tumor resection 95% did increase from 33% to 54% (p<.001). Positive prognostic factors for survival were young age, good performance status, absence of inflammatory disease, absence of diabetes or metabolic disease, tumor resection 95%, and completion of postoperative radiochemotherapy.

    Discussion: The results of this study are consistent with earlier results regarding survival and prognostic factors and confirm results from randomized controlled trials in a clinical setting. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.

  • 368.
    Eriksson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Epidemiological studies on multiple myeloma1992Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple myeloma is a painful and uncurable malignant disease with an increasing incidence and mortality in several countries, e.g., Sweden. Some factors are suspected to be of aetiological significance, such as ionising radiation and chronic antigenic stimulation in certain inflammatory diseases. A familial factor has also been indicated. Furthermore, some studies have demonstrated farming as an occupation entailing an increased risk for the disease.

    The aim of this investigation was to further elucidate the impact of different aetiological factors in relation to multiple myeloma. The knowledge of aetiology is always a prerequisite for prevention.

    A case-control study on multiple myeloma was performed in a high-inddence area, the northern part of Sweden. One part of this study dealt with occupations and different exposures. The results supported farming as being an occupation with an increased risk. Within farming two kinds of pesticides, phenoxyacetic adds and DDT, and contact with certain domestic animals, i.e., cattle, horses and goats, were assodated with multiple myeloma.

    Farming as a risk factor was also confirmed by a register-based linkage study using the Swedish Cancer Environment Register. In this study a time trend was indicated, with increasing standardized inddence ratios over the different time periods studied.

    Another part of the case-control study showed that rheumatoid arthritis entailed an increased risk for multiple myeloma, a finding earlier suggested from register-based linkage studies, but not from any çase-control study.

    A third part of the case-control study indicated an increased risk for multiple myeloma if any first-degree relative had a history of haematological malignancy, or other malignant tumour, espedally prostatic cancer, brain tumour, and renal cancer.

    A case study encompassing 942 patients with haematological malignandes in the county of Jämtland, Sweden, during a 22-year period showed that about 5% of the patients had at least one relative who also suffered from such a disease. An espedally strong familial occurrence was found in the group of chronic lymphoprohferative diseases, including multiple myeloma.

  • 369. Erlandsson, Ann
    et al.
    Carlsson, Jessica
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fält, Anna
    Andersson, Sven-Olof
    Andrén, Ove
    Davidsson, Sabina
    M2 macrophages and regulatory T cells in lethal prostate cancer2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 4, p. 363-369Article in journal (Refereed)
    Abstract [en]

    Background: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs) can contribute to cancer progression by suppressing the anti‐tumor immune response. This study investigated the number of CD163‐positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs.

    Methods: This nested case‐control study included subjects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infiltrating CD163‐positive M2 macrophages and FOXP3/CD4‐positive Tregs in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and Tregs were assessed using Spearman's rank‐order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.

    Results: The number of M2 macrophages and Tregs showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23‐3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis.

    Conclusions: Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs, promote an immunosuppressive environment.

  • 370. Escudier, Bernard
    et al.
    Osanto, Susanne
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Porta, Camillo
    Wagstaff, John
    Mulders, Peter
    Gore, Martin
    Bex, Axel
    Bellmunt, Joaquim
    Bracarda, Sergio
    Franklin, Alex
    Honoré, Per Hartvig
    Ravaud, Alain
    van Steijn, Jeanne
    Aziz, Zeba
    Akaza, Hideyuki
    Multidisciplinary management of metastatic renal cell carcinoma in the era of targeted therapies2012In: Cancer Treatment Reviews, ISSN 0305-7372, E-ISSN 1532-1967, Vol. 38, no 2, p. 127-132Article, review/survey (Refereed)
    Abstract [en]

    The use of targeted agents to treat metastatic renal cell carcinoma (mRCC) has significantly extended progression-free and overall survival but raises issues relating to the long-term delivery of care and the sustained monitoring of efficacy and toxicities, certain of which have not previously been experienced. In this paper, an expert group of medical oncologists, urologists and oncology nurses and pharmacists review and make informal recommendations on the multidisciplinary management of mRCC in the light of progress made and problems that have arisen. Decentralisation of care, with a shift in emphasis from large to small hospitals and possibly to the community, may offer advantages of cost and convenience. However, the major responsibility for care should continue to lie with clinicians (either medical oncologists or urologists) with extensive experience in mRCC, assisted by specialist nurses, and working in centres with facilities adequate to monitor efficacy and manage toxicities. That said, the extended survival of patients emphasises the importance of compliance and the long-term prevention, detection and management of side effects. Much of this will take place in the community. There is therefore a need for multidisciplinary working to extend beyond specialist centres to include general practitioners, community nurses and pharmacists. Although this paper focuses on mRCC, many of the considerations discussed are also relevant to the management of more common solid tumours in the era of targeted therapy.

  • 371. Espersen, Anne Dorte Lerche
    et al.
    Noren-Nyström, Ulrika
    Department of Pediatrics, Umeå University Hospital, Umeå, Sweden.
    Abrahamsson, Jonas
    Ha, Shau-Yin
    Pronk, Cornelis Jan
    Jahnukainen, Kirsi
    Jónsson, Ólafur G
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Palmqvist, Lars
    Hasle, Henrik
    Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature2018In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 57, no 7, p. 359-365Article in journal (Refereed)
    Abstract [en]

    The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.

  • 372. Espinosa-Parrilla, Yolanda
    et al.
    Munoz, Xavier
    Bonet, Catalina
    Garcia, Nadia
    Vencesla, Adoracion
    Yiannakouris, Nikos
    Naccarati, Alessio
    Sieri, Sabina
    Panico, Salvatore
    Huerta, Jose M.
    Barricarte, Aurelio
    Menendez, Virginia
    Sanchez-Cantalejo, Emilio
    Dorronsoro, Miren
    Brennan, Paul
    Duarte-Salles, Talita
    Bueno-de-Mesquita, H. B. (As)
    Weiderpass, Elisabete
    Lund, Eiliv
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Numans, Mattijs E.
    Tumino, Rosario
    Canzian, Federico
    Campa, Daniele
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Ohlsson, Bodil
    Lindkvist, Bjorn
    Overvad, Kim
    Tjonneland, Anne
    Palli, Domenico
    Travis, Ruth C.
    Khaw, Kay-Tee
    Wareham, Nick
    Boeing, Heiner
    Nesi, Gabriella
    Riboli, Elio
    Gonzalez, Carlos A.
    Sala, Nuria
    Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: Results from the EPIC-EURGAST study2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 9, p. 2065-2076Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value=1.7 x 10(-4); odds ratio, OR=1.72; 95% confidence interval, CI=1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value=5.38 x 10(-3); OR=0.56, 95% CI=0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value=5.40 x 10(-3); OR=1.41, 95% CI=1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.

  • 373. Eussen, Simone J P M
    et al.
    Vollset, Stein Emil
    Hustad, Steinar
    Midttun, Øivind
    Meyer, Klaus
    Fredriksen, Ase
    Ueland, Per Magne
    Jenab, Mazda
    Slimani, Nadia
    Ferrari, Pietro
    Agudo, Antonio
    Sala, Núria
    Capellá, Gabriel
    Del Giudice, Giuseppe
    Palli, Domenico
    Boeing, Heiner
    Weikert, Cornelia
    Bueno-de-Mesquita, H Bas
    Büchner, Frederike L
    Carneiro, Fátima
    Berrino, Franco
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Manjer, Jonas
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, Carmen
    Arrizola, Larraitz
    Barricarte, Aurelio
    Navarro, Carmen
    Rodriguez, Laudina
    Bingham, Sheila
    Linseisen, Jakob
    Kaaks, Rudolf
    Overvad, Kim
    Tjønneland, Anne
    Peeters, Petra H M
    Numans, Mattijs E
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Trichopoulou, Antonia
    Lund, Eiliv
    Plebani, Mario
    Riboli, Elio
    González, Carlos A
    Vitamins B2 and B6 and genetic polymorphisms related to one-carbon metabolism as risk factors for gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 1, p. 28-38Article in journal (Refereed)
    Abstract [en]

    B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P(trend)) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93, <0.01) for vitamin B6. Both relations were stronger in individuals with severe chronic atrophic gastritis. The polymorphisms were not associated with GC risk and did not modify the observed vitamin-cancer associations. In summary, results from this large European cohort study showed an inverse association between vitamin B2 and GC risk, which is borderline significant, and a significant inverse association between vitamin B6 and GC risk.

  • 374.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Detection of human papillomavirus: a study of normal cells, cervical intraepithelial neoplasia and cancer of the uterine cervix1991Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human papillomavirus (HPV) infections of the genital tract are now recognized to be among the most prevalent sexually transmitted diseases and also a contributing factor to some cancers of the lower genital tract of women and men. Presence of HPV in a clinical specimen is confined to detection of the HPV genome by DNA hybridization techniques.

    In this thesis, the commonly used DNA hybridization techniques Southern blot and filter in situ hybridization (FISH), were first used for detection of genital HPV infection. In order to increase and simplify the detection of HPV in clinical specimens a more sensitive technique, the polymerase chain reaction (PCR) was subsequently utilized.

    For type-specific amplificaiton of HPV 6, 16, 18 and 33 by PCR, oligonucleotide primers located in the E6 and E7 regions of the HPV genome were selected. They were found to specifically amplify the four types. To be able to amplify a broad spectrum of genital HPV types, general primers located in the E7 and El region of the HPV genome, were designed and evaluated. They were found to amplify a wide range of genital HPV types. To further increase the sensitivity and specificity, a two-step PCR using general primers, was assembled and evaluated against a one-step PCR on cervical scrapes from young women in a population-based study. The two-step PCR increased the sensitivity about three-fold compared to the one-step PCR.

    By Southern blot and FISH, 46% of women with abnormal Papanicolaou (Pap) smears were shown to carry HPV DNA. Of the women analysed by Southern blot, 39 % harboured HPV DNA and 25 % proved HPV 16 positive. Of the samples analysed with FISH, 27 % contained HPV DNA, compared to 11 % of samples from a group of reference women with normal cytology. With the Southern blot technique, HPV DNA was detected in 66% of women with cervical intraepithelial neoplasia grade III (CIN III) lesions. Fifty-four percent of the women with CIN III lesions were positive for HPV 16 DNA.

    By type-specific PCR, 12 out of 13 women with cervical squamous carcinoma were shown to carry HPV 16 and/or 18. Among women with adenosquamous carcinoma of the cervix, HPV 18 was the most prevalent type (26%) but HPV 16 was also found in a proportion of the women(15 %). Nine of 13 premenopausal cases with cervical adenocarcinoma were HPV positive compared to only 2 of 13 postmenopausal cases (p< 0.015). HPV 16 DNA was detected in 48%of women with cervical intraepithelial neoplasia (CIN), by the use of type-specific PCR.

    Three different groups of women with normal cytology were studied. Among women attending a family planning clinic in Kenya, 19% were shown to carry HPV virus, by the use of general primers. HPV 16 was found in 5.2% of these women and HPV 18 in 3.9%. In anothergroup of women, attending the gynecological department in Umeå, HPV 16 DNA was detected in 21 % by type-specific PCR. However, if consideration was taken to the medical status of the women, only 10% of women without any medical history were HPV 16 DNA positive, versus 54% of women with diseases and women with a relative progesterone dominance. Finally, by use of a two-step PCR using general primers, 20% of young women from Umeå taking part in a population-based study were demonstrated to carry HPV DNA. The most prevalent types were HPV 6 (2.0%) and HPV 16(2.7%). Among the women in this study with normal cytology, 19%were HPV positive.

  • 375.
    Evelönn, Emma Andersson
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Köhn, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10219-10228Article in journal (Refereed)
    Abstract [en]

    Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.

  • 376.
    Fallah, Mahsa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen: a pleiotropic inflammatory regulator in radiation-induced wound formation and wound repair2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The plasminogen activator (PA) system plays important roles in many physiological and pathological processes, including inflammation and wound healing. Plasmin, the central component of the PA system, is a broad-spectrum serine protease that is derived from its inactive precursor form, plasminogen. The first aim of this thesis was to study the role of plasminogen in the formation of radiation-induced wounds, which are an inflammatory side effect of radiotherapy. The second aim was to investigate the molecular mechanisms behind the potentiating effect of plasminogen in the healing of radiation-induced wounds. The third aim was to explore the therapeutic potential of plasminogen in the healing of radiation-induced wounds.

    Radiation therapy in cancer patients is often limited by side effects such as radiation-induced skin damage (radiodermatitis). The mechanisms behind the formation of radiodermatitis are not fully elucidated, and there are no effective preventive therapies for clinical use. In this study, we show that irradiation of skin in WT (wild-type) mice induces plasminogen accumulation, which is followed by activation of TGF-β (transforming growth factor-beta) signaling and the development of inflammation that leads to skin damage. However, plasminogen-deficient mice and mice lacking PAs were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreases radiodermatitis in WT mice and prevented radiodermatitis in heterozygous mice. Thus, plasmin is required for the formation of radiodermatitis, and inhibition of plasminogen activation might be a novel treatment strategy to reduce or prevent radiodermatitis in patients undergoing radiotherapy.

    Wound healing consists of partially overlapping inflammatory, proliferation, and tissue remodeling phases, and failure to terminate inflammation leads to the formation of chronic wounds. Previous studies by our group have shown that plasminogen is transported to acute wounds by inflammatory cells where it potentiates inflammation and enhances wound healing. Here, we report that plasminogen-deficient mice, which have delayed wound healing, have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialization, indicating inefficient debridement and chronic inflammation. The delayed formation of granulation tissue suggests that fibroblast function is also impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for the resolution of inflammation and the activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing capacity that is comparable to that in WT mice. Therefore, plasminogen might be an important future therapeutic agent for treatment of wounds.

    In radiation-induced wounds, inflammation often cannot resolve and the wounds become chronic and fibrotic. Currently, there is no gold standard for the treatment of radiation-induced wounds. In this study, we have shown that radiation-induced wounds treated with plasminogen healed faster than placebo-treated wounds, had diminished inflammation and granulation tissue formation, and had enhanced re-epithelialization and collagen maturation. Transcriptome analysis showed that plasminogen has a pleiotropic effect on gene expression during wound healing, influencing the expression of 33 genes out of the 84 genes studied. In particular, plasminogen decreased the expression of 11 pro-inflammatory genes early in the healing process. Later, plasminogen decreased WNT (Wingless/Integrated) and TGF-β signaling, as well as the expression of 5 growth factors and 13 factors involved in granulation tissue formation. From the genes downregulated by plasminogen, 19 genes are known to be involved in fibrosis. These results show that in radiation-induced wounds with excessive inflammation and tissue formation plasminogen is able to direct the healing process to a normal outcome without the risk for developing fibrosis. This makes plasminogen an attractive drug candidate for treating radiodermatitis in cancer patients. Taken together, our results indicate that plasminogen is a pleiotropic inflammatory regulator involved in radiation-induced wound formation as well as in wound repair.

  • 377.
    Fallah, Mahsa
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Viklund, Emil
    Shen, Yue
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bäckman, Assar
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundskog, Bertil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Blomqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen enhances the healing of radiation-induced wounds via decreased expression of pro-inflammatory and pro-fibrotic factorsManuscript (preprint) (Other academic)
  • 378.
    Fallbjörk, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Karlsson, Stig
    Umeå University, Faculty of Medicine, Department of Nursing.
    Salander, Pär
    Umeå University, Faculty of Social Sciences, Department of Social Work. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rasmussen, Birgit H
    Umeå University, Faculty of Medicine, Department of Nursing.
    Differences between women who have and have not undergone breast reconstruction after mastectomy due to breast cancer2010In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, no 2, p. 174-179Article in journal (Refereed)
    Abstract [en]

    Aim: This study compares potential differences between women with breast cancer who after mastectomy had undergone breast reconstruction with those who had not. Material and methods: All women (N=149) in the northern medical region of Sweden who had undergone mastectomy in 2003 received a self-reported questionnaire entitled “Life After Mastectomy (LAM)” that included standardized measures of sociodemographic, decision-making process, breast reconstruction (BR) yes or no, sexuality, and body image. SPSS was used for data processing. Results: In total 85% of the women returned the questionnaire and of these 25% had undergone BR. In accordance with previous studies, we found that the mean age of the women in the BR group was significantly lower (52 vs. 64 years), they had a higher education, and a higher proportion were employed, influenced by the physician's opinion regarding BR, sexually active, and rated a negative impact concerning the factors attractiveness and body disclosure. A multiple regression analysis, however, showed that the choice to undergo breast reconstruction or not was only independently associated with age, feeling of attractiveness and sexual interest. Discussion: Age explained most differences found between the two groups. When researchers try to identify what differentiates the groups of women who undergo reconstruction between those who do not undergo reconstruction after mastectomy, it is thus necessary to take into consideration that the meanings of mastectomy, body image, attractiveness and similar variables may vary due to the phase of a woman's life. In conclusion, considering the impact of age is of paramount importance in future studies for our understanding of women's experiences.

  • 379.
    Fallbjörk, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Rasmussen, Birgit H
    Umeå University, Faculty of Medicine, Department of Nursing.
    Karlsson, Stig
    Umeå University, Faculty of Medicine, Department of Nursing.
    Salander, Pär
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Aspects of body image after mastectomy due to breast cancer: a two-year follow up study2013In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 17, no 3, p. 340-345Article in journal (Refereed)
    Abstract [en]

    Purpose: This 2-year follow-up study explores aspects of body image after mastectomy due to breast cancer.

    Materials and Methods: This population-based study included 76 women living in northern Sweden who, during November 2006 to October 2007, underwent mastectomy due to breast cancer. The women completed a questionnaire entitled “Life After Mastectomy (LAM)” 10 months after the mastectomy and again 2 years later. We used SPSS version 18.0 for data processing and analysis.

    Results:The findings indicate that few significant changes in body image had taken place during the 2-year interval between the first and second completion of the questionnaire. An exception was a significant decrease in feelings of sexual attractiveness and comfort during sexual intimacy. At follow-up, 21% of the women had undergone breast reconstruction (BR). They were significantly younger than the women who had not had BR (53 v. 63 years). Besides being younger, no other significant differences could be found between those women who had undergone BR and those who had not. The fact that the decrease in sexual attractiveness and feelings of comfort during sexual intimacy also applied to the subgroup of women who had had BR may therefore be surprising. A better understanding of issues related to breast cancer treatment and sexual function is vital.

    Conclusion: It is important for health care professionals to be aware of problems related to sexual intimacy and to be prepared not just to provide information about these, but also to reflect on expectations v. reality together with the women.

  • 380.
    Fallbjörk, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Salander, Pär
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Rasmussen Holritz, Birgit
    Umeå University, Faculty of Medicine, Department of Nursing.
    Different meanings of mastectomy due to breast cancer and reflections about breast reconstruction2011In: European journal of cancer: Vol. 47 Suppl. 1, Oxford: Pergamon , 2011, Vol. 47, p. S323-S323Conference paper (Refereed)
  • 381. Fanidi, Anouar
    et al.
    Carreras-Torres, Robert
    Larose, Tricia L.
    Yuan, Jian-Min
    Stevens, Victoria L.
    Weinstein, Stephanie J.
    Albanes, Demetrius
    Prentice, Ross
    Pettinger, Mary
    Cai, Qiuyin
    Blot, William J.
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    McCullough, Marjorie L.
    Le Marchand, Loic
    Wilkens, Lynne R.
    Haiman, Christopher A.
    Zhang, Xuehong
    Stampfer, Meir J.
    Smith-Warner, Stephanie A.
    Giovannucci, Edward
    Giles, Graham G.
    Hodge, Allison M.
    Severi, Gianluca
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Langhammer, Arnulf
    Brumpton, Ben M.
    Wang, Renwei
    Gao, Yu-Tang
    Ericson, Ulrika
    Bojesen, Stig E.
    Arnold, Susanne M.
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Li, Honglan
    Zheng, Wei
    Lan, Qing
    Visvanathan, Kala
    Hoffman-Bolton, Judith
    Ueland, Per M.
    Midttun, Oivind
    Caporaso, Neil E.
    Purdue, Mark
    Freedman, Neal D.
    Buring, Julie E.
    Lee, I-Min
    Sesso, Howard D.
    Gaziano, J. Michael
    Manjer, Jonas
    Relton, Caroline L.
    Hung, Rayjean J.
    Amos, Chris, I
    Johansson, Mattias
    Brennan, Paul
    Is high vitamin B12 status a cause of lung cancer?2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 6, p. 1499-1503Article in journal (Refereed)
    Abstract [en]

    Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case–control study, complemented with a Mendelian randomization (MR) approach in an independent case–control sample. We used pre‐diagnostic biomarker data from 5183 case–control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case–control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06–1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD] = 1.08, 95%CI = 1.00–1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

  • 382. Fanidi, Anouar
    et al.
    Muller, David C
    Midttun, Øivind
    Ueland, Per Magne
    Vollset, Stein Emil
    Relton, Caroline
    Vineis, Paolo
    Weiderpass, Elisabete
    Skeie, Guri
    Brustad, Magritt
    Palli, Domenico
    Tumino, Rosario
    Grioni, Sara
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H B As
    Peeters, Petra H
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Cadeau, Claire
    Huerta, José María
    Sánchez, Maria-José
    Agudo, Antonio
    Lasheras, Cristina
    Quirós, J Ramón
    Chamosa, Saioa
    Riboli, Elio
    Travis, Ruth C
    Ward, Heather
    Murphy, Neil
    Khaw, Kay-Tee
    Trichopoulou, Antonia
    Lagiou, Pagona
    Papatesta, Eleni-Maria
    Boeing, Heiner
    Kuehn, Tilman
    Katzke, Verena
    Steffen, Annika
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brennan, Paul
    Johansson, Mattias
    Circulating vitamin D in relation to cancer incidence and survival of the head and neck and oesophagus in the EPIC cohort2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36017Article in journal (Refereed)
    Abstract [en]

    Experimental and epidemiological data suggest that vitamin D play a role in pathogenesis and progression of cancer, but prospective data on head and neck cancer (HNC) and oesophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants with blood samples between 1992 and 2000. This analysis includes 497 case-control pairs of the head and neck and oesophagus, as well as 443 additional controls. Circulating 25(OH)D3 were measured in pre-diagnostic samples and evaluated in relation to HNC and oesophagus cancer risk and post-diagnosis all-cause mortality. After controlling for risk factors, a doubling of 25(OH)D3 was associated with 30% lower odds of HNC (OR 0.70, 95% confidence interval [95% CI] 0.56-0.88, Ptrend = 0.001). Subsequent analyses by anatomical sub-site indicated clear inverse associations with risk of larynx and hypopharynx cancer combined (OR 0.55, 95CI% 0.39-0.78) and oral cavity cancer (OR 0.60, 95CI% 0.42-0.87). Low 25(OH)D3 concentrations were also associated with higher risk of death from any cause among HNC cases. No clear association was seen with risk or survival for oesophageal cancer. Study participants with elevated circulating concentrations of 25(OH)D3 had decreased risk of HNC, as well as improved survival following diagnosis.

  • 383. Fanidi, Anouar
    et al.
    Muller, David C
    Yuan, Jian-Min
    Stevens, Victoria L
    Weinstein, Stephanie J
    Albanes, Demetrius
    Prentice, Ross
    Thomsen, Cynthia A
    Pettinger, Mary
    Cai, Qiuyin
    Blot, William J
    Wu, Jie
    Arslan, Alan A
    Zeleniuch-Jacquotte, Anne
    McCullough, Marjorie L
    Le Marchand, Loic
    Wilkens, Lynne R
    Haiman, Christopher A
    Zhang, Xuehong
    Han, Jiali
    Stampfer, Meir J
    Smith-Warner, Stephanie A
    Giovannucci, Edward
    Giles, Graham G
    Hodge, Allison M
    Severi, Gianluca
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Langhammer, Arnulf
    Krokstad, Steinar
    Næss, Marit
    Wang, Renwei
    Gao, Yu-Tang
    Butler, Lesley M
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Li, Honglan
    Zheng, Wei
    Lan, Qing
    Visvanathan, Kala
    Bolton, Judith Hoffman
    Ueland, Per Magne
    Midttun, Øivind
    Ulvik, Arve
    Caporaso, Neil E
    Purdue, Mark
    Ziegler, Regina G
    Freedman, Neal D
    Buring, Julie E
    Lee, I-Min
    Sesso, Howard D
    Gaziano, J Michael
    Manjer, Jonas
    Ericson, Ulrika
    Relton, Caroline
    Brennan, Paul
    Johansson, Mattias
    Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)2018In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, no 1, article id djx119Article in journal (Refereed)
    Abstract [en]

    Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.

    Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.

    Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.

    Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.

  • 384. Fanidi, Anouar
    et al.
    Relton, Caroline
    Ueland, Per Magne
    Midttun, Øivind
    Vollset, Stein Emil
    Travis, Ruth C.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Bueno-de-Mesquita, H. B(as)
    Ros, Martine
    Boeing, Heiner
    Tumino, Rosario
    Panico, Salvatore
    Palli, Domenico
    Sieri, Sabina
    Vineis, Paolo
    Sánchez, María-José
    Huerta, José María
    Barricarte Gurrea, Aurelio
    Luján-Barroso, Leila
    Quirós, J. Ramón
    Tjønneland, Anne
    Halkjær, Jytte
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Cadeau, Claire
    Weiderpass, Elisabete
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Riboli, Elio
    Brennan, Paul
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    A prospective study of one-carbon metabolism biomarkers and cancer of the head and neck and esophagus2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 4, p. 915-927Article in journal (Refereed)
    Abstract [en]

    Experimental and epidemiological data suggest that factors of one-carbon metabolism are important in the pathogenesis of several cancers, but prospective data on head and neck cancer (HNC) and esophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants from 10 countries who donated a blood sample. The current study included 516 cancer cases of the head and neck and esophagus and 516 individually matched controls. Plasma levels of vitamins B2, B6, B9 (folate), B12, and methionine and homocysteine were measured in pre-diagnostic plasma samples and analyzed in relation to HNC and esophagus cancer risk, as well as post-diagnosis all-cause mortality. After controlling for risk factors, study participants with higher levels of homocysteine had elevated risk of HNC, the odds ratio (OR) in conditional analysis when comparing the top and bottom quartiles of homocysteine [ORQ4vs. Q1] being 2.13 (95% confidence interval [95% CI] 1.13-4.00, p for trend 0.009). A slight decrease in HNC risk was also seen among subjects with higher levels of folate (ORQ4vs. Q1 0.63, 95% CI 0.35-1.16, p for trend 0.02). Subgroup analyses by anatomical sub-site indicated particularly strong associations with circulating homocysteine for oral cavity and gum cancer (p for trend 8 x 10(-4)), as well as for oropharynx cancer (p for trend 0.008). Plasma concentrations of the other investigated biomarkers did not display any clear association with risk or survival. In conclusion, study participants with elevated circulating levels of homocysteine had increased risk of developing squamous cell carcinoma of the head and neck. What's new? One-carbon metabolism (OCM) involves the transfer of a carbon unit from methyl donor nutrients to molecules involved in the synthesis and methylation of DNA. As a result, dietary imbalances or deficiencies in nutrients crucial for OCM may affect DNA replication, repair, and regulation, potentially facilitating cancer development. This analysis of circulating levels of OCM nutrients in head and neck cancer and esophageal cancer patients and matched controls reveals an association between elevated levels of the amino acid homocysteine and increased risk of squamous cell carcinoma of the head and neck. Risk was decreased slightly by elevated folate levels.

  • 385.
    Faraz, Mahmood
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Investigations of Leucine-rich repeats and immunoglobulin-like domain-proteins 1 and 2 (LRIG1 and LRIG2) and their genes in cancer2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mammalian leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family consists of three different members, LRIG1, LRIG2, and LRIG3. These genes are expressed in all human and mouse tissues analyzed to date. All LRIG proteins share similar and evolutionary conserved structural domains including a leucine-rich repeat domain, three immunoglobulin-like domains, a transmembrane domain, and a cytosolic tail. Since the discovery of this family, around 20 years ago, various research groups have shown the importance of this family in cancer biology and prognosis. The aim of this thesis was to further investigate the role of LRIG1 and LRIG2 in cancer.

    To investigate the roles of LRIG1 and LRIG2 in physiology and gliomagenesis, we generated Lrig1- and Lrig2-deficient mice and induced platelet-derived growth factor B (PDGFB)-driven gliomagenesis. We studied the effects of Lrig2 ablation on mouse development and survival and investigated if the ablation of Lrig1 or Lrig2 affects the incidence or malignancy of induced gliomas. We also investigated if Lrig2 ablation affects Pdgfr signaling in mouse embryonic fibroblasts (MEFs). Additionally, we analyzed the effects of ectopic LRIG1 expression in human primary glioblastoma cell lines TB101 and TB107, in vivo and in vitro. We reported no macroscopic anatomical defect but reduced growth and increased spontaneous mortality rate in Lrig2-deficient mice. However, the Lrig2-deficient mice were protected against the induced gliomagenesis. Lrig2-deficient MEFs showed faster kinetics of induction of immediate-early genes in response to PDGFB stimulation, whereas the phosphorylations of Pdgfra, Pdgfrb, Erk1/2, and Akt1 appeared unaltered. Lrig1-heterozygote mice showed a higher incidence of high-grade tumors (grade IV) compared to wildtype mice, demonstrating a haploinsufficient function of Lrig1. LRIG1 overexpression suppressed TB107 cell invasion in vivo and in vitro, which was partially mediated through the suppression of the MET receptor tyrosine kinase.

    To identify LRIG1-interacting proteins, we used the yeast-two hybrid system and data-mined the Bio-Plex network of high throughput protein-protein interaction database. To study the function of interactors, we used a triple co-transfection system to overexpress LRIG1 and PDGFRA and downregulate endogenous levels of interactors by short hairpin RNAs (shRNAs), simultaneously. This analysis demonstrated that CNPY3, CNPY4, GAL3ST1, GML, HLA-DRA, LRIG2, LRIG3, LRRC40, PON2, RAB4A, and ZBTB16 were important for the PDGFRA-downregulating function of LRIG1.

    To investigate the clinical significance of LRIG1 copy number alterations (CNAs) in breast cancer, we used droplet digital PCR (ddPCR) to analyze 423 breast cancer tumors. We found that LRIG1 CNAs were significantly different in steroid-receptor-positive vs steroid-receptor-negative tumors and in ERBB2-amplified vs ERBB2-non-amplified tumors. In the whole cohort, patients with LRIG1 loss or gain had a worse metastasis-free survival than patients with normal LRIG1 copy numbers, however, among the early-stage breast cancer subgroup, this difference was not significant. 

    In summary, Lrig1 behaved like a haploinsufficient tumor suppressor gene in malignant glioma, whereas Lrig2 appeared to promote malignant glioma. Our functional analysis of LRIG1 interactome uncovered several unanticipated and novel proteins that might be important for the regulation of receptor tyrosine kinases by LRIG1. LRIG1 CNAs predicted metastasis-free survival time in breast cancer. Hopefully, our findings might lead to a better understanding of the regulation of growth factor signaling and its importance in cancer biology and prognosis.

     

  • 386. Farkas, Sanja A.
    et al.
    Befekadu, Rahel
    Hahn-Stroemberg, Victoria
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    DNA methylation and expression of the folate transporter genes in colorectal cancer2015In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 36, no 7, p. 5581-5590Article in journal (Refereed)
    Abstract [en]

    Folate has a central role in the cell metabolism. This study aims to explore the DNA methylation pattern of the folate transporter genes FOLR1, PCFT, and RFC1 as well as the corresponding protein expressions in colorectal cancer (CRC) tissue and adjacent non-cancerous mucosa (ANCM). Our results showed statistically significant differences in the DNA-methylated fraction of all three genes at several gene regions; we identified three differentially methylated CpG sites in the FOLR1 gene, five CpG sites in the PCFT gene, and six CpG sites in the RFC1 gene. There was a pronounced expression of the FR alpha and RFC proteins in both the CRC and ANCM tissues, though the expression was attenuated in cancer compared to the paired ANCM tissues. The PCFT protein was undetectable or expressed at a very low level in both tissue types. Higher methylated fractions of the CpG sites 3-5 in the RFC1 gene were associated with a lower protein expression, suggestive of epigenetic regulation by DNA methylation of the RFC1 gene in the colorectal cancer. Our results did not show any association between the RFC and FR alpha protein expression and tumor stage, TNM classification, or tumor location. In conclusion, this is the first study to simultaneously evaluate both DNA methylation and protein expression of all three folate transporter genes, FOLR1, PCFT, and RFC1, in colorectal cancer. The results encourage further investigation into the possible prognostic implications of folate transporter expression and DNA methylation.

  • 387.
    Farkas, Sanja A
    et al.
    Department of Laboratory Medicine, Örebro University Hospital, Örebro.
    Milutin-Gašperov, Nina
    Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
    Grce, Magdalena
    Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Genome-wide DNA methylation assay reveals novel candidate biomarker genes in cervical cancer2013In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 8, no 11, p. 1213-1225Article in journal (Refereed)
    Abstract [en]

    The oncogenic human papilloma viruses (HPVs) are associated with precancerous cervical lesions and development of cervical cancer. The DNA methylation signatures of the host genome in normal, precancerous and cervical cancer tissue may indicate tissue-specific perturbation in carcinogenesis. The aim of this study was to identify new candidate genes that are differentially methylated in squamous cell carcinoma compared with DNA samples from cervical intraepithelial neoplasia grade 3 (CIN3) and normal cervical scrapes. The Illumina Infinium HumanMethylation450 BeadChip method identifies genome-wide DNA methylation changes in CpG islands, CpG shores and shelves. Our findings showed an extensive differential methylation signature in cervical cancer compared with the CIN3 or normal cervical tissues. The identified candidate biomarker genes for cervical cancer represent several types of mechanisms in the cellular machinery that are epigenetically deregulated by hypermethylation, such as membrane receptors, intracellular signaling and gene transcription. The results also confirm extensive hypomethylation of genes in the immune system in cancer tissues. These insights into the functional role of DNA methylome alterations in cervical cancer could be clinically applicable in diagnostics and prognostics, and may guide the development of new epigenetic therapies.

  • 388. Farkas, Sanja A.
    et al.
    Sorbe, Bengt G.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Epigenetic changes as prognostic predictors in endometrial carcinomas2017In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 12, no 1, p. 19-26Article in journal (Refereed)
    Abstract [en]

    Endometrial carcinoma is one of the most frequent gynecological malignancies of the female. The diagnostic and prognostic markers for the high-risk subgroups with unfavorable prognosis are under intense debate worldwide, and, therefore, the aim of this study was to identify new potential DNA methylation markers for the high-risk groups. We used the Illumina Infinium HumanMethylation450 BeadChip to analyze the DNA methylation pattern and investigated its association with clinicopathological features important for defining the high-risk (FIGO-grade 3) and low-risk (FIGO-grade 1) groups of patients with endometrial cancer (n = 31 and n = 39, respectively). We identified specific DNA methylation signature in high-risk endometrial tumors, and potential molecular biomarker genes (TBX2, CHST11, and NID2) associated with unfavorable clinical predictive and prognostic factors.

  • 389. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 10192Article in journal (Refereed)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

  • 390. Fedirko, V.
    et al.
    Lukanova, A.
    Bamia, C.
    Trichopolou, A.
    Trepo, E.
    Noethlings, U.
    Schlesinger, S.
    Aleksandrova, K.
    Boffetta, P.
    Tjonneland, A.
    Johnsen, N. F.
    Overvad, K.
    Fagherazzi, G.
    Racine, A.
    Boutron-Ruault, M. C.
    Grote, V.
    Kaaks, R.
    Boeing, H.
    Naska, A.
    Adarakis, G.
    Valanou, E.
    Palli, D.
    Sieri, S.
    Tumino, R.
    Vineis, P.
    Panico, S.
    Bueno-de-Mesquita, H. B(as).
    Siersema, P. D.
    Peeters, P. H.
    Weiderpass, E.
    Skeie, G.
    Engeset, D.
    Quiros, J. R.
    Zamora-Ros, R.
    Sanchez, M. J.
    Amiano, P.
    Huerta, J. M.
    Barricarte, A.
    Johansen, D.
    Lindkvist, B.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Crowe, F.
    Khaw, K. T.
    Ferrari, P.
    Romieu, I.
    Chuang, S. C.
    Riboli, E.
    Jenab, M.
    Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 2, p. 543-553Article in journal (Refereed)
    Abstract [en]

    The type and quantity of dietary carbohydrate as quantified by glycemic index (GI) and glycemic load (GL), and dietary fiber may influence the risk of liver and biliary tract cancers, but convincing evidence is lacking. The association between dietary GI/GL and carbohydrate intake with hepatocellular carcinoma (HCC; N = 191), intrahepatic bile duct (IBD; N = 66), and biliary tract (N = 236) cancer risk was investigated in 477 206 participants of the European Prospective Investigation into Cancer and Nutrition cohort. Dietary intake was assessed by country-specific, validated dietary questionnaires. Hazard ratios and 95% confidence intervals were estimated from proportional hazard models. HBV/HCV status was measured in a nested case-control subset. Higher dietary GI, GL, or increased intake of total carbohydrate was not associated with liver or biliary tract cancer risk. For HCC, divergent risk estimates were observed for total sugar = 1.43 (1.17-1.74) per 50 g/day, total starch = 0.70 (0.55-0.90) per 50 g/day, and total dietary fiber = 0.70 (0.52-0.93) per 10 g/day. The findings for dietary fiber were confirmed among HBV/HCV-free participants [0.48 (0.23-1.01)]. Similar associations were observed for IBD [dietary fiber = 0.59 (0.37-0.99) per 10 g/day], but not biliary tract cancer. Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk.

  • 391. Fedirko, V
    et al.
    Trichopolou, A
    Bamia, C
    Duarte-Salles, T
    Trepo, E
    Aleksandrova, K
    Nöthlings, U
    Lukanova, A
    Lagiou, P
    Boffetta, P
    Trichopoulos, D
    Katzke, VA
    Overvad, K
    Tjønneland, A
    Hansen, L
    Boutron-Ruault, MC
    Fagherazzi, G
    Bastide, N
    Panico, S
    Grioni, S
    Vineis, P
    Palli, D
    Tumino, R
    Bueno-de-Mesquita, HB
    Peeters, PH
    Skeie, G
    Engeset, D
    Parr, CL
    Jakszyn, P
    Sánchez, MJ
    Barricarte, A
    Amiano, P
    Chirlaque, M
    Quirós, JR
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sonestedt, E
    Ericson, U
    Key, TJ
    Khaw, KT
    Ferrari, P
    Romieu, I
    Riboli, E
    Jenab, M
    Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC)2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 8, p. 2166-2173Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: While higher intake of fish and lower consumption of red/processed meats have been suggested to play a protective role in the etiology of several cancers, prospective evidence for hepatocellular carcinoma (HCC) is limited, particularly in Western European populations.

    METHODS: The associations of fish and meats with HCC risk were analyzed in the EPIC cohort. Between 1992 and 2010, 191 incident HCC were identified among 477 206 participants. Baseline diet was assessed using validated dietary questionnaires. A single 24-h diet recall from a cohort subsample was used for calibration. Multivariable proportional hazard regression was utilized to estimate hazard ratios (HR) and 95% confidence intervals (CI). In a nested case-control subset (HCC = 122), HBV/HCV status and liver function biomarkers were measured.

    RESULTS: HCC risk was inversely associated with intake of total fish (per 20 g/day increase, HR = 0.83, 95% CI 0.74-0.95 and HR = 0.80, 95% CI 0.69-0.97 before and after calibration, respectively). This inverse association was also suggested after adjusting for HBV/HCV status and liver function score (per 20-g/day increase, RR = 0.86, 95% CI 0.66-1.11 and RR = 0.74, 95% CI 0.50-1.09, respectively) in a nested case-control subset. Intakes of total meats or subgroups of red/processed meats, and poultry were not associated with HCC risk.

    CONCLUSIONS: In this large European cohort, total fish intake is associated with lower HCC risk.

  • 392. Fedirko, Veronika
    et al.
    Riboli, Elio
    Tjønneland, Anne
    Ferrari, Pietro
    Olsen, Anja
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel J B
    Norat, Teresa
    Jansen, Eugène H J M
    Dahm, Christina C
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Lukanova, Annekatrin
    Teucher, Birgit
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Trichopoulos, Dimitrios
    Grioni, Sara
    Vineis, Paolo
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Siersema, Peter D
    Peeters, Petra H
    Skeie, Guri
    Brustad, Magritt
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Quirós, Jose Ramón
    Sánchez, Maria José
    Dorronsoro, Miren
    Bonet, Catalina
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Key, Timothy J
    Crowe, Francesca
    Khaw, Kay-Tee
    Wareham, Nick
    Romieu, Isabelle
    McKay, James
    Wark, Petra A
    Romaguera, Dora
    Jenab, Mazda
    Prediagnostic 25-Hydroxyvitamin D, VDR and CASR polymorphisms, and survival in patients with colorectal cancer in Western European populations2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 4, p. 582-593Article in journal (Refereed)
    Abstract [en]

    Background: Individuals with higher blood 25-hydroxyvitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis is unknown.

    Methods: The association between prediagnostic 25(OH)D levels and CRC-specific (N ¼ 444) and overall mortality (N ¼ 541) was prospectively examined among 1,202 participants diagnosed with CRC between 1992 and 2003 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.Multivariable Cox proportional hazards models were used to calculate HRs and corresponding 95% CIs according to 25(OH)D quintiles and genetic variation within the VDR and CASR genes. Potential dietary, lifestyle, and metabolic effect modifiers were also investigated.

    Results: There were 541 deaths, 444 (82%) due to CRC. Mean follow-up was 73 months. In multivariable analysis, higher 25(OH)D levels were associated with a statistically significant reduction in CRC-specific (Ptrend ¼ 0.04) and overall mortality (Ptrend ¼ 0.01). Participants with 25(OH)D levels in the highest quintile had an adjusted HR of 0.69 (95% CI: 0.50–0.93) for CRC-specific mortality and 0.67 (95% CI: 0.50–0.88) for overall mortality, compared with the lowest quintile. Except for a possible interaction by prediagnostic dietary calcium intake (Pinteraction ¼ 0.01), no other potential modifying factors related to CRC survival were noted. The VDR (FokI and BsmI) and CASR (rs1801725) genotypes were not associated with survival.

    Conclusions: High prediagnostic 25(OH)D levels are associated with improved survival of patients with CRC. 

    Impact: Our findings may stimulate further research directed at investigating the effects of blood vitamin D levels before, at, and after CRC diagnosis on outcomes in CRC patients.

  • 393. Fedirko, Veronika
    et al.
    Romieu, Isabelle
    Aleksandrova, Krasimira
    Pischon, Tobias
    Trichopoulos, Dimitrios
    Peeters, Petra H.
    Romaguera-Bosch, Dora
    Bueno-de-Mesquita, H. B(as)
    Dahm, Christina C.
    Overvad, Kim
    Chirlaque, Maria-Dolores
    Johansen, Christoffer
    Bidstrup, Pernille E.
    Dalton, Susanne O.
    Gunter, Marc J.
    Wark, Petra A.
    Norat, Teresa
    Halkjaer, Jytte
    Tjonneland, Anne
    Dik, Vincent K.
    Siersema, Peter D.
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Bastide, Nadia
    Kuehn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Trichopoulou, Antonia
    Klinaki, Eleni
    Katsoulis, Michalis
    Pala, Valeria
    Panico, Salvatore
    Tumino, Rosario
    Palli, Domenico
    Vineis, Paolo
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Sanchez, Maria-Jose
    Barricarte, Aurelio
    Amiano, Pilar
    Ramon Quiros, J.
    Manjer, Jonas
    Jirstroem, Karin
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Bradbury, Kathryn E.
    Stepien, Magdalena
    Duarte-Salles, Talita
    Riboli, Elio
    Jenab, Mazda
    Pre-diagnostic anthropometry and survival after colorectal cancer diagnosis in Western European populations2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 8, p. 1949-1960Article in journal (Refereed)
    Abstract [en]

    General and abdominal adiposity are associated with a high risk of developing colorectal cancer (CRC), but the role of these exposures on cancer survival has been less studied. The association between pre-diagnostic anthropometric characteristics and CRC-specific and all-cause death was examined among 3,924 men and women diagnosed with CRC between 1992 and 2009 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate hazard ratios (FIRS) and corresponding 95% confidence intervals (as). Over a mean follow-up period of 49 months, 1,309 deaths occurred of which 1,043 (79.7%) were due to CRC. In multivariable analysis, prediagnostic BMI kg/m2 was associated with a high risk for CRC-specific (HR = 1.26, 95% CI = 1.04-1.52) and all-cause (HR = 1.32, 95% CI = 1.12-1.56) death relative to BMI <25 kg/m(2). Every 5 kg/m(2) increase in BMI was associated with a high risk for CRC-specific (HR = 1.10, 95% CI = 1.02-1.19) and all-cause death (HR = 1.12, 95% Cl = 1.05-1.20); and every 10 cm increase in waist circumference was associated with a high risk for CRC-specific (HR = 1.09, 95% Cl = 1.02-1.16) and allcause death (HR= 1.11, 95% CI= 1.05-1.18). Similar associations were observed for waist-to-hip and waist-to-height ratios. Height was not associated with CRC-specific or all-cause death. Associations tended to be stronger among men than in women. Possible interactions by age at diagnosis, cancer stage, tumour location, and hormone replacement therapy use among postmenopausal women were noted. Pre-diagnostic general and abdominal adiposity are associated with lower survival after CRC diagnosis.

  • 394. Fehr, André
    et al.
    Hansson, Magnus C
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kindblom, Lars-Gunnar
    Stenman, Göran
    YWHAE-FAM22 gene fusion in clear cell sarcoma of the kidney2012In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 227, no 4, p. e5-e7Article in journal (Refereed)
  • 395. Fehringer, Gordon
    et al.
    Kraft, Peter
    Pharoah, Paul D P
    Eeles, Rosalind A
    Chatterjee, Nilanjan
    Schumacher, Fredrick R
    Schildkraut, Joellen M
    Lindstrom, Sara
    Brennan, Paul
    Bickeböller, Heike
    Houlston, Richard S
    Landi, Maria Teresa
    Caporaso, Neil E
    Risch, Angela
    Amin Al Olama, Ali
    Berndt, Sonja I
    Giovannucci, Edward
    Gronberg, Henrik
    Kote-Jarai, Zsofia
    Ma, Jing
    Muir, Kenneth
    Stampfer, Meir J
    Stevens, Victoria L
    Wiklund, Fredrik
    Willett, Walter C
    Goode, Ellen L
    Permuth, Jennifer B
    Risch, Harvey A
    Reid, Brett M
    Bezieau, Stéphane
    Brenner, Hermann
    Chan, Andrew T
    Chang-Claude, Jenny
    Hudson, Thomas J
    Kocarnik, Jonathan
    Newcomb, Polly A
    Schoen, Robert E
    Slattery, Martha L
    White, Emily
    Adank, Muriel A
    Ahsan, Habibul
    Aittomaki, Kristiina
    Baglietto, Laura
    Blomquist, Carl
    Canzian, Federico
    Czene, Kamila
    Dos Santos Silva, Isabel
    Eliassen, A Heather
    Figueroa, Jonine D
    Flesch-Janys, Dieter
    Fletcher, Olivia
    Garcia-Closas, Montserrat
    Gaudet, Mia M
    Johnson, Nichola
    Hall, Per
    Hazra, Aditi
    Hein, Rebecca
    Hofman, Albert
    Hopper, John L
    Irwanto, Astrid
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Kaaks, Rudolf
    Kibriya, Muhammad G
    Lichtner, Peter
    Liu, Jian-Jun
    Lund, Eiliv
    Makalic, Enes
    Meindl, Alfons
    Müller-Myhsok, Bertram
    Muranen, Taru A
    Nevanlinna, Heli
    Peeters, Petra H
    Peto, Julian
    Prentice, Ross L
    Rahman, Nazneen
    Sanchez, Maria-Jose
    Schmidt, Daniel F
    Schmutzler, Rita K
    Southey, Melissa C
    Tamimi, Rulla M
    Travis, Ruth C
    Turnbull, Clare
    Uitterlinden, Andre G
    Wang, Zhaoming
    Whittemore, Alice S
    Yang, Xiaohong R
    Zheng, Wei
    Rafnar, Thorunn
    Gudmundsson, Julius
    Stacey, Simon N
    Stefansson, Kari
    Sulem, Patrick
    Chen, Y Ann
    Tyrer, Jonathan P
    Christiani, David C
    Wei, Yongyue
    Shen, Hongbing
    Hu, Zhibin
    Shu, Xiao-Ou
    Shiraishi, Kouya
    Takahashi, Atsushi
    Bossé, Yohan
    Obeidat, Ma'en
    Nickle, David
    Timens, Wim
    Freedman, Matthew L
    Li, Qiyuan
    Seminara, Daniela
    Chanock, Stephen J
    Gong, Jian
    Peters, Ulrike
    Gruber, Stephen B
    Amos, Christopher I
    Sellers, Thomas A
    Easton, Douglas F
    Hunter, David J
    Haiman, Christopher A
    Henderson, Brian E
    Hung, Rayjean J
    Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 17, p. 5103-5114Article in journal (Refereed)
    Abstract [en]

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.

  • 396. Figueroa, Jonine D.
    et al.
    Han, Summer S.
    Garcia-Closas, Montserrat
    Baris, Dalsu
    Jacobs, Eric J.
    Kogevinas, Manolis
    Schwenn, Molly
    Malats, Nuria
    Johnson, Alison
    Purdue, Mark P.
    Caporaso, Neil
    Landi, Maria Teresa
    Prokunina-Olsson, Ludmila
    Wang, Zhaoming
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Vineis, Paolo
    Siddiq, Afshan
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Bueno-de-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Françoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth
    Tjønneland, Anne
    Brenan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Rodabough, Rebecca
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Chen, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Karagas, Margaret R.
    Schned, Alan
    Armenti, Karla R.
    Hosain, G. M. Monawar
    Haiman, Chris A.
    Fraumeni, Joseph F., Jr.
    Chanock, Stephen J.
    Chatterjee, Nilanjan
    Rothman, Nathaniel
    Silverman, Debra T.
    Genome-wide interaction study of smoking and bladder cancer risk2014In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, no 8, p. 1737-1744Article in journal (Refereed)
    Abstract [en]

    Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 x 10(-5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 x 10(-7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 x 10-7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.

  • 397. Figueroa, Jonine D.
    et al.
    Ye, Yuanqing
    Siddiq, Afshan
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Prokunina-Olsson, Ludmila
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Dinney, Colin P.
    Malats, Nuria
    Baris, Dalsu
    Purdue, Mark
    Jacobs, Eric J.
    Albanes, Demetrius
    Wang, Zhaoming
    Deng, Xiang
    Chung, Charles C.
    Tang, Wei
    Bueno-De-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Frangoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth
    Tjonneland, Anne
    Brenan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Rodabough, Rebecca
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Chen, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Kamat, Ashish M.
    Lerner, Seth P.
    Grossman, H. Barton
    Lin, Jie
    Gu, Jian
    Pu, Xia
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Schwenn, Molly
    Karagas, Margaret R.
    Johnson, Alison
    Schned, Alan
    Armenti, Karla R.
    Hosain, G. M.
    Andriole, Gerald, Jr.
    Grubb, Robert, III
    Black, Amanda
    Diver, W. Ryan
    Gapstur, Susan M.
    Weinstein, Stephanie J.
    Virtamo, Jarmo
    Haiman, Chris A.
    Landi, Maria T.
    Caporaso, Neil
    Fraumeni, Joseph F., Jr.
    Vineis, Paolo
    Wu, Xifeng
    Silverman, Debra T.
    Chanock, Stephen
    Rothman, Nathaniel
    Genome-wide association study identifies multiple loci associated with bladder cancer risk2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 5, p. 1387-1398Article in journal (Refereed)
    Abstract [en]

    andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

  • 398. Fisher Pedersen, Anette
    et al.
    Forbes, Lindsay
    Brain, Kate
    Hvindberg, Line
    Nielsen Wulff, Christian
    Lagerlund, Magdalena
    Hajdarevic, Senada
    Umeå University, Faculty of Medicine, Department of Nursing.
    Quaife, Samantha L
    Vedsted, Peter
    Negative cancer beliefs, recognition of cancer symptoms and anticipated time to help-seeking: an international cancer benchmarking partnership (ICBP) study2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, article id 363Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Understanding what influences people to seek help can inform interventions to promote earlier diagnosis of cancer, and ultimately better cancer survival. We aimed to examine relationships between negative cancer beliefs, recognition of cancer symptoms and how long people think they would take to go to the doctor with possible cancer symptoms (anticipated patient intervals).

    METHODS: Telephone interviews of 20,814 individuals (50+) in the United Kingdom, Australia, Canada, Denmark, Norway and Sweden were carried out using the Awareness and Beliefs about Cancer Measure (ABC). ABC included items on cancer beliefs, recognition of cancer symptoms and anticipated time to help-seeking for cough and rectal bleeding. The anticipated time to help-seeking was dichotomised as over one month for persistent cough and over one week for rectal bleeding.

    RESULTS: Not recognising persistent cough/hoarseness and unexplained bleeding as cancer symptoms increased the likelihood of a longer anticipated patient interval for persistent cough (OR = 1.66; 95%CI = 1.47-1.87) and rectal bleeding (OR = 1.90; 95%CI = 1.58-2.30), respectively. Endorsing four or more out of six negative beliefs about cancer increased the likelihood of longer anticipated patient intervals for persistent cough and rectal bleeding (OR = 2.18; 95%CI = 1.71-2.78 and OR = 1.97; 95%CI = 1.51-2.57). Many negative beliefs about cancer moderated the relationship between not recognising unexplained bleeding as a cancer symptom and longer anticipated patient interval for rectal bleeding (p = 0.005).

    CONCLUSIONS: Intervention studies should address both negative beliefs about cancer and knowledge of symptoms to optimise the effect.

  • 399. FitzGerald, L. M.
    et al.
    Zhao, S.
    Leonardson, A.
    Geybels, M. S.
    Kolb, S.
    Lin, D. W.
    Wright, J. L.
    Eeles, R.
    Kote-Jarai, Z.
    Govindasami, K.
    Giles, G. G.
    Southey, M. C.
    Schleutker, J.
    Tammela, T. L.
    Sipeky, C.
    Penney, K. L.
    Stampfer, M. J.
    Gronberg, H.
    Wiklund, F.
    Stattin, P.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hugosson, J.
    Karyadi, D. M.
    Ostrander, E. A.
    Feng, Z.
    Stanford, J. L.
    Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: an analysis of 12,082 prostate cancer cases2018In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608, Vol. 21, no 2, p. 228-237Article in journal (Refereed)
    Abstract [en]

    Background Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 x 10(-2)) and IL4 (rs2070874; HR 1.22; p-value = 1.1 x 10(-3)) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 x 10(-2)). Conclusions This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

  • 400. Fogelstrand, Linda
    et al.
    Staffas, Anna
    Wasslavik, Carina
    Sjogren, Helene
    Soderhall, Stefan
    Frost, Britt-Marie
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Behrendtz, Mikael
    Heldrup, Jesper
    Karrman, Kristina
    Johansson, Bertil
    Heyman, Mats
    Abrahamsson, Jonas
    Palmqvist, Lars
    Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols2014In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, no 3, p. 424-430Article in journal (Refereed)
    Abstract [en]

    Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.

    Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.

    Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.

    Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.

567891011 351 - 400 of 1698
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf