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  • 151. Brendle, Annika
    et al.
    Brandt, Andreas
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enquist, Kerstin
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Försti, Asta
    Single nucleotide polymorphisms in chromosomal instability genes and risk and clinical outcome of breast cancer: a Swedish prospective case-control study.2009In: European journal of cancer (Oxford, England : 1990), ISSN 1879-0852, Vol. 45, no 3, p. 435-442Article in journal (Refereed)
    Abstract [en]

    Chromosomal instability (CIN) is a major characteristic of many cancers. We investigated whether putatively functional single nucleotide polymorphisms (SNPs) in genes related to CIN (CENPF, ESPL1, NEK2, PTTG1, ZWILCH, ZWINT) affect breast cancer (BC) risk and clinical outcome in a Swedish cohort of 749 incident BC cases with detailed clinical data and up to 15 years of follow-up and 1493 matched controls. As a main observation, carriers of the A allele of the CENPF SNP rs438034 had a worse BC-specific survival compared to the wild type genotype GG carriers (hazard ratio (HR) 2.65, 95% confidence interval (CI) 1.19-5.90), although they were less likely to have regional lymph node metastases (odds ratio (OR) 0.71, 95% CI 0.51-1.01) and tumours of stage II-IV (OR 0.73, 95% CI 0.54-0.99). As there is increasing evidence that CENPF is associated with poor prognosis in patients with primary BC, further independent studies are needed to clarify the importance of genetic variation in the CENPF gene in the clinic.

  • 152. Brendle, Annika
    et al.
    Lei, Haixin
    Brandt, Andreas
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enquist, Kerstin
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hemminki, Kari
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Försti, Asta
    Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer ITGB4 as prognostic marker.2008In: Carcinogenesis, ISSN 1460-2180, Vol. 29, no 7, p. 1394-1399Article in journal (Refereed)
    Abstract [en]

    Integrins control the cell attachment to the extracellular matrix and play an important role in mediating cell proliferation, migration and survival. A number of important cancer-associated integrin genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3' untranslated regions. We examined the effect of single-nucleotide polymorphisms (SNPs) in predicted miRNA target sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4 and ITGB5) on breast cancer (BC) risk and clinical outcome. Six SNPs were genotyped in 749 Swedish incident BC cases with detailed clinical data and up to 15 years of follow-up together with 1493 matched controls. We evaluated associations between genotypes and BC risk and clinical tumour characteristics. Survival probabilities were compared between different subgroups. As a novel finding, several SNPs seemed to associate with the hormone receptor status. The strongest association was observed between the A allele of the SNP rs743554 in the ITGB4 gene and oestrogen receptor-negative tumours [odds ratio 2.09, 95% confidence intervals (CIs) 1.19-3.67]. The same SNP was associated with survival. The A allele carriers had a worse survival compared with the wild-type genotype carriers (hazard ratio 2.11, 95% CIs 1.21-3.68). The poor survival was significantly associated with the aggressive tumour characteristics: high grade, lymph node metastasis and high stage. None of the SNPs was significantly associated with BC risk. As the ITGB4 SNP seems to influence tumour aggressiveness and survival, it may have prognostic value in the clinic.

  • 153. Breugom, A. J.
    et al.
    Bastiaannet, E.
    Boelens, P. G.
    Iversen, L. H.
    Martling, A.
    Johansson, R.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Evans, T.
    Lawton, S.
    O'Brien, K. M.
    Van Eycken, E.
    Janciauskiene, R.
    Liefers, G. J.
    Cervantes, A.
    Lemmens, V. E. P. P.
    van de Velde, C. J. H.
    Adjuvant chemotherapy and relative survival of patients with stage II colon cancer - A EURECCA international comparison between the Netherlands, Denmark, Sweden, England, Ireland, Belgium, and Lithuania2016In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 63, p. 110-117Article in journal (Refereed)
    Abstract [en]

    Background: The aim of the present EURECCA international comparison is to compare adjuvant chemotherapy and relative survival of patients with stage II colon cancer between European countries.

    Methods: Population-based national cohort data (2004-2009) from the Netherlands (NL), Denmark (DK), Sweden (SE), England (ENG), Ireland (IE), and Belgium (BE) were obtained, as well as single-centre data from Lithuania. All surgically treated patients with stage II colon cancer were included. The proportion of patients receiving adjuvant chemotherapy was calculated and compared between countries. Besides, relative survival was calculated and compared between countries.

    Results: Overall, 59,154 patients were included. The proportion of patients receiving adjuvant chemotherapy ranged from 7.1% to 29.0% (p < 0.001). Compared with NL, a better adjusted relative survival was observed in SE (stage II: relative excess risks (RER) 0.53, 95% confidence interval (CI) 0.44-0.64; p < 0.001), and BE (stage II: RER 0.84, 95% CI 0.76-0.92; p < 0.001), and in IE for patients with stage IIA disease (RER 0.80, 95% CI 0.65-0.98; p = 0.03).

    Conclusion: The proportion of patients with stage II colon cancer receiving adjuvant chemotherapy varied largely between seven European countries. No clear linear pattern between adjuvant chemotherapy and adjusted relative survival was observed. Compared with NL, SE and BE showed an improved adjusted relative survival for stage II disease, and IE for patients with stage IIA disease only. Further research into selection criteria for adjuvant chemotherapy could eventually lead to individually tailored, optimal treatment of patients with stage II colon cancer.

  • 154. Breugom, A. J.
    et al.
    Bastiaannet, E.
    Boelens, P. G.
    Van Eycken, E.
    Iversen, L. H.
    Martling, A.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Evans, T.
    Lawton, S.
    O'Brien, K. M.
    Ortiz, H.
    Janciauskiene, R.
    Dekkers, O. M.
    Rutten, H. J. T.
    Liefers, G. J.
    Lemmens, V. E. P. P.
    van de Velde, C. J. H.
    Oncologic treatment strategies and relative survival of patients with stage I-III rectal cancer - A EURECCA international comparison between the Netherlands, Belgium, Denmark, Sweden, England, Ireland, Spain, and Lithuania2018In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 44, no 9, p. 1338-1343Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of this EURECCA international comparison is to compare oncologic treatment strategies and relative survival of patients with stage I-III rectal cancer between European countries.

    Material and methods: Population-based national cohort data from the Netherlands (NL), Belgium (BE), Denmark (DK), Sweden (SE), England (ENG), Ireland (IE), Spain (ES), and single-centre data from Lithuania (LT) were obtained. All operated patients with (y)pTNM stage I-III rectal cancer diagnosed between 2004 and 2009 were included. Oncologic treatment strategies and relative survival were calculated and compared between neighbouring countries.

    Results: We included 57,120 patients. Treatment strategies differed between NL and BE (p < 0.001), DK and SE (p < 0.001), and ENG and IE (p < 0.001). More preoperative radiotherapy as single treatment before surgery was administered in NL compared with BE (59.7% vs. 13.1%), in SE compared with DK (55.1% vs. 10.4%), and in ENG compared with IE (15.2% vs. 9.6%). Less postoperative chemotherapy was given in NL (9.6% vs. 39.1%), in SE (7.9% vs. 14.1%), and in IE (12.6% vs. 18.5%) compared with their neighbouring country. In ES, 55.1% of patients received preoperative chemoradiation and 62.3% post-operative chemotherapy. There were no significant differences in relative survival between neighbouring countries.

    Conclusion: Large differences in oncologic treatment strategies for patients with (y)pTNM I-III rectal cancer were observed across European countries. No clear relation between oncologic treatment strategies and relative survival was observed. Further research into selection criteria for specific treatments could eventually lead to individualised and optimal treatment for patients with non-metastasised rectal cancer. 

  • 155. Britton, Julie A
    et al.
    Khan, Aneire E
    Rohrmann, Sabine
    Becker, Nikolaus
    Linseisen, Jakob
    Nieters, Alexandra
    Kaaks, Rudolf
    Tjønneland, Anne
    Halkjaer, Jytte
    Severinsen, Marianne Tang
    Overvad, Kim
    Pischon, Tobias
    Boeing, Heiner
    Trichopoulou, Antonia
    Kalapothaki, Victoria
    Trichopoulos, Dimitrios
    Mattiello, Amalia
    Tagliabue, Giovanna
    Sacerdote, Carlotta
    Peeters, Petra H M
    Bueno-de-Mesquita, H Bas
    Ardanaz, Eva
    Navarro, Carmen
    Jakszyn, Paula
    Altzibar, Jone M
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Berglund, Göran
    Manjer, Jonas
    Allen, Naomi
    Key, Timothy
    Bingham, Sheila
    Besson, Hervé
    Ferrari, Pietro
    Jenab, Mazda
    Boffetta, Paolo
    Vineis, Paolo
    Riboli, Elio
    Anthropometric characteristics and non-Hodgkin's lymphoma and multiple myeloma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).2008In: Haematologica, ISSN 1592-8721, Vol. 93, no 11, p. 1666-1677Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The incidences of non-Hodgkin's lymphoma and multiple myeloma are increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. It is biologically plausible that anthropometric characteristics can infuence the risk of non-Hodgkin's lymphoma and multiple myeloma.

    DESIGN AND METHODS:

    In the context of the European Prospective Investigation into Cancer and Nutrition (EPIC), anthropometric characteristics were assessed in 371,983 cancer-free individuals at baseline. During the 8.5 years of follow-up, 1,219 histologically confirmed incident cases of non-Hodgkin's lymphoma and multiple myeloma occurred in 609 men and 610 women. Gender-specific proportional hazards models were used to estimate relative risks and 95% confidence intervals (95% CI) of development of non-Hodgkin's lymphoma and multiple myeloma in relation to the anthropometric characteristics.

    RESULTS:

    Height was associated with overall non-Hodgkin's lymphoma and multiple myeloma in women (RR 1.50, 95% CI 1.14-1.98) for highest versus lowest quartile; p-trend < 0.01) but not in men. Neither obesity (weight and body mass index) nor abdominal fat (waist-to-hip ratio, waist or hip circumference) measures were positively associated with overall non-Hodgkin's lymphoma and multiple myeloma. Relative risks for highest versus lowest body mass index quartile were 1.09 (95% CI 0.85-1.38) and 0.92 (95% CI 0.71-1.19) for men and women, respectively. Women in the upper body mass index quartile were at greater risk of diffuse large B-cell lymphoma (RR 2.18, 95% CI 1.05-4.53) and taller women had an elevated risk of follicular lymphoma (RR 1.25, 95% CI 0.59-2.62). Among men, height and body mass index were non-significantly, positively related to follicular lymphoma. Multiple myeloma risk alone was elevated for taller women (RR 2.34, 95% CI 1.29-4.21) and heavier men (RR 1.77, 95% CI 1.02-3.05).

    CONCLUSIONS:

    The EPIC analyses support an association between height and overall non-Hodgkin's lymphoma and multiple myeloma among women and suggest heterogeneous subtype associations. This is one of the first prospective studies focusing on central adiposity and non-Hodgkin's lymphoma subtypes.

  • 156. Broeders, Mireille
    et al.
    Moss, Sue
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Njor, Sisse
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Poop, Ellen
    Massat, Nathalie
    Duffy, Stephen
    Lynge, Elsebeth
    Paci, Eugenio
    The impact of mammographic screening on breast cancer mortality in Europe: a review of observational studies2012In: Journal of Medical Screening, ISSN 0969-1413, E-ISSN 1475-5793, Vol. 19, p. 14-25Article in journal (Refereed)
    Abstract [en]

    Objectives To assess the impact of population-based mammographic screening on breast cancer mortality in Europe, considering different methodologies and limitations of the data. Methods We conducted a systematic literature review of European trend studies (n = 17), incidence-based mortality (IBM) studies (n = 20) and case-control (CC) studies (n = 8). Estimates of the reduction in breast cancer mortality for women invited versus not invited and/or for women screened versus not screened were obtained. The results of IBM studies and CC studies were each pooled using a random effects meta-analysis. Results Twelve of the 17 trend studies quantified the impact of population-based screening on breast cancer mortality. The estimated breast cancer mortality reductions ranged from 1% to 9% per year in studies reporting an annual percentage change, and from 28% to 36% in those comparing post- and prescreening periods. In the IBM studies, the pooled mortality reduction was 25% (relative risk [RR] 0.75, 95% confidence interval [CI] 0.69-0.81) among invited women and 38% (RR 0.62, 95% CI 0.56-0.69) among those actually screened. The corresponding pooled estimates from the CC studies were 31% (odds ratio [OR] 0.69, 95% CI 0.57-0.83), and 48% (OR 0.52, 95% CI 0.42-0.65) adjusted for self-selection. Conclusions Valid observational designs are those where sufficient longitudinal individual data are available, directly linking a woman's screening history to her cause of death. From such studies, the best 'European' estimate of breast cancer mortality reduction is 25-31% for women invited for screening, and 38-48% for women actually screened. Much of the current controversy on breast cancer screening is due to the use of inappropriate methodological approaches that are unable to capture the true effect of mammographic screening.

  • 157.
    Bromée, Emil
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pilot study for the REPAC study: This study is a pilot study for the larger REPAC (Rehabilitation of Patients receiving Adjuvant Chemotherapy) study2016Independent thesis Basic level (degree of Bachelor of Fine Arts), 20 credits / 30 HE creditsStudent thesis
  • 158.
    Brynolfsson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nilsson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Torheim, Turid
    Asklund, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Thellenberg Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Haralick texture features from apparent diffusion coefficient (ADC) MRI images depend on imaging and pre-processing parameters2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4041Article in journal (Refereed)
    Abstract [en]

    In recent years, texture analysis of medical images has become increasingly popular in studies investigating diagnosis, classification and treatment response assessment of cancerous disease. Despite numerous applications in oncology and medical imaging in general, there is no consensus regarding texture analysis workflow, or reporting of parameter settings crucial for replication of results. The aim of this study was to assess how sensitive Haralick texture features of apparent diffusion coefficient (ADC) MR images are to changes in five parameters related to image acquisition and pre-processing: noise, resolution, how the ADC map is constructed, the choice of quantization method, and the number of gray levels in the quantized image. We found that noise, resolution, choice of quantization method and the number of gray levels in the quantized images had a significant influence on most texture features, and that the effect size varied between different features. Different methods for constructing the ADC maps did not have an impact on any texture feature. Based on our results, we recommend using images with similar resolutions and noise levels, using one quantization method, and the same number of gray levels in all quantized images, to make meaningful comparisons of texture feature results between different subjects.

  • 159. Budäus, Lars
    et al.
    Bolla, Michel
    Bossi, Alberto
    Cozzarini, Cesare
    Crook, Juanita
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wiegel, Thomas
    Functional Outcomes and Complications Following Radiation Therapy for Prostate Cancer: A Critical Analysis of the Literature2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 61, no 1, p. 112-127Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Prostate cancer (PCa) patients have many options within the realms of surgery or radiation therapy (RT). Technical advancements in RT planning and delivery have yielded different approaches, such as external beam, brachytherapy, and newer approaches such as image-guided tomotherapy or volumetric-modulated arc therapy. The selection of the optimal RT treatment for the individual is still a point of discussion, and the debate centres on two important outcomes-namely, cancer control and reduction of side-effects.

    OBJECTIVE: To critically review and summarise the available literature on functional outcomes and rectal sequelae following RT for PCa treatment.

    EVIDENCE ACQUISITION: A review of the literature published between 1999 and 2010 was performed using Medline and Scopus search. Relevant reports were identified using the terms prostate cancer, radiotherapy, functional outcomes, external beam radiation, brachytherapy, IMRT, quality of life, and tomotherapy and were critically reviewed and summarised.

    EVIDENCE SYNTHESIS: Related to nonuniform definition of their assessed functional end points and uneven standards of reporting, only a minority of series retrieved could be selected for analyses. Moreover, patterns of patient selection for different types of RT, inherent differences in the RT modalities, and the presence or absence of hormonal treatment also limit the ability to synthesise results from different publications or perform meta-analyses across the different treatment types. Nonetheless, several studies agree that recent technical improvements in the field of RT planning and delivery enable the administration of higher doses with equal or less toxicity. Regardless of the type of RT, the most frequently considered functional end points in the published analyses are gastrointestinal (GI) complications and rectal bleeding. Established risk factors for acute or late toxicities after RT include advanced age, larger rectal volume, a history of prior abdominal surgery, the concomitant use of androgen deprivation, preexisting diabetes mellitus, haemorrhoids, and inflammatory bowel disease (IBD). Similarly, mild acute irritative urinary symptoms are reported in several studies, whereas total urinary incontinence and other severe urinary symptoms are rare. Pretreatment genitourinary complaints, prior transurethral resection of the prostate (TURP), and the presence of acute genitourinary toxicity are suggested as contributing to long-term urinary morbidity. Erectile dysfunction (ED) is not an immediate side-effect of RT, and the occurrence of spontaneous erections before treatment is the best predictor for preserving erections sufficient for intercourse. In addition, the use of magnetic resonance imaging (MRI) permits a reduction in the dose delivered to vascular structures critical for erectile function.

    CONCLUSIONS: In the future, further improvement in RT planning and delivery will decrease side-effects and permit administration of higher doses. Related to the anatomy of the prostate, these higher doses may favour rectal sparing while not readily sparing the urethra and bladder neck. As a consequence, there may be a future shift from dose-limiting long-term rectal morbidity towards long-term urinary morbidity. In the absence of prospective randomised trials comparing different types of surgical and RT-based treatments in PCa, the introduction of validated tools for reporting functional and clinical outcomes is crucial for evaluating and identifying each individual's best treatment choice.

  • 160.
    Bylund, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Saarinen, Niina
    Zhang, Jie-Xian
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Periodontology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adlercreutz, Herman
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Mäkelä, Sari
    Anticancer effects of a plant lignan 7-hydroxymatairesinol on a prostate cancer model in vivo.2005In: Experimental biology and medicine (Maywood, N.J.: Print), ISSN 1535-3702, E-ISSN 1535-3699, Vol. 230, no 3, p. 217-223Article in journal (Refereed)
    Abstract [en]

    Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.

  • 161. Büchner, F L
    et al.
    Bueno-de-Mesquita, H B
    Linseisen, J
    Boshuizen, H C
    Kiemeney, L A L M
    Ros, M M
    Overvad, K
    Hansen, L
    Tjonneland, A
    Raaschou-Nielsen, O
    Clavel-Chapelon, F
    Boutron-Ruault, M-C
    Touillaud, M
    Kaaks, R
    Rohrmann, S
    Boeing, H
    Nöthlings, U
    Trichopoulou, A
    Zylis, D
    Dilis, V
    Palli, D
    Sieri, S
    Vineis, P
    Tumino, R
    Panico, S
    Peeters, P H M
    van Gils, C H
    Lund, E
    Gram, I T
    Braaten, T
    Martinez, C
    Agudo, A
    Arriola, L
    Ardanaz, E
    Navarro, C
    Rodríguez, L
    Manjer, J
    Wirfält, E
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Key, T J
    Roddam, A W
    Bingham, S
    Khaw, K-T
    Slimani, N
    Bofetta, P
    Byrnes, G
    Norat, T
    Michaud, D
    Riboli, E
    Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)2010In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 3, p. 357-371Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation into Cancer and Nutrition study. METHODS: Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors. RESULTS: During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89-0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90-0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76-0.94), while no clear effects were seen for the other histological subtypes. CONCLUSION: We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas.

  • 162. Büchner, Frederike L
    et al.
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Overvad, Kim
    Dahm, Christina C
    Hansen, Louise
    Tjønneland, Anne
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Touillaud, Marina
    Kaaks, Rudolf
    Rohrmann, Sabine
    Boeing, Heiner
    Nöthlings, Ute
    Trichopoulou, Antonia
    Zylis, Dimosthenis
    Dilis, Vardis
    Palli, Domenico
    Sieri, Sabina
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Peeters, Petra H M
    van Gils, Carla H
    Lund, Eiliv
    Gram, Inger T
    Braaten, Tonje
    Sánchez, María-José
    Agudo, Antonio
    Larrañaga, Nerea
    Ardanaz, Eva
    Navarro, Carmen
    Argüelles, Marcial V
    Manjer, Jonas
    Wirfält, Elisabet
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Key, Tim J
    Khaw, Kay-Tee
    Wareham, Nick
    Slimani, Nadia
    Vergnaud, Anne-Claire
    Xun, Wei W
    Kiemeney, Lambertus A L M
    Riboli, Elio
    Variety in fruit and vegetable consumption and the risk of lung cancer in the European prospective investigation into cancer and nutrition2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 9, p. 2278-2286Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We investigated whether a varied consumption of vegetables and fruits is associated with lower lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study. METHODS: After a mean follow-up of 8.7 years, 1,613 of 452,187 participants with complete information were diagnosed with lung cancer. Diet diversity scores (DDS) were used to quantify the variety in fruit and vegetable consumption. Multivariable proportional hazards models were used to assess the associations between DDS and lung cancer risk. All models were adjusted for smoking behavior and the total consumption of fruit and vegetables. RESULTS: With increasing variety in vegetable subgroups, risk of lung cancer decreases [hazard ratios (HR), 0.77; 95% confidence interval (CI), 0.64-0.94 highest versus lowest quartile; P trend = 0.02]. This inverse association is restricted to current smokers (HR, 0.73; 95% CI, 0.57-0.93 highest versus lowest quartile; P trend = 0.03). In continuous analyses, in current smokers, lower risks were observed for squamous cell carcinomas with more variety in fruit and vegetable products combined (HR/two products, 0.88; 95% CI, 0.82-0.95), vegetable subgroups (HR/subgroup, 0.88; 95% CI, 0.79-0.97), vegetable products (HR/two products, 0.87; 95% CI, 0.79-0.96), and fruit products (HR/two products, 0.84; 95% CI, 0.72-0.97). CONCLUSION: Variety in vegetable consumption was inversely associated with lung cancer risk among current smokers. Risk of squamous cell carcinomas was reduced with increasing variety in fruit and/or vegetable consumption, which was mainly driven by the effect in current smokers. IMPACT: Independent from quantity of consumption, variety in fruit and vegetable consumption may decrease lung cancer risk.

  • 163. Cai, Feng Feng
    et al.
    Kohler, Corina
    Zhang, Bei
    Chen, Wei Jie
    Barekati, Zeinab
    Garritsen, Henk SP
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Toniolo, Paolo
    Zhang, Jing Jie
    Zhong, Xiao Yan
    Mutations of mitochondrial DNA as potential biomarkers in breast cancer2011In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 31, no 12, p. 4267-4271Article in journal (Refereed)
    Abstract [en]

    Background: Alterations of mitochondrial DNA (mtDNA) have been found in cancer patients, therefore informative mtDNA mutations could serve as biomarkers for the disease.

    Materials and Methods: The two hypervariable regions HVR1 and HVR2 in the D-Loop region were sequenced in ten paired tissue and plasma samples from breast cancer patients.

    Results: MtDNA mutations were found in all patients' samples, suggesting a 100% detection rate. Examining germline mtDNA mutations, a total of 85 mutations in the D-loop region were found; 31 of these mutations were detected in both tissues and matched plasma samples, the other 54 germline mtDNA mutations were found only in the plasma samples. Regarding somatic mtDNA mutations, a total of 42 mutations in the D-loop region were found in breast cancer tissues.

    Conclusion: Somatic mtDNA mutations in the D-loop region were detected in breast cancer tissues but not in the matched plasma samples, suggesting that more sensitive methods will be needed for such detection to be of clinical utility.

  • 164. Caini, Saverio
    et al.
    Masala, Giovanna
    Saieva, Calogero
    Kvaskoff, Marina
    Sacerdote, Carlotta
    Savoye, Isabelle
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Bech, Bodil Hammer
    Overvad, Kim
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Mancini, Francesca Romana
    Boutron-Ruault, Marie-Christine
    Cervenka, Iris
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Floegel, Anna
    Trichopoulou, Antonia
    Valanou, Elisavet
    Kritikou, Maria
    Tagliabue, Giovanna
    Panico, Salvatore
    Tumino, Rosario
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H.
    Veierod, Marit B.
    Ghiasvand, Reza
    Lukic, Marko
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Salamanca Fernandez, Elena
    Larranaga, Nerea
    Zamora-Ros, Raul
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirstrom, Karin
    Sonestedt, Emily
    Key, Timothy J.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc
    Huybrechts, Inge
    Murphy, Neil
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Palli, Domenico
    Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 10, p. 2246-2255Article in journal (Refereed)
    Abstract [en]

    What's new? Laboratory studies suggest that coffee and tea protect against melanoma, but epidemiological findings are inconsistent. Here the authors studied more than 400,000 participants within the European Prospective Investigation into Cancer and Nutrition (EPIC) and confirmed an inverse association between caffeinated coffee consumption and melanoma risk. No association was found with decaffeinated coffee or tea. Interestingly, drinking coffee only protected men, but not women, from developing the often fatal skin cancer, raising interesting questions about gender-specific hormones or coffee habits influencing this association. In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma.

  • 165. Camp, Nicola J
    et al.
    Cannon-Albright, Lisa A
    Farnham, James M
    Baffoe-Bonnie, Agnes B
    George, Asha
    Powell, Isaac
    Bailey-Wilson, Joan E
    Carpten, John D
    Giles, Graham G
    Hopper, John L
    Severi, Gianluca
    English, Dallas R
    Foulkes, William D
    Maehle, Lovise
    Moller, Pal
    Eeles, Ros
    Easton, Douglas
    Badzioch, Michael D
    Whittemore, Alice S
    Oakley-Girvan, Ingrid
    Hsieh, Chih-Lin
    Dimitrov, Latchezar
    Xu, Jianfeng
    Stanford, Janet L
    Johanneson, Bo
    Deutsch, Kerry
    McIntosh, Laura
    Ostrander, Elaine A
    Wiley, Kathleen E
    Isaacs, Sarah D
    Walsh, Patrick C
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Hebbring, Scott
    Schaid, Daniel J
    Lange, Ethan M
    Cooney, Kathleen A
    Tammela, Teuvo L J
    Schleutker, Johanna
    Paiss, Thomas
    Maier, Christiane
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Isaacs, William B
    Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics.2007In: Hum Mol Genet, ISSN 0964-6906, Vol. 16, no 11, p. 1271-1278Article in journal (Refereed)
  • 166. Campa, Daniele
    et al.
    Claus, Rainer
    Dostal, Lucie
    Stein, Angelika
    Chang-Claude, Jenny
    Meidtner, Karina
    Boeing, Heiner
    Olsen, Anja
    Tjønneland, Anne
    Overvad, Kim
    Rodríguez, Laudina
    Bonet, Catalina
    Sánchez, Maria-José
    Amiano, Pilar
    Huerta, José María
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C
    Allen, Naomi E
    Trichopoulou, Antonia
    Bamia, Christina
    Benetou, Vassiliki
    Palli, Domenico
    Agnoli, Claudia
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    van Kranen, Henk
    Bas Bueno-de-Mesquita, H
    Peeters, Petra H M
    van Gils, Carla H
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lund, Eiliv
    Gram, Inger Torhild
    Rinaldi, Sabina
    Chajes, Veronique
    Romieu, Isabelle
    Engel, Pierre
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Françoise
    Siddiq, Afshan
    Riboli, Elio
    Canzian, Federico
    Kaaks, Rudolf
    Variation in genes coding for AMP-activated protein kinase (AMPK) and breast cancer risk in the European Prospective Investigation on Cancer (EPIC).2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 127, no 3, p. 761-767Article in journal (Refereed)
    Abstract [en]

    AMP-activated protein kinase (AMPK) is an energy sensing/signalling intracellular protein which is activated by an increase in the cellular AMP:ATP ratio after ATP depletion. Once activated, AMPK inhibits fatty acid synthesis and the Akt-mTOR pathway, and activates the p53-p21 axis. All these molecular mechanisms are thought to play a key role in breast carcinogenesis. We investigated the genetic variability of four genes encoding AMPK (PRKAA1, PRKAA2, PRKAB1 and PRKAB2). Using a tagging approach and selecting SNPs we covered all the common genetic variation of these genes. We tested association of tagging SNPs in our four candidate genes with breast cancer (BC) risk in a study of 1340 BC cases and 2536 controls nested into the European Prospective Investigation into Cancer and Nutrition (EPIC). Given the relevance of AMPK on fatty acid synthesis and the importance of body fatness as a BC risk factor, we tested association of SNPs and body-mass index as well. We observed no statistically significant association between the SNPs in the PRKAs genes and BC risk and BMI after correction for multiple testing.

  • 167. Campa, Daniele
    et al.
    Hüsing, Anika
    McKay, James D
    Sinilnikova, Olga
    Vogel, Ulla
    Tjønneland, Anne
    Overvad, Kim
    Stegger, Jakob
    Clavel-Chapelon, Françoise
    Chabbert-Buffet, Nathalie
    Fagherazzi, Guy
    Trichopoulou, Antonia
    Zylis, Dimosthenis
    Oustoglou, Erifili
    Rohrmann, Sabine
    Teucher, Birgit
    Fisher, Eva
    Boeing, Heiner
    Masala, Giovanna
    Krogh, Vittorio
    Sacerdote, Carlotta
    Panico, Salvatore
    Tumino, Rosario
    Onland-Moret, N Charlotte
    van Gils, Carla H
    Bueno-de-Mesquita, H Bas
    Lund, Eiliv
    Chirlaque, María Dolores
    Sala, Núria
    Quirós, José Ramon
    Ardanaz, Eva
    Amiano, Pilar
    Molina-Montes, Esther
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Travis, Ruth C
    Key, Timothy J
    Wareham, Nick
    Khaw, Kay-Tee
    Rinaldi, Sabina
    Slimani, Nadia
    Chajes, Veronique
    Siddiq, Afshan
    Riboli, Elio
    Kaaks, Rudolf
    Canzian, Federico
    The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk2010In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 10, p. 563-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC).

    METHODS: we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk.

    RESULTS AND CONCLUSIONS: In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status.

  • 168. Campa, Daniele
    et al.
    McKay, James
    Sinilnikova, Olga
    Hüsing, Anika
    Vogel, Ulla
    Hansen, Rikke
    Overvad, Kim
    Witt, Petra
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Chajes, Veronique
    Rohrmann, Sabine
    Chang-Claude, Jenny
    Boeing, Heiner
    Fisher, Eva
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Palli, Domenico
    Villarini, Anna
    Sacerdote, Carlotta
    Mattiello, Amalia
    Tumino, Rosario
    Peeters, Petra
    van Gils, Carla
    Bas Bueno-de-Mesquita, H
    Lund, Eiliv
    Chirlaque, María
    Sala, Núria
    Suarez, Laudina
    Barricarte, Aurelio
    Dorronsoro, Miren
    Sánchez, Maria-José
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Tsilidis, Kostas
    Bingham, Sheila
    Khaw, Kay-Tee
    Gallo, Valentina
    Norat, Teresa
    Riboli, Elio
    Rinaldi, Sabina
    Lenoir, Gilbert
    Tavtigian, Sean
    Canzian, Federico
    Kaaks, Rudolf
    Genetic variation in genes of the fatty acid synthesis pathway and breast cancer risk.2009In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 118, no 3, p. 565-574Article in journal (Refereed)
    Abstract [en]

    Fatty acid synthase (FAS) is the major enzyme of lipogenesis. It catalyzes the NADPH-dependent condensation of acetyl-CoA and malonyl-CoA to produce palmitic acid. Transcription of the FAS gene is controlled synergistically by the transcription factors ChREBP (carbohydrate response element-binding protein), which is induced by glucose, and SREBP-1 (sterol response element-binding protein-1), which is stimulated by insulin through the PI3K/Akt signal transduction pathway. We investigated whether the genetic variability of the genes encoding for ChREBP, SREBP and FAS (respectively, MLXIPL, SREBF1 and FASN) is related to breast cancer risk and body-mass index (BMI) by studying 1,294 breast cancer cases and 2,452 controls from the European Prospective Investigation on Cancer (EPIC). We resequenced the FAS gene and combined information of SNPs found by resequencing and SNPs from public databases. Using a tagging approach and selecting 20 SNPs, we covered all the common genetic variation of these genes. In this study we were not able to find any statistically significant association between the SNPs in the FAS, ChREBP and SREPB-1 genes and an increased risk of breast cancer overall and by subgroups of age, menopausal status, hormone replacement therapy (HRT) use or BMI. On the other hand, we found that two SNPs in FASN were associated with BMI.

  • 169. Campanella, Gianluca
    et al.
    Gunter, Marc J.
    Polidoro, Silvia
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Fiorito, Giovanni
    Guarrera, Simonetta
    Iacoviello, Licia
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    de Kok, Theo M. C. M.
    Georgiadis, Panagiotis
    Kleinjans, Jos C. S.
    Kyrtopoulos, Soterios A.
    Bueno-de-Mesquita, H. Bas
    Lillycrop, Karen A.
    May, Anne M.
    Onland-Moret, N. Charlotte
    Murray, Robert
    Riboli, Elio
    Verschuren, Monique
    Lund, Eiliv
    Mode, Nicolle
    Sandanger, Torkjel M.
    Fiano, Valentina
    Trevisan, Morena
    Matullo, Giuseppe
    Froguel, Philippe
    Elliott, Paul
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Epigenome-wide association study of adiposity and future risk of obesity-related diseases2018In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 42, no 12, p. 2022-2035Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.

    Methods: DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.

    Results: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10−7), higher triglyceride levels (P = 5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10−3), independently of obesity and established risk factors.

    Conclusion: Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

  • 170. Campanella, Gianluca
    et al.
    Gunter, Marc J.
    Polidoro, Silvia
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Fiorito, Giovanni
    Guarrera, Simonetta
    Iacoviello, Licia
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    de Kok, Theo M. C. M.
    Georgiadis, Panagiotis
    Kleinjans, Jos C. S.
    Kyrtopoulos, Soterios A.
    Bueno-de-Mesquita, H. Bas
    Lillycrop, Karen A.
    May, Anne M.
    Onland-Moret, N. Charlotte
    Murray, Robert
    Riboli, Elio
    Verschuren, Monique
    Lund, Eiliv
    Mode, Nicolle
    Sandanger, Torkjel M.
    Fiano, Valentina
    Trevisan, Morena
    Matullo, Giuseppe
    Froguel, Philippe
    Elliott, Paul
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Epigenome-wide association study of adiposity and future risk of obesity-related diseases2018In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 42, no 12, p. 2022-2035Article in journal (Refereed)
    Abstract [en]

    Background Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction. Methods DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waistheight ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population. Results We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P=9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P=6.00×10−7), higher triglyceride levels (P=5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P=1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P<1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P<1.25×10−3), independently of obesity and established risk factors. Conclusion Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

  • 171. Canzian, Federico
    et al.
    Kaaks, Rudolf
    Cox, David G
    Henderson, Katherine D
    Henderson, Brian E
    Berg, Christine
    Bingham, Sheila
    Boeing, Heiner
    Buring, Julie
    Calle, Eugenia E
    Chanock, Stephen
    Clavel-Chapelon, Francoise
    Dossus, Laure
    Feigelson, Heather Spencer
    Haiman, Christopher A
    Hankinson, Susan E
    Hoover, Robert
    Hunter, David J
    Isaacs, Claudine
    Lenner, Per
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Lund, Eiliv
    Overvad, Kim
    Palli, Domenico
    Pearce, Celeste Leigh
    Quiros, Jose R
    Riboli, Elio
    Stram, Daniel O
    Thomas, Gilles
    Thun, Michael J
    Trichopoulos, Dimitrios
    van Gils, Carla H
    Ziegler, Regina G
    Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).2009In: BMC cancer, ISSN 1471-2407, Vol. 9, p. 257-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3). METHODS: We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects. RESULTS: Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. CONCLUSION: Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.

  • 172. Carlsson, J
    et al.
    Nordgren, H
    Sjöström, J
    Wester, K
    Villman, K
    Bengtsson, Nils-Olof
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ostenstad, B
    Lundqvist, H
    Blomqvist, C
    HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review2004In: Br J Cancer, ISSN 0007-0920, Vol. 90, no 12, p. 2344-2348Article in journal (Refereed)
  • 173. Carlsson, Sigrid
    et al.
    Drevin, Linda
    Loeb, Stacy
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Franck Lissbrant, Ingela
    Robinson, David
    Johansson, Eva
    Stattin, Pär
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Nursing.
    Population-based study of long-term functional outcomes after prostate cancer treatment2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 117, no 6B, p. E36-E45Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate long-term urinary, sexual and bowel functional outcomes after prostate cancer treatment at a median follow-up of 12 years (IQR 11-13).

    PATIENTS AND METHODS: In this nationwide, population-based study, we identified from the National Prostate Cancer Register, Sweden, 6,003 men diagnosed with localized prostate cancer (clinical local stage T1-2, any Gleason score, prostate specific antigen < 20 ng/mL, NX or N0, MX or M0) between 1997 and 2002 who were ≤70 years at diagnosis. 1,000 prostate cancer-free controls were selected, matched for age and county of residence. Functional outcomes were evaluated with a validated self-reported questionnaire.

    RESULTS: Responses were obtained from 3,937/6,003 cases (66%) and 459/1,000 (46%) controls. Twelve years post diagnosis, at a median age of 75 years, the proportion of cases with adverse symptoms was 87% for erectile dysfunction or sexually inactive, 20% for urinary incontinence and 14% for bowel disturbances. The corresponding proportions for controls were 62%, 6% and 7%, respectively. Men with prostate cancer, except those on surveillance, had an increased risk of erectile dysfunction, compared to control men. Radical prostatectomy was associated with increased risk of urinary incontinence (odds ratio; OR 2.29 [95% CI 1.83-2.86] and radiotherapy increased the risk of bowel dysfunction (OR 2.46 [95% CI 1.73-3.49]) compared to control men. Multi-modal treatment, in particular including androgen deprivation therapy (ADT), was associated with the highest risk of adverse effects; for instance radical prostatectomy followed by radiotherapy and ADT was associated with an OR of 3.74 [95 CI 1.76-7.95] for erectile dysfunction and OR 3.22 [95% CI 1.93-5.37] for urinary incontinence.

    CONCLUSION: The proportion of men who suffer long-term impact on functional outcomes after prostate cancer treatment was substantial.

  • 174. Carreras-Torres, Robert
    et al.
    Johansson, Mattias
    Haycock, Philip C.
    Wade, Kaitlin H.
    Relton, Caroline L.
    Martin, Richard M.
    Smith, George Davey
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline
    Arnold, Susanne M.
    Bickeböller, Heike
    Bojesen, Stig E.
    Brunnström, Hans
    Manjer, Jonas
    Brüske, Irene
    Caporaso, Neil E.
    Chen, Chu
    Christiani, David C.
    Christian, W. Jay
    Doherty, Jennifer A.
    Duell, Eric J.
    Field, John K.
    Davies, Michael P. A.
    Marcus, Michael W.
    Goodman, Gary E.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Haugen, Aage
    Hong, Yun-Chul
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Kraft, Peter
    Johansson, Mikael B.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lam, Stephen
    Landi, Maria Teresa
    Lazarus, Philip
    Le Marchand, Loïc
    Liu, Geoffrey
    Melander, Olle
    Park, Sungshim L.
    Rennert, Gad
    Risch, Angela
    Haura, Eric B.
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Savić, Milan
    Lissowska, Jolanta
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Mates, Dana
    Schabath, Matthew B.
    Shen, Hongbing
    Tardon, Adonina
    Teare, Dawn
    Woll, Penella
    Tsao, Ming-Sound
    Wu, Xifeng
    Yuan, Jian-Min
    Hung, Rayjean J.
    Amos, Christopher I.
    McKay, James
    Brennan, Paul
    Obesity, metabolic factors and risk of different histological types of lung cancer: a Mendelian randomization study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0177875Article in journal (Refereed)
    Abstract [en]

    Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95% CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m(2)]), but not for adenocarcinoma (OR [95% CI] = 0.93 [0.79-1.08]) (P-heterogeneity = 4.3x10(-3)). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10(-3)), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95% CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95% CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

  • 175. Carstam, Louise
    et al.
    Smits, Anja
    Milos, Peter
    Corell, Alba
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bartek, Jiri, Jr.
    Jakola, Asgeir Store
    Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 20152019In: Neuro-Oncology Practice, ISSN 2054-2577, Vol. 6, no 2, p. 124-133Article in journal (Refereed)
    Abstract [en]

    Background: In the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care.

    Methods: The Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted.

    Results: A total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P= .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04).

    Conclusion: In this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors.

  • 176. Castellsagué, Xavier
    et al.
    Pawlita, Michael
    Roura, Esther
    Margall, Núria
    Waterboer, Tim
    Bosch, F Xavier
    de Sanjosé, Silvia
    Gonzalez, Carlos Alberto
    Dillner, Joakim
    Gram, Inger T
    Tjønneland, Anne
    Munk, Christian
    Pala, Valeria
    Palli, Domenico
    Khaw, Kay-Tee
    Barnabas, Ruanne V
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Steffen, Annika
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Klinaki, Eleni
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H
    Lund, Eiliv
    Weiderpass, Elisabete
    Quirós, J Ramón
    Sánchez, María-José
    Navarro, Carmen
    Barricarte, Aurelio
    Larrañaga, Nerea
    Ekström, Johanna
    Hortlund, Maria
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wareham, Nick
    Travis, Ruth C
    Rinaldi, Sabina
    Tommasino, Massimo
    Franceschi, Silvia
    Riboli, Elio
    Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: Evidence from the EPIC cohort2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 2, p. 440-452Article in journal (Refereed)
    Abstract [en]

    To evaluate prospectively the association between serological markers of selected infections, including HPV, and risk of developing cervical cancer (CC) and pre-cancer, we performed a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study that included 184 cases of invasive CC (ICC), 425 cases of cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS), and 1,218 matched control women. At enrollment participants completed lifestyle questionnaires and provided sera. Subjects were followed-up for a median of 9 years. Immunoassays were used to detect serum antibodies to Human Herpes Virus 2 (HHV-2), Chlamydia trachomatis (CT), Chlamydia pneumoniae, L1 proteins of mucosal and cutaneous HPV types, E6/E7 proteins of HPV16/18, as well as to four polyomaviruses. Adjusted odds ratios (OR) (and 95% confidence intervals (CI)) for CIN3/CIS and ICC risk were, respectively: 1.6 (1.2-2.0) and 1.8 (1.1-2.7) for L1 seropositivity to any mucosal HPV type, 1.0 (0.4-2.4) and 7.4 (2.8-19.7) for E6 seropositivity to HPV16/18, 1.3 (0.9-1.9) and 2.3 (1.3-4.1) for CT seropositivity, and 1.4 (1.0-2.0) and 1.5 (0.9-2.6) for HHV-2 seropositivity. The highest OR for ICC was observed for HPV16 E6 seropositivity (OR=10.2 (3.3-31.1)). Increasing number of sexually transmitted infections (STIs) was associated with increasing risk. Non-STIs were not associated with CC risk. In conclusion, this large prospective study confirms the important role of HPV and a possible contribution of CT and HHV-2 in cervical carcinogenesis. It further identifies HPV16 E6 seropositivity as the strongest marker to predict ICC well before disease development.

  • 177.
    Cederquist, Kristina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Göransson, Ingela
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Holinski-Feder, Elke
    Müller-Koch, Yvonne
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden2004In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 109, no 3, p. 370-376Article in journal (Refereed)
    Abstract [en]

    Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population-based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. Fourteen of the 23 patients (61%) had sequence variants in MLH1, MSH2 or MSH6 that likely affect the protein function. A majority (10/14) of the mutations was found among probands diagnosed before age 50. Five of the mutations (36%) were located in MLH1, 3 (21%) in MSH2 and 6 (43%) in MSH6. MSH6 seem to have larger impact in our population than in other populations, due to a founder effect since all of the MSH6 families originate from the same geographical area. MSH6 mutation carriers have later age of onset of both colorectal cancer (62 vs. 51 years) and endometrial cancer (58 vs. 48 years) and a larger proportion of endometrial cancer than MLH1 or MSH2 mutation carriers. We can conclude that patients with microsatellite unstable double primary cancers of the colorectum and the endometrium have a very high risk of carrying a mutation not only in MLH1 or MSH2 but also in MSH6, especially if they get their first cancer diagnosis before the age of 50. Copyright 2004 Wiley-Liss, Inc.

  • 178.
    Cederquist, Kristina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.2005In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 68, no 6, p. 533-541Article in journal (Refereed)
    Abstract [en]

    Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.

  • 179.
    Cederquist, Kristina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    A population based cohort study of patients with multiple colon and endometrial cancer: correlation of microsatellite instability (MSI) staus, age at diagnosis and cancer risk2001In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 91, no 4, p. 486-491Article in journal (Refereed)
    Abstract [en]

    Hereditary non-polyposis colorectal cancer, HNPCC, is an autosomal dominant condition predisposing to cancers of primarily the colorectum and the endometrium. The aim of our study was to identify persons at a high risk of hereditary colorectal cancer and to estimate their risk of colon and other HNPCC-associated tumours. Family histories of cancer were obtained on 89 persons with double primary (DP) cancers of the colon and the endometrium. The cancer risks in their 649 first-degree-relatives (FDR) were analysed. The microsatellite instability (MSI) status of the tumour of the proband was also analysed and the cancer risks were estimated in relation to MSI status and age at diagnosis in the proband (over or under 50 years). The overall standardised incidence ratio (SIR) was 1.69 (95% CI; 1.39-2.03). In the =50-year-old cohort the SIR was 2.67 (95% CI; 2.08-3.38). Colon, rectal and uterus cancer exhibited significantly increased risks. This risk was further increased in the =50-year-old MSI positive families. Several =50-year-old MSI negative HNPCC-like families with increased risks were also identified. In conclusion a FDR to a person with a DP cancer of the colorectum or the colon/endometrium have a significantly increased risk of having a colorectal or other HNPCC-associated cancers if the proband is diagnosed with one of the cancers before age 50. These families are candidates for genetic counselling and colorectal screening programmes. Mutations in mismatch repair genes can explain some of the increased risk in these families, but mutations in MSI negative families are probably due to other colon cancer susceptibility genes not yet described. Copyright 2001 Wiley-Liss, Inc.

  • 180. Cesaro, Simone
    et al.
    Marsh, Judith
    Tridello, Gloria
    Rovò, Alicia
    Maury, Sebastien
    Montante, Barbara
    Masszi, Tamás
    Van Lint, Maria Teresa
    Afanasyev, Boris
    Iriondo Atienza, Arturo
    Bierings, Marc
    Carbone, Cecilia
    Doubek, Michael
    Lanino, Edoardo
    Sarhan, Mahmoud
    Risitano, Antonio
    Steinerova, Katerina
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pegoraro, Anna
    Passweg, Jakob
    Retrospective survey on the prevalence and outcome of prior autoimmune diseases in patients with aplastic anemia reported to the registry of the European group for blood and marrow transplantation.2010In: Acta Haematologica, ISSN 0001-5792, E-ISSN 1421-9662, Vol. 124, no 1, p. 19-22Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aplastic anemia (AA) is rarely described after a diagnosis of autoimmune disease (aID). AIMS: To assess the prevalence of prior aID in patients with AA recorded in the registry of the European Group for Blood and Marrow Transplantation (EBMT) and to evaluate treatment and outcome. METHODS: 1,251 AA patients from 18 EBMT centers were assessed. RESULTS: Fifty patients (4%) were eligible: 22 males and 28 females with a median age of 46 years at the diagnosis of aID and of 51 years at the diagnosis of AA. Information on the treatment of AA was available in 49 patients: 38 received only immunosuppressive therapy (IST), 8 patients underwent hematopoietic stem cell transplantation (HSCT) - 6 as first-line therapy and 2 after failure of IST - whilst 3 patients had a spontaneous recovery. After a median follow-up of 3.19 years, 32 patients were alive, including 7 of the 8 patients who underwent HSCT. Only 6 of 32 patients who were alive at the last follow-up were receiving IST for AA. CONCLUSIONS: Most cases of AA following aID benefitted from IST or HSCT if a matched donor was available. Further prospective investigation is needed to assess the effects of IST on the outcome of underlying aID.

  • 181. Chadda, S.
    et al.
    Larkin, M.
    Jones, C.
    Sykes, D.
    Barber, B.
    Zhao, Z.
    Gao, S.
    Bengtsson, Nils-Olof
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    The impact of infusion reactions associated with monoclonal antibodies in metastatic colorectal cancer: a european perspective2011In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 14, no 3, p. A173-A173Article in journal (Refereed)
  • 182. Chang, Bao-Li
    et al.
    Lange, Ethan M
    Dimitrov, Latchezar
    Valis, Christopher J
    Gillanders, Elizabeth M
    Lange, Leslie A
    Wiley, Kathleen E
    Isaacs, Sarah D
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Baffoe-Bonnie, Agnes
    Langefeld, Carl D
    Zheng, S Lilly
    Matikainen, Mika P
    Ikonen, Tarja
    Fredriksson, Henna
    Tammela, Teuvo
    Walsh, Patrick C
    Bailey-Wilson, Joan E
    Schleutker, Johanna
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Cooney, Kathleen A
    Isaacs, William B
    Suh, Edward
    Trent, Jeffrey M
    Xu, Jianfeng
    Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect2006In: Hum Genet, ISSN 0340-6717, Vol. 118, no 6, p. 716-724Article in journal (Refereed)
  • 183. Chang, Ellen T
    et al.
    Hedelin, Maria
    Adami, Hans-Olov
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    A Bälter, Katarina
    Re: Zinc supplement use and risk of prostate cancer2004In: J Natl Cancer Inst, ISSN 1460-2105, Vol. 96, no 14, p. 1108; author reply 1108-9Article in journal (Refereed)
  • 184. Chen, Dan
    et al.
    Hammer, Joanna
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gyllensten, Ulf
    A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population2014In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 1, p. 190-198Article in journal (Refereed)
    Abstract [en]

    In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide-related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case–control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65–0.82; P = 1.6 × 10−7), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19–1.49; P = 5.8 × 10−7), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68–0.94; P = 6.7 × 10−3) and MICA-A5 (OR = 0.60, 95% CI = 0.50–0.72; P = 3.0 × 10−8) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer.

  • 185. Chen, Tianhui
    et al.
    Lukanova, Annekatrin
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schock, Helena
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    IGF-I during primiparous pregnancy and maternal risk of breast cancer2010In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 121, no 1, p. 169-175Article in journal (Refereed)
    Abstract [en]

    Previously, we reported that insulin-like growth factor (IGF)-I during early pregnancy is positively associated with maternal risk of breast cancer. To further explore this association, we designed a new study limited to women who donated a blood sample during their first pregnancy ending with childbirth. A case-control study was nested within the Northern Sweden Maternity Cohort in which repository since 1975, serum specimens remaining after early pregnancy screening for infectious diseases had been preserved. Study subjects were selected among women who donated a blood sample during the full-term pregnancy that led to the birth of their first child. Two hundred and forty-four women with invasive breast cancer were eligible. Two controls, matching the index case for age and date at blood donation were selected (n = 453). IGF-I was measured in serum samples on an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. A significant positive association of breast cancer with IGF-I was observed, with OR of 1.73 (95% CI: 1.14-2.63) for the top tertile, P < 0.009. Subgroup analyses did not indicate statistical heterogeneity of the association by ages at sampling and diagnosis or by lag time to cancer diagnosis, although somewhat stronger associations with risk were observed in women < or = age 25 at index pregnancy and for cases diagnosed within 15 years of blood donation. The results of the study add further evidence for an adverse effect of elevated IGF-I concentrations during early reproductive life on risk of breast cancer.

  • 186. Chen, Tianhui
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Afanasyeva, Yelena
    Schock, Helena
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Toniolo, Paolo
    Lukanova, Annekatrin
    Maternal hormones during early pregnancy: a cross-sectional study2010In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 5, p. 719-727Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II. METHODS: About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models. RESULTS: In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed. CONCLUSIONS: Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations.

  • 187. Chien, Ming-Hsien
    et al.
    Ku, Chia-Chi
    Johansson, Gunnar
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Chen, Min-Wei
    Hsiao, Michael
    Su, Jen-Liang
    Inoue, Hiroyasu
    Hua, Kuo-Tai
    Wei, Lin-Hung
    Kuo, Min-Liang
    Vascular endothelial growth factor-C (VEGF-C) promotes angiogenesis by induction of COX-2 in leukemic cells via the VEGF-R3/JNK/AP-1 pathway.2009In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 30, no 12, p. 2005-13Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF)-C is recognized as a tumor lymphangiogenic factor based on the effects of activated VEGF-R3 on lymphatic endothelial cells. Many tumor cells express VEGF-R3 but the function of this receptor in tumor cells is largely unknown. It has been reported that the VEGF-C/VEGF-R3 axis is activated in subsets of leukemia patients. Herein, we have shown that VEGF-C induces angiogenic activity in the tube formation assay invitro and Matrigel plug assay in vivo by upregulating an angiogenic factor, cyclooxygenase-2 (COX-2), through VEGF-R3 in the human acute myeloid leukemia (AML) cell line, THP-1. COX-2 induction by VEGF-C was also observed in other VEGF-R3(+) human AML cell lines (U937 and HL60). Moreover, immunohistochemical analysis of bone marrow specimens of 37 patients diagnosed with AML revealed that VEGF-C expression in specimens was associated with the expression of COX-2 (P < 0.001). The manner by which signaling pathways transduced by VEGF-C is responsible for COX-2 upregulation was further investigated. Blocking the p42/44 mitogen-activated protein kinase (MAPK) pathway with the MAPK kinase inhibitor, PD 98059, failed to inhibit VEGF-C-mediated COX-2 expression. However, VEGF-C-induced COX-2 upregulation was effectively abolished by overexpression of dominant-negative c-Jun N-terminal kinase (JNK) or treatment with the JNK inhibitor, SP 600125. VEGF-C induced JNK-dependent nuclear translocation of c-Jun. Furthermore, chromatin immunoprecipitation and reporter assays revealed that VEGF-C enhanced c-Jun binding to the cyclic adenosine 3',5'-monophosphate-response element of the COX-2 promoter and induced COX-2 expression. In sum, the data herein highlight the pathogenic role of VEGF-C in leukemia via regulation of angiogenesis through upregulation of COX-2.

  • 188. Chinot, O.
    et al.
    Cloughesy, T.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Saran, F.
    Mason, W.
    Nishikawa, R.
    Hilton, M.
    Abrey, L.
    Wick, W.
    Efficacy and safety of bevacizumab (By) plus standard combination temozolomide (T) and radiotherapy (RT) in newly diagnosed glioblastoma: final results from AVAglio2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no Supplement 2, p. S774-S775, Meeting Abstract: 3301AArticle in journal (Other academic)
  • 189. Chinot, Olivier
    et al.
    Garcia, Josep
    Romain, Sylvie
    Revil, Cedric
    Cloughesy, Timothy
    Mason, Warren
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm, Sweden.
    Saran, Frank
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana M.
    Brandes, Alba A.
    Kerloeguen, Yannick
    Mancao, Christoph
    Ouafik, L'Houcine
    Abrey, Lauren
    Wick, Wolfgang
    Tabouret, Emeline
    BASELINE PLASMA MATRIX METALLOPROTEINASE 9 (MMP9) PREDICTS OVERALL SURVIVAL (OS) BENEFIT FROM BEVACIZUMAB INDEPENDENTLY OF MOLECULAR SUBTYPES IN NEWLY DIAGNOSED GLIOBLASTOMA: RETROSPECTIVE ANALYSIS OF AVAglio2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 5-5Article in journal (Refereed)
  • 190. Chinot, Olivier L.
    et al.
    Nishikawa, Ryo
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm Gotland, Stockholm, Sweden.
    Saran, Frank
    Cloughesy, Timothy
    Garcia, Josep
    Revil, Cedric
    Abrey, Lauren
    Wick, Wolfgang
    Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, no 9, p. 1313-1318Article in journal (Refereed)
    Abstract [en]

    Background: In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy. Methods: Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan-Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated. Results: Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P =.0016) and median OS (HR: 0.67, P =.0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P<.0001); OS was comparable between the treatment arms (HR: 0.88, P =.1502). No significant differences in safety were observed between the 2 groups. Conclusion: This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.

  • 191. Chinot, Olivier L.
    et al.
    Taphoorn, Martin J. B.
    Bais, Carlos
    Bourgon, Richard
    Phillips, Heidi S.
    Abrey, Lauren E.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm.
    Saran, Frank
    Nishikawa, Ryo
    Cloughesy, Timothy
    Identification of Patients Who Benefit From Bevacizumab in High-Grade Glioma-An Easy Question Turned Difficult: Treat the Scan or the Patient? Reply2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 11, p. 1282-1283Article in journal (Other academic)
  • 192. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Abrey, Lauren
    Cloughesy, Timothy
    Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 8, p. 709-722Article in journal (Refereed)
    Abstract [en]

    BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. 

  • 193. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Reg Canc Ctr Stockholm,.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Kerloeguen, Yannick
    Guijarro, Abajo
    Cloughsey, Timothy
    FINAL EFFICACY AND SAFETY RESULTS FROM AVAglio, A PHASE III TRIAL OF BEVACIZUMAB (BEV) PLUS TEMOZOLOMIDE (TMZ) ANDRADIOTHERAPY (RT) IN NEWLY DIAGNOSED GLIOBLASTOMA2013In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, no Supplement: 3, p. 105-106Article in journal (Other academic)
  • 194. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    van den Bent, Martin J.
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center, Karolinska University Hospital, Stockholm, Sweden.
    Saran, Frank
    Nishikawa, Ryo
    Revil, Cedric
    Kerloeguen, Yannick
    Cloughesy, Timothy
    Re-analysis of PFS/response using original Macdonald criteria and response evaluation criteria in solid tumors in the phase III AVAglio study of bevacizumab plus radiotherapy and temozolomide in newly diagnosed glioblastoma2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no suppl 5Article in journal (Other academic)
  • 195. Christensen, G Bryce
    et al.
    Baffoe-Bonnie, Agnes B
    George, Asha
    Powell, Isaac
    Bailey-Wilson, Joan E
    Carpten, John D
    Giles, Graham G
    Hopper, John L
    Severi, Gianluca
    English, Dallas R
    Foulkes, William D
    Maehle, Lovise
    Moller, Pal
    Eeles, Ros
    Easton, Douglas
    Badzioch, Michael D
    Whittemore, Alice S
    Oakley-Girvan, Ingrid
    Hsieh, Chih-Lin
    Dimitrov, Latchezar
    Xu, Jianfeng
    Stanford, Janet L
    Johanneson, Bo
    Deutsch, Kerry
    McIntosh, Laura
    Ostrander, Elaine A
    Wiley, Kathleen E
    Isaacs, Sarah D
    Walsh, Patrick C
    Isaacs, William B
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Hebbring, Scott
    Schaid, Daniel J
    Lange, Ethan M
    Cooney, Kathleen A
    Tammela, Teuvo L J
    Schleutker, Johanna
    Paiss, Thomas
    Maier, Christiane
    Grönberg, Henrik
    Wiklund, Fredrik
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Farnham, James M
    Cannon-Albright, Lisa A
    Camp, Nicola J
    Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, p. 735-744Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS: We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS: Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS: Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate (c) 2010 Wiley-Liss, Inc.

  • 196. Chuang, Shu-Chun
    et al.
    Boeing, Heiner
    Vollset, Stein Emil
    Midttun, Oivind
    Ueland, Per Magne
    Bueno-de-Mesquita, Bas
    Lajous, Martin
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Kuehn, Tilman
    Pischon, Tobias
    Drogan, Dagmar
    Tjonneland, Anne
    Overvad, Kim
    Quiros, J. Ramon
    Agudo, Antonio
    Molina-Montes, Esther
    Dorronsoro, Miren
    Maria Huerta, Jose
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Travis, Ruth C.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Masala, Giovanna
    Agnoli, Claudia
    Tumino, Rosario
    Mattiello, Amalia
    Peeters, Petra H.
    Weiderpass, Elisabete
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gunter, Marc
    Lu, Yunxia
    Cross, Amanda J.
    Riboli, Elio
    Vineis, Paolo
    Aleksandrova, Krasimira
    Cellular immune activity biomarker neopterin is associated hyperlipidemia: results from a large population-based study2016In: Immunity & Ageing, ISSN 1742-4933, E-ISSN 1742-4933, Vol. 13, article id 5Article in journal (Refereed)
    Abstract [en]

    Background: Increased serum neopterin had been described in older age two decades ago. Neopterin is a biomarker of systemic adaptive immune activation that could be potentially implicated in metabolic syndrome (MetS). Measurements of waist circumference, triglycerides, high-density lipoprotein cholesterol (HDLC), systolic and diastolic blood pressure, glycated hemoglobin as components of MetS definition, and plasma total neopterin concentrations were performed in 594 participants recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC).

    Results: Higher total neopterin concentrations were associated with reduced HDLC (9.7 %, p < 0.01 for men and 9.2 %, p < 0.01 for women), whereas no association was observed with the rest of the MetS components as well as with MetS overall (per 10 nmol/L: OR = 1.42, 95 % CI = 0.85-2.39 for men and OR = 1.38, 95 % CI = 0.79-2.43).

    Conclusions: These data suggest that high total neopterin concentrations are cross-sectionally associated with reduced HDLC, but not with overall MetS.

  • 197. Chuang, Shu-Chun
    et al.
    Fanidi, Anouar
    Ueland, Per Magne
    Relton, Caroline
    Midttun, Oivind
    Vollset, Stein Emil
    Gunter, Marc J.
    Seckl, Michael J.
    Travis, Ruth C.
    Wareham, Nicholas
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H. M.
    Bueno-de-Mesquita, H. Bas
    Boeing, Heiner
    Wientzek, Angelika
    Kuehn, Tilman
    Kaaks, Rudolf
    Tumino, Rosario
    Agnoli, Claudia
    Palli, Domenico
    Naccarati, Alessio
    Ardanaz Aicua, Eva
    Sanchez, Maria-Jose
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Agudo, Antonio
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Weiderpass, Elisabete
    Riboli, Elio
    Brennan, Paul J.
    Vineis, Paolo
    Johansson, Mattias
    Circulating Biomarkers of Tryptophan and the Kynurenine Pathway and Lung Cancer Risk2014In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 23, no 3, p. 461-468Article in journal (Refereed)
    Abstract [en]

    Background: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer. Methods: We conducted a nested case-control study within the European Prospective Investigation into Cancer andNutrition (EPIC) that included 893 incident lung cancer cases and 1,748matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk. Results: Tryptophan (P-trend = 2 Chi 10(-5)) and the kynurenine/ tryptophan ratio (KTR; P-trend 4 Chi 10(-5)) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th (vs. 1st)) were 0.52 [ 95% confidence interval (CI), 0.37-0.74] for tryptophan and 1.74 (95% CI, 1.24-2.45) for KTR. After adjusting for plasma methionine (available fromprevious work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted P-trend 0.13) and KTR (P-trend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62-4.94, P-trend -3 Chi 10(-5)) that was only marginally affected by adjusting for methionine. Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology. Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk.

  • 198. Claassen, Y. H. M.
    et al.
    Bastiaannet, E.
    van Eycken, E.
    Van Damme, N.
    Martling, A.
    Johansson, R.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Iversen, L. H.
    Ingeholm, P.
    Lemmens, V. E. P. P.
    Liefers, G. J.
    Holman, F. A.
    Dekker, J. W. T.
    Portielje, J. E. A.
    Rutten, H. J.
    van de Velde, C. J. H.
    Time trends of short-term mortality for octogenarians undergoing a colorectal resection in North Europe2019In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 45, no 8, p. 1396-1402Article in journal (Refereed)
    Abstract [en]

    Background: Decreased cancer specific survival in older colorectal patients is mainly due to mortality in the first year, emphasizing the importance of the first postoperative year. This study aims to gain an overview and time trends of short-term mortality in octogenarians (>= 80 years) with colorectal cancer across four North European countries. Methods: Patients of 80 years or older, operated for colorectal cancer (stage I-Ill) between 2005 and 2014, were included. Population-based cohorts from Belgium, Denmark, the Netherlands, and Sweden were collected. Separately for colon- and rectal cancer, 30-day, 90-day, one-year, and excess one-year mortality were calculated. Also, short-term mortality over three time periods (2005-2008, 2009-2011, 2012-2014) was analyzed. Results: In total, 35,158 colon cancer patients and 10,144 rectal cancer patients were included. For colon cancer, 90-day mortality rate was highest in Denmark (15%) and lowest in Sweden (8%). For rectal cancer, 90-day mortality rate was highest in Belgium (11%) and lowest in Sweden (7%). One-year excess mortality rate of colon cancer patients decreased from 2005 to 2008 to 2012-2014 for all countries (Belgium: 17%-11%, Denmark: 21%-15%, the Netherlands: 18%-10%, and Sweden: 10%-8%). For rectal cancer, from 2005 to 2008 to 2012-2014 one-year excess mortality rate decreased in the Netherlands from 16% to 7% and Sweden: 8%-2%). Conclusions: Short-term mortality rates were high in octogenarians operated for colorectal cancer. Short-term mortality rates differ across four North European countries, but decreased over time for both colon and rectal cancer patients in all countries.

  • 199. Claassen, Yvette H. M.
    et al.
    Vermeer, Nina C. A.
    Iversen, Lene H.
    van Eycken, Elizabeth
    Guren, Marianne G.
    Mroczkowski, Pawel
    Martling, Anna
    Codina Cazador, Antonio
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vandendael, Tamara
    Wibe, Arne
    Møller, Bjørn
    Lippert, Hans
    Rutten, Harm J. T.
    Portielje, Johanneke E. A.
    Liefers, Gerrit J.
    Holman, Fabian A.
    van de Velde, Cornelis J. H.
    Bastiaannet, Esther
    Treatment and survival of rectal cancer patients over the age of 80 years: a EURECCA international comparison2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 119, no 4, p. 517-522Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The optimal treatment strategy for older rectal cancer patients remains unclear. The current study aimed to compare treatment and survival of rectal cancer patients aged 80+.

    METHODS: Patients of >= 80 years diagnosed with rectal cancer between 2001 and 2010 were included. Population-based cohorts from Belgium (BE), Denmark (DK), the Netherlands (NL), Norway (NO) and Sweden (SE) were compared side by side for neighbouring countries on treatment strategy and 5-year relative survival (RS), adjusted for sex and age. Analyses were performed separately for stage I-III patients and stage IV patients.

    RESULTS: Overall, 19 634 rectal cancer patients were included. For stage I-III patients, 5-year RS varied from 61.7% in BE to 72.3% in SE. Proportion of preoperative radiotherapy ranged between 7.9% in NO and 28.9% in SE. For stage IV patients, 5-year RS differed from 2.8% in NL to 5.6% in BE. Rate of patients undergoing surgery varied from 22.2% in DK to 40.8% in NO.

    CONCLUSIONS: Substantial variation was observed in the 5-year relative survival between European countries for rectal cancer patients aged 80+, next to a wide variation in treatment, especially in the use of preoperative radiotherapy in stage I-III patients and in the rate of patients undergoing surgery in stage IV patients.

  • 200. Clendenen, Tess
    et al.
    Zeleniuch-Jacquotte, Anne
    Wirgin, Isaac
    Koenig, Karen L
    Afanasyeva, Yelena
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Arslan, Alan A
    Axelsson, Tomas
    Försti, Asta
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roy, Nirmal
    Shore, Roy E
    Chen, Yu
    Genetic variants in hormone-related genes and risk of breast cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e69367-Article in journal (Refereed)
    Abstract [en]

    Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

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