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  • 1. Aguilo, Francesca
    et al.
    Zhou, Ming-Ming
    Walsh, Martin J
    Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression.2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 16Article in journal (Refereed)
    Abstract [en]

    Polycomb group proteins (PcG) function as transcriptional repressors of gene expression. The important role of PcG in mediating repression of the INK4b-ARF-INK4a locus, by directly binding to the long noncoding RNA (lncRNA) transcript antisense noncoding RNA in the INK4 locus (ANRIL), was recently shown. INK4b-ARF-INK4a encodes 3 tumor-suppressor proteins, p15(INK4b), p14(ARF), and p16(INK4a), and its transcription is a key requirement for replicative or oncogene-induced senescence and constitutes an important barrier for tumor growth. ANRIL gene is transcribed in the antisense orientation of the INK4b-ARF-INK4a gene cluster, and different single-nucleotide polymorphisms are associated with increased susceptibility to several diseases. Although lncRNA-mediated regulation of INK4b-ARF-INK4a gene is not restricted to ANRIL, both polycomb repressive complex-1 (PRC1) and -2 (PRC2) interact with ANRIL to form heterochromatin surrounding the INK4b-ARF-INK4a locus, leading to its repression. This mechanism would provide an increased advantage for bypassing senescence, sustaining the requirements for the proliferation of stem and/or progenitor cell populations or inappropriately leading to oncogenesis through the aberrant saturation of the INK4b-ARF-INK4a locus by PcG complexes. In this review, we summarize recent findings on the underlying epigenetic mechanisms that link PcG function with ANRIL, which impose gene silencing to control cellular homeostasis as well as cancer development.

  • 2. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bueno-de-Mesquita, H. Bas
    Jansen, Eugene
    van Duijnhoven, Franzel J. B.
    Rinaldi, Sabina
    Fedirko, Veronika
    Romieu, Isabelle
    Riboli, Elio
    Gunter, Marc J.
    Westphal, Sabine
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Mattiello, Amalia
    Pala, Valeria
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Buckland, Genevieve
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Menendez, Virginia
    Peeters, Petra H.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Allen, Naomi E.
    Crowe, Francesca L.
    Khaw, Kay-Tee
    Wareham, Nickolas
    Pischon, Tobias
    Leptin and soluble leptin receptor in risk of colorectal cancer in the European prospective investigation into Cancer and nutrition cohort2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72, no 20, p. 5328-5337Article in journal (Refereed)
    Abstract [en]

    Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P-trend = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P-trend = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P-trend = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P-trend = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis. Cancer Res; 72(20); 5328-37. (C) 2012 AACR.

  • 3. Anantharaman, Devasena
    et al.
    Gheit, Tarik
    Waterboer, Tim
    Halec, Gordana
    Carreira, Christine
    Abedi-Ardekani, Behnoush
    McKay-Chopin, Sandrine
    Zaridze, David
    Mukeria, Anush
    Szeszenia-Dabrowska, Neonila
    Lissowska, Jolanta
    Mates, Dana
    Janout, Vladimir
    Foretova, Lenka
    Bencko, Vladimir
    Rudnai, Peter
    Fabianova, Eleonora
    Tjonneland, Anne
    Travis, Ruth C
    Boeing, Heiner
    Quiros, J Ramon
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krogh, Vittorio
    Bueno-de-Mesquita, H Bas
    Kotanidou, Anastasia
    Clavel-Chapelon, Francoise
    Weiderpass, Elisabete
    Johansson, Mattias
    Pawlita, Michael
    Scelo, Ghislaine
    Tommasino, Massimo
    Brennan, Paul
    No causal association identified for human papillomavirus infections in lung cancer2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3525-3534Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer. (C) 2014 AACR.

  • 4. Antoniou, Antonis C
    et al.
    Beesley, Jonathan
    McGuffog, Lesley
    Sinilnikova, Olga M
    Healey, Sue
    Neuhausen, Susan L
    Ding, Yuan Chun
    Rebbeck, Timothy R
    Weitzel, Jeffrey N
    Lynch, Henry T
    Isaacs, Claudine
    Ganz, Patricia A
    Tomlinson, Gail
    Olopade, Olufunmilayo I
    Couch, Fergus J
    Wang, Xianshu
    Lindor, Noralane M
    Pankratz, Vernon S
    Radice, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Barile, Monica
    Viel, Alessandra
    Allavena, Anna
    Dall'Olio, Valentina
    Peterlongo, Paolo
    Szabo, Csilla I
    Zikan, Michal
    Claes, Kathleen
    Poppe, Bruce
    Foretova, Lenka
    Mai, Phuong L
    Greene, Mark H
    Rennert, Gad
    Lejbkowicz, Flavio
    Glendon, Gord
    Ozcelik, Hilmi
    Andrulis, Irene L
    Thomassen, Mads
    Gerdes, Anne-Marie
    Sunde, Lone
    Cruger, Dorthe
    Birk Jensen, Uffe
    Caligo, Maria
    Friedman, Eitan
    Kaufman, Bella
    Laitman, Yael
    Milgrom, Roni
    Dubrovsky, Maya
    Cohen, Shimrit
    Borg, Åke
    Jernström, Helena
    Lindblom, Annika
    Rantala, Johanna
    Stenmark-Askmalm, Marie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nathanson, Kate
    Domchek, Susan
    Jakubowska, Ania
    Lubinski, Jan
    Huzarski, Tomasz
    Osorio, Ana
    Lasa, Adriana
    Durán, Mercedes
    Tejada, Maria-Isabel
    Godino, Javier
    Benitez, Javier
    Hamann, Ute
    Kriege, Mieke
    Hoogerbrugge, Nicoline
    van der Luijt, Rob B
    van Asperen, Christi J
    Devilee, Peter
    Meijers-Heijboer, EJ
    Blok, Marinus J
    Aalfs, Cora M
    Hogervorst, Frans
    Rookus, Matti
    Cook, Margaret
    Oliver, Clare
    Frost, Debra
    Conroy, Don
    Evans, D Gareth
    Lalloo, Fiona
    Pichert, Gabriella
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Hodgson, Shirley
    Morrison, Patrick J
    Porteous, Mary E
    Walker, Lisa
    Kennedy, M John
    Dorkins, Huw
    Peock, Susan
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    de Pauw, Antoine
    Mazoyer, Sylvie
    Bonadona, Valérie
    Lasset, Christine
    Dreyfus, Hélène
    Leroux, Dominique
    Hardouin, Agnès
    Berthet, Pascaline
    Faivre, Laurence
    Loustalot, Catherine
    Noguchi, Tetsuro
    Sobol, Hagay
    Rouleau, Etienne
    Nogues, Catherine
    Frénay, Marc
    Vénat-Bouvet, Laurence
    Hopper, John L
    Daly, Mary B
    Terry, Mary B
    John, Esther M
    Buys, Saundra S
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F
    Dressler, Anne Catharina
    Gschwantler-Kaulich, Daphne
    Pfeiler, Georg
    Hansen, Thomas VO
    Jønson, Lars
    Agnarsson, Bjarni A
    Kirchhoff, Tomas
    Offit, Kenneth
    Devlin, Vincent
    Dutra-Clarke, Ana
    Piedmonte, Marion
    Rodriguez, Gustavo C
    Wakeley, Katie
    Boggess, John F
    Basil, Jack
    Schwartz, Peter E
    Blank, Stephanie V
    Toland, Amanda Ewart
    Montagna, Marco
    Casella, Cinzia
    Imyanitov, Evgeny
    Tihomirova, Laima
    Blanco, Ignacio
    Lazaro, Conxi
    Ramus, Susan J
    Sucheston, Lara
    Karlan, Beth Y
    Gross, Jenny
    Schmutzler, Rita
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Lochmann, Magdalena
    Arnold, Norbert
    Heidemann, Simone
    Varon-Mateeva, Raymonda
    Niederacher, Dieter
    Sutter, Christian
    Deissler, Helmut
    Gadzicki, Dorothea
    Preisler-Adams, Sabine
    Kast, Karin
    Schönbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Aittomäki, Kristiina
    Nevanlinna, Heli
    Simard, Jacques
    Spurdle, Amanda B
    Holland, Helene
    Chen, Xiaoqing
    Platte, Radka
    Chenevix-Trench, Georgia
    Easton, Douglas F
    Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  • 5. Arroyo, Vidal M.
    et al.
    Lupo, Philip J.
    Melin, Beatrice S.
    Umeå University.
    Styring, Emelie
    Zaikova, Olga
    Papworth, Karin
    Umeå University.
    Soft tissue sarcoma clinical presentation, treatment, and survival in adolescents and young adults compared to older adults: A report from the Scandinavian Sarcoma Group2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13Article in journal (Other academic)
    Abstract [en]

    Background: Five-year survival rates for those diagnosed with soft tissue sarcoma (STS) have improved significantly among children and older adults (OAs), but these same trends have not been observed for adolescents and young adults (AYAs). While these disparities could be due to differences in biology or treatment, few studies have evaluated STS occurrence and outcome in AYAs. Therefore, the purpose of this study was to evaluate differences between adolescents and young adults (AYAs) and older adults (OAs) diagnosed with STS by stratifying analysis by: (1) clinical presentation; (2) treatment; and (3) survival.

    Methods: Data were obtained from the Scandinavian Sarcoma Group (SSG) Central Register, which includes information on 5,747 patients from Sweden and Norway, diagnosed with a STS during 1986-2011. Variables included: age at diagnosis, metastasis at diagnosis, tumor size, histology, adjuvant treatment, date of death or last follow-up. AYAs were defined as those diagnosed ages 15-39 years. Categorical variables were analyzed using chi-square tests, and continuous variables were analyzed using t-tests. Overall survival (OS) and recurrence-free survival (RFS) were compared between AYAs and OAs using Kaplan-Meier estimates and log-rank tests. All analyses were conducted overall and by common STS subtypes.

    Results: Overall and by STS subtype, there were significant differences between AYAs and OAs on presentation, treatment, and survival. The distribution of STS subtypes was different between OAs and AYAs. For example, OAs were more likely to be diagnosed with leiomyosarcoma compared to AYAs (18% vs. 10%, p<0.001), whereas AYAs were more likely to be diagnosed with malignant peripheral nerve sheath tumor (MPNST, 9% vs. 4%, p<0.001). OAs were also more likely to have larger tumors (>5 cm, 67% vs. 52%, p<0.001) and higher malignancy grade (grade IV, 45% vs. 31%, p<0.001). Interestingly, AYAs were more likely to be treated with radiotherapy and chemotherapy compared to OAs (12% vs. 5%, p<0.001). There were also differences within STS subtypes. For example, OAs were more likely to have metastasis compared to AYAs if diagnosed with leiomyosarcoma (18% vs. 10%, p=0.04). In most scenarios AYAs had significantly better OS and RFS compared to OAs, other than for MPNST (OS: p=0.19, RFS: p=0.28).

    Conclusions: There were several differences between AYAs and OAs on STS presentation, treatment, and outcome. AYAs not only had differences in terms of STS subtypes but also tumor size and malignancy grade within subtypes. Additional work is needed to characterize the biology underlying these differences, which will inform future treatment strategies for both AYAs and OAs with STS.

  • 6. Atkins, Isabelle
    et al.
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Il'yasova, Dora
    Armstrong, Georgina N.
    Eckel-Passow, Jeanette E.
    Schoemaker, Minouk J.
    Nothen, Markus M.
    Barnholtz-Sloan, Jill S.
    Swerdlow, Anthony J.
    Simon, Matthias
    Rajaraman, Preetha
    Chanock, Stephen J.
    Shildkraut, Joellen
    Bernstein, Jonine L.
    Hoffman, Per
    Jockel, Karl-Heinz
    Lai, Rose K.
    Claus, Elizabeth B.
    Olson, Sara H.
    Johansen, Christoffer
    Wrensch, Margaret R.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Jenkins, Robert B.
    Sanson, Marc
    Bondy, Melissa L.
    Houlston, Richard S.
    Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 8, p. 2065-2071Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 x 10(-6), candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 x 10(-6)). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis.

    Significance: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.

  • 7. Baranov, Vladimir
    et al.
    Yeung, Moorix Mo-Wai
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Expression of carcinoembryonic antigen and nonspecific cross-reacting 50-kDa antigen in human normal and cancerous colon mucosa: comparative ultrastructural study with monoclonal antibodies1994In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 54, no 12, p. 3305-3314Article in journal (Refereed)
    Abstract [en]

    The precise localization of carcinoembryonic antigen (CEA) and non-specific cross-reacting 50-kDa antigen (NCA 50) in normal colon mucosa and colon adenocarcinoma was investigated by using an indirect immunoperoxidase electron microscopic technique with specific monoclonal antibodies. In normal adult colon both antigens were localized to microvesicles and filaments of the "fuzzy coat" on the apical surface of the epithelial cells. In addition, NCA 50 was found in the narrow spaces between adjoining microvilli. Mature columnar cells at the free luminal surface contained most of the antigen positive material. CEA and NCA 50 were also detected as intracellular components of goblet cells. In multilayered tumor glands, the cell surface expression of the antigens was dependent on the position of the tumor cell in the gland. The neoplastic cells showed either a predominant apical labeling or a positive staining of almost the entire cell surface. Some of the neoplastic cells contained CEA in so-called "intracellular lumina." In contrast to normal colon epithelial cells most tumor cells synthesized NCA 50 actively. In normal colonic mucosa, unlike in cancerous tissue, CEA and NCA 50 appear to be released via vesicles formed from the microvillous membrane of mature columnar cells. These results are consistent with the hypothesis that CEA and NCA play a role in the nonspecific defense against microorganisms in the large intestine.

  • 8. Barton, Maria
    et al.
    Santucci-Pereira, Julia
    de Cicco, Ricardo Lopez
    Russo, Irma H.
    Ross, Eric A.
    Slifker, Michael
    Peri, Suraj
    Bordas, Pal
    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. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Russo, Jose
    Long noncoding RNAs in the postmenopausal breast and their role in cancer prevention2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 9.
    Best, Myron
    et al.
    VU Medical Center, Amsterdam, Netherlands.
    Sol, Nik
    VU Medical Center, Amsterdam, Netherlands.
    Kooi, Irsan
    VU Medical Center, Amsterdam, Netherlands.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Westerman, Bart
    VU Medical Center, Amsterdam, Netherlands.
    Yistra, Bauke
    VU Medical Center, Amsterdam, Netherlands.
    Dorsman, Josephine
    VU Medical Center, Amsterdam, Netherlands.
    Smit, Egbert
    VU Medical Center, Amsterdam, Netherlands.
    Verheui, Henk
    VU Medical Center, Amsterdam, Netherlands.
    Reijneveld, Jaap
    VU Medical Center, Amsterdam, Netherlands.
    Tannous, Bakhos
    Massachusetts General Hospital, Boston, MA, USA.
    Wesseling, Pieter
    VU Medical Center, Amsterdam, Netherlands.
    Wurdinger, Thomas
    VU Medical Center, Amsterdam, Netherlands.
    Tumor-educated platelets allow for multiclass liquid biopsy-based diagnosis of cancer2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no Suppl. 15, article id LB-124Article in journal (Other academic)
  • 10.
    Bovinder Ylitalo, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 50-50Article in journal (Other academic)
  • 11. Bremer, T.
    et al.
    Savala, J.
    Leesman, G.
    Wärnberg, F.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wadsten, Charlotta
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Whitworth, P. W.
    A biologic signature to predict ipsilateral breast event risk at 10 years for early breast cancer2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 4Article in journal (Other academic)
  • 12. Bruzzese, Francesca
    et al.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Leone, Alessandra
    Sjöberg, Elin
    Roca, Maria Serena
    Kiflemariam, Sara
    Sjöblom, Tobias
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Östman, Arne
    Budillon, Alfredo
    Augsten, Martin
    Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF152014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed)
    Abstract [en]

    The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. (C)2014 AACR.

  • 13. Cha, Shih-Ting
    et al.
    Chen, Pai-Sheng
    Johansson, Gunnar
    1Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University.
    Chu, Chia-Yu
    Wang, Ming-Yang
    Jeng, Yung-Ming
    Yu, Sung-Liang
    Chen, Jin-Shing
    Chang, King-Jen
    Jee, Shiou-Hwa
    Tan, Ching-Ting
    Lin, Ming-Tsan
    Kuo, Min-Liang
    MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis.2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 7, p. 2675-2685Article in journal (Refereed)
    Abstract [en]

    Hypoxia-inducible factor-1alpha (HIF-1alpha) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1alpha, acting through direct binding to the HIF-1alpha 3' untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1alpha protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1alpha protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1alpha-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1alpha levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1alpha inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells.

  • 14. Chen, Min-Wei
    et al.
    Hua, Kuo-Tai
    Kao, Hsin-Jung
    Chi, Chia-Chun
    Wei, Lin-Hung
    Johansson, Gunnar
    Graduate Institute of Toxicology, National Taiwan University College of Medicine.
    Shiah, Shine-Gwo
    Chen, Pai-Sheng
    Jeng, Yung-Ming
    Cheng, Tsu-Yao
    Lai, Tsung-Ching
    Chang, Jeng-Shou
    Jan, Yi-Hua
    Chien, Ming-Hsien
    Yang, Chih-Jen
    Huang, Ming-Shyan
    Hsiao, Michael
    Kuo, Min-Liang
    H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 20, p. 7830-7840Article in journal (Refereed)
    Abstract [en]

    G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression.

  • 15. Di Cecilia, Serena
    et al.
    Zhang, Fan
    Sancho, Ana
    Li, SiDe
    Aguiló, Francesca
    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York.
    Sun, Yifei
    Rengasamy, Madhumitha
    Zhang, Weijia
    Del Vecchio, Luigi
    Salvatore, Francesco
    Walsh, Martin J.
    RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 19, p. 5615-5627Article in journal (Refereed)
    Abstract [en]

    Cancer-initiating cells (CIC) undergo asymmetric growth patterns that increase phenotypic diversity and drive selection for chemotherapeutic resistance and tumor relapse. WNT signaling is a hallmark of colon CIC, often caused by APC mutations, which enable activation of β-catenin and MYC Accumulating evidence indicates that long noncoding RNAs (lncRNA) contribute to the stem-like character of colon cancer cells. In this study, we report enrichment of the lncRNA RBM5-AS1/LUST during sphere formation of colon CIC. Its silencing impaired WNT signaling, whereas its overexpression enforced WNT signaling, cell growth, and survival in serum-free media. RBM5-AS1 has been little characterized previously, and we determined it to be a nuclear-retained transcript that selectively interacted with β-catenin. Mechanistic investigations showed that silencing or overexpression of RBM5-AS1 caused a respective loss or retention of β-catenin from TCF4 complexes bound to the WNT target genes SGK1, YAP1, and MYC Our work suggests that RBM5-AS1 activity is critical for the functional enablement of colon cancer stem-like cells. Furthermore, it defines the mechanism of action of RBM5-AS1 in the WNT pathway via physical interactions with β-catenin, helping organize transcriptional complexes that sustain colon CIC function. 

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

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

  • 17. Fortner, Renée T
    et al.
    Schock, Helena
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Surcel, Helja-Marja
    Early pregnancy sex steroids and maternal breast cancer: a nested case-control study2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 23, p. 6958-6967Article in journal (Refereed)
    Abstract [en]

    Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association.

  • 18. Fortner, Renée T
    et al.
    Schock, Helena
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Korpela, Jaana
    Toriola, Adetunji T
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zeleniuch-Jacquotte, Anne
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Surcel, Heljä-Marja
    Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 1, p. 134-141Article in journal (Refereed)
    Abstract [en]

    Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1, 1.10; 95% CI, 0.64-1.89; ≥15 years, ORQ4 vs. Q1, 1.36; 95% CI, 0.86-2.13; pheterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. 

  • 19.
    Frängsmyr, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Prall, F
    Yeung, Moorix Mo-Wai
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Wagener, C
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Cell- and region-specific expression of biliary glycoprotein and its messenger RNA in normal human colonic mucosa1995In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 55, no 14, p. 2963-2967Article in journal (Refereed)
    Abstract [en]

    The localization of biliary glycoprotein (BGP) and its mRNA in normal colonic mucosa was studied by immunohistochemistry and in situ hybridization. BGP mRNA was confined to columnar epithelial cells and expressed abundantly in the superficial mature cells and at low levels in differentiating cells in the upper crypts. Epithelial expression of BGP coincided with that of BGP mRNA. Ultrastructurally, BGP was localized to microfilaments of the fuzzy coat of the columnar cells at the luminal surface and the upper crypts. Additionally, BGP was found in cryptal caveolated cells. The results are consistent with primary transcriptional regulation of BGP production and suggest that BGP synthesis is controlled by the degree of cytodifferentiation. The fuzzy-coat localization of BGP implies a role in nonspecific defense mechanisms against pathogens.

  • 20. Fu, Yi-Ping
    et al.
    Kohaar, Indu
    Moore, Lee E.
    Lenz, Petra
    Figueroa, Jonine D.
    Tang, Wei
    Porter-Gill, Patricia
    Chatterjee, Nilanjan
    Scott-Johnson, Alexandra
    Garcia-Closas, Montserrat
    Muchmore, Brian
    Baris, Dalsu
    Paquin, Ashley
    Ylaya, Kris
    Schwenn, Molly
    Apolo, Andrea B.
    Karagas, Margaret R.
    Tarway, McAnthony
    Johnson, Alison
    Mumy, Adam
    Schned, Alan
    Guedez, Liliana
    Jones, Michael A.
    Kida, Masatoshi
    Hosain, G. M. Monawar
    Malats, Nuria
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Wu, Xifeng
    Purdue, Mark
    Andriole, Gerald L., Jr.
    Grubb, Robert L., III
    Black, Amanda
    Landi, Maria T.
    Caporaso, Neil E.
    Vineis, Paolo
    Siddiq, Afshan
    Bueno-de-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Severi, Gianluca
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth C.
    Tjonneland, Anne
    Brennan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Prescott, Jennifer
    Chen, Constance
    De Vivo, Immaculata
    Govannucci, Edward
    Hunter, David
    Kraft, Peter
    Lindstrom, Sara
    Gapstur, Susan M.
    Jacobs, Eric J.
    Diver, W. Ryan
    Albanes, Demetrius
    Weinstein, Stephanie J.
    Virtamo, Jarmo
    Kooperberg, Charles
    Hohensee, Chancellor
    Rodabough, Rebecca J.
    Cortessis, Victoria K.
    Conti, David V.
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van Den Berg, David
    Yuan, Jian-Min
    Haiman, Christopher A.
    Cussenot, Olivier
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Porru, Stefano
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Grossman, H. Barton
    Wang, Zhaoming
    Deng, Xiang
    Chung, Charles C.
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Fraumeni, Joseph, Jr.
    Chanock, Stephen J.
    Hewitt, Stephen M.
    Silverman, Debra T.
    Rothman, Nathaniel
    Prokunina-Olsson, Ludmila
    The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 20, p. 5808-5818Article in journal (Refereed)
    Abstract [en]

    A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P-trend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.

  • 21.
    Halin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Doll, Jennifer A
    Crawford, Susan E
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Decreased pigment epithelium-derived factor is associated with metastatic phenotype in human and rat prostate tumors.2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 16, p. 5664-71Article in journal (Refereed)
  • 22. Harrison, Tabitha A.
    et al.
    Lu, Yiwen
    Zeng, Chenjie
    Qu, Flora
    Anderson, Kristin
    Brenner, Hermann
    Buchanan, Daniel D.
    Campbell, Peter T.
    Chan, Andrew T.
    Chang-Claude, Jenny
    Giles, Graham G.
    van Guelpen, Bethany
    Umeå University.
    Hoffmeister, Michael
    Jenkins, Mark A.
    Lindor, Noralane M.
    Milne, Roger L.
    Newcomb, Polly A.
    Nishihara, Reiko
    Woods, Michael O.
    Ogino, Shuji
    Potter, John D.
    Slattery, Martha L.
    Sun, Wei
    Thibodeau, Stephen N.
    Hsu, Li
    Peters, Ulrike
    Genome-wide association study by colorectal carcinoma subtype2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13Article in journal (Other academic)
    Abstract [en]

    Over 50 genetic variants have been associated with colorectal cancer (CRC) risk through genome-wide association studies (GWAS), yet these variants represent only a fraction of the total estimated heritability. CRC is a heterogenous disease with diverse tumor etiology. Assessing genetic risk in molecular subtypes may help to identify novel loci and characterize genetic risk among tumor subtypes. We used microsatellite instability (MSI), an established CRC classifier with etiological and therapeutic relevance, to define CRC subtypes for GWAS analyses. We conducted a case-case analysis to estimate odds ratios (OR) and 95% confidence intervals (CI) for association of genome-wide variants with microsatellite stable (MSS) versus unstable (MSI) carcinomas. We ran an inverse-variance weighted fixed-effects meta-analysis across GWAS in a discovery set of 4,163 population-based CRC cases with harmonized microsatellite instability (MSI) marker and imputed genotype data. For each analysis, we used log-additive logistic regression, adjusting for age, sex, and principal components to account for population substructure. We then followed up with replication of 102 SNPs that reached p-values less than 5x10-6 in 1,698 cases. A total of 845 (20.3%) cancer cases were microsatellite unstable in the discovery population and 174 (10.2%) were unstable in the replication population. No variants reached the genome-wide significance level of 5x10-8 in the discovery set. However, we identified two variants that reached a Bonferroni corrected p-value of 4.0x10-4 in the replication set. This included one variant in MLH1 (Replication: OR=1.74, 95% CI=1.53-1.98, p=1.63x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76x10-11) and one variant in LOC105377645 (Replication: OR=1.70, 95% CI=1.49-1.94, p=5.13x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76 x 10-11). The MLH1 gene is a DNA mismatch repair gene implicated in Lynch Syndrome, the hallmark of which is microsatellite instability. This is the first genome-wide scan to identify a common variant in MLH1 that is associated with CRC. This variant (minor allele frequency, MAF = 23% in this all European ancestry population) is located in the 5'-untranslated region of MLH1 and is thought to act as a long-range regulator of DCLK3, a potential tumor driver gene. The second variant, located in LOC105377645 with an MAF of 22%, is in an uncharacterized region of the genome and has not previously been implicated in cancer development. These findings suggest that accounting for molecular heterogeneity is important for discovery and characterization of genetic variants associated with CRC risk. We plan to run polytomous regression analyses, increase our sample size, and further investigate CRC subtypes by CIMP, BRAF mutation, KRAS mutation status.

  • 23.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Still, Maria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ASNA-1 activity modulates sensitivity to cisplatin2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 24, p. 10321-10328Article in journal (Refereed)
    Abstract [en]

    Cancer can be cured by platinum based chemotherapy but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutations in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologs, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms and propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.

  • 24. Hersi, A-F
    et al.
    Obondo, C.
    Pistioli, L.
    Abdsaleh, S.
    Nilsson, Fredrik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Mohammed, I.
    Eriksson, S.
    Wärnberg, F.
    Karakatsanis, A.
    SentiDose interim analysis. A dose optimizing study with a super paramagnetic iron oxide for sentinel node detection2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 4Article in journal (Other academic)
  • 25. Iglesias-Gato, Diego
    et al.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Mann, Matthias
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Flores-Morales, Amilcar
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The proteome of prostate cancer bone metastases2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 91-92Article in journal (Other academic)
  • 26. Jacobs, Daniel I.
    et al.
    Fukumura, Kazutaka
    Bainbridge, Matthew N.
    Armstrong, Georgina N.
    Muzny, Donna M.
    Melin, Beatrice S.
    Umeå University.
    Huse, Jason T.
    Bondy, Melissa L.
    Elucidating the molecular pathogenesis of familial glioma2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13Article in journal (Other academic)
    Abstract [en]

    In recent years, the molecular characterization of sporadically arising diffuse gliomas has identified recurrent driving alterations and delineated molecularly and clinically distinct subclasses of disease. However, less is known about the molecular nature of gliomas that are familial in origin. To address this question, we integrated germline and somatic genomic data to characterize the molecular pathogenesis of 20 tumors arising in unrelated individuals with a family history of glioma collected through the Gliogene International Consortium. METHODS: FFPE tumor specimens were sectioned and reviewed to localize neoplastic tissue for DNA extraction. Library preparation, exome plus targeted capture, and paired-end sequencing on the Illumina HiSeq 2000 platform was performed at the Baylor College of Medicine Human Genome Sequencing Center. Single-nucleotide variants and indels were called with respect to germline DNA sequencing data for each case using MuTect2. Copy number profiling was performed on the Illumina HumanOmniExpress BeadChip and analyzed using GenomeStudio v2.0. Genotypes at known glioma risk polymorphisms were determined from germline DNA profiled on the Illumina Infinium OncoArray and rare, predicted deleterious germline mutations were identified from germline whole-exome sequencing data. RESULTS: Tumor exome sequencing was completed at an average read depth of 116X and we detected a median of 54 non-silent somatic mutations per tumor across the 20 tumors profiled. All three molecular subtypes of sporadic glioma were represented, including IDH-mutant, 1p/19q codeleted (n=3), IDH-mutant, 1p/19q intact (n=7), and IDH-wildtype tumors (n=10). Characteristic subtype-specific mutations and copy number alterations (e.g., TP53 and ATRX mutations among IDH-mutant, 1p/19q intact tumors) were observed, and the frequencies of recurrent alterations were comparable to sporadic glioma cases analyzed by The Cancer Genome Atlas. Notably, all 20 cases had alterations in genes regulating telomere length; 17 had acquired mutations in ATRX or the TERT promoter as typically seen in sporadic glioma, while three instead had germline mutations in telomere shelterin complex genes POT1 or TERF2. Frequencies of known common glioma risk alleles were similar to those among sporadic cases and correlations between risk alleles and specific somatic mutations were not observed. CONCLUSIONS: This study illustrates: 1) the complementarity of inherited and acquired alterations in driving gliomagenesis in some individuals with a familial predisposition to the disease; and 2) that the molecular characteristics of familial tumors profiled largely recapitulate what is known about sporadic glioma. In the majority of cases, the source of germline genetic susceptibility is not known but does not appear to be conferred by common risk polymorphisms.

  • 27.
    Johansson, A.
    et al.
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Sandström, P.
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Ullén, A.
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Behrvan, G.
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Erlandsson, A.
    Levi, M.
    Sundström, B.
    Stigbrand, T.
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Epitope specificity of the monoclonal anticytokeratin antibody TS11999In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 59, no 1, p. 48-51Article in journal (Refereed)
    Abstract [en]

    Due to their abundance in epithelial cells and deposition in necrotic regions intratumorally, cytokeratins (CKs) have been established as valuable targets for both radioimmunolocalization and radioimmunotherapy. The target epitope for the monoclonal anti-CK8 antibody, TS1, used for both experimental radioimmunolocalization and radioimmunotherapy, was determined by means of synthesis of 96 overlapping peptides that covered the entire CK8 molecule. A highly conserved peptide sequence, spanning amino acids (aa) 343-357 and covering the discontinuous epitope in the helical 2B domain, was identified. The epitope retains its helical structure, as shown with circular dichroism spectroscopy, although the length of the peptide (ie., >20 aa) is crucial for maintenance of immunoreactivity. To determine which aa residues are crucial for binding to the monoclonal antibody, alanine scanning was performed on a 26-mer covering aa 340-365, with the sequence QRGELAIKDANAKLSELEAALQRAKQ. The 26 modified peptides were evaluated using ELISA and BIAcore technology. The uniqueness of this epitope has been established by data base sequence comparisons.

  • 28. Kaaks, Rudolf
    et al.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Villar, Stéphanie
    Poetsch, Anna R
    Dossus, Laure
    Nieters, Alexandra
    Riboli, Elio
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Plass, Christoph
    Friesen, Marlin D
    Insulin-like Growth Factor-II Methylation Status in Lymphocyte DNA and Colon Cancer Risk in the Northern Sweden Health and Disease Cohort2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 13, p. 5400-5405Article in journal (Refereed)
    Abstract [en]

    Loss of imprinting (LOI) of the insulin-like growth factor II (IGFII) gene is a frequent phenomenon in colorectal tumor tissues. Previous reports indicated that subjects with colorectal neoplasias show LOI of IGFII in circulating lymphocytes. Furthermore, LOI of IGFII is strongly related to the methylation of a differentially methylated region (DMR) in intron 2 of IGFII, suggesting that the methylation status could serve as a biomarker for early detection. Thus, hypermethylation of this DMR, even at a systemic level, e.g., in lymphocyte DNA, could be used for screening for colon cancer. To validate this, we performed a case-control study of 97 colon cancer cases and 190 age-matched and gender-matched controls, nested within the prospective Northern Sweden Health and Disease Study cohort. Methylation levels of the IGFII-DMR in lymphocyte DNA were measured at two specific CpG sites of the IGFII-DMR using a mass-spectrometric method called short oligonucleotide mass analysis, the measurements of which showed high reproducibility between replicate measurements for the two CpG sites combined and showed almost perfect validity when performed on variable mixtures of methylated and unmethylated standards. Mean fractions of CpG methylation, for the two CpG sites combined, were identical for cases and controls (0.47 and 0.46, respectively; Pdifference = 0.75), and logistic regression analyses showed no relationship between colon cancer risk and quartile levels of CpG methylation. The results from this study population do not support the hypothesis that colon cancer can be predicted from the different degrees of methylation of DMR in the IGFII gene from lymphocyte DNA. [Cancer Res 2009;69(13):5400-5].

  • 29.
    Karlsson, Terese
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Botling, Johan
    Micke, Patrick
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Interactions between LRIG proteins and LMO7 and the expression of LMO7 in human lung cancer.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8: suppl 1, p. 5315-Article in journal (Refereed)
  • 30.
    Lindström, Sara
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences.
    Wiklund, Fredrik
    Adami, Hans-Olov
    Bälter, Katarina
    Adolfsson, Jan
    Grönberg, Henrik
    Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-alpha-reductase type 2 is important for prostate cancer development2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 22, p. 11077-11083Article in journal (Refereed)
  • 31. Lupo, Philip J.
    et al.
    Danysh, Heather E.
    Plon, Sharon E.
    Malkin, David
    Hettmer, Simone
    Hawkins, Douglas S.
    Skapek, Stephen X.
    Spector, Logan G.
    Papworth, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Erhardt, Erik B.
    Grufferman, Seymour
    Family history of cancer and rhabdomyosarcoma in children: a report from the Children's Oncology Group2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 32.
    Martinsson, Tommy
    et al.
    Clinical Genetics, University of Gothenburg.
    Eriksson, Therese
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Abrahamsson, Jonas
    Pediatrics, University of Gothenburg.
    Caren, Helena
    Clinical Genetics, University of Gothenburg.
    Hansson, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Kogner, Per
    Dept. of Women and Child Health, Karolinska Institutet.
    Kamaraj, Sattu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schönherr, Christina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Weinmar, Joel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Palmer, Ruth
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumour progression and unresponsiveness to therapy2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 1, p. 98-105Article in journal (Other academic)
    Abstract [en]

    Mutations in the kinase domain of the ALK kinase have emerged recently as important players in the genetics of the childhood tumor neuroblastoma. Here we report the appearance of a novel ALK mutation in neuroblastoma, correlating with aggressive tumor behaviour. Analyses of genomic DNA from biopsy samples initially showed ALK sequence to be wild type. However, during disease progression mutation of amino acid F1174 to a serine within the ALK kinase domain was observed, which correlated with aggressive neuroblastoma progression in the patient. We show that mutation of F1174 to serine generates a potent gain-of-function mutant, as observed in two independent systems. Firstly, PC12 cell lines expressing ALKF1174S display ligand independent activation of ALK and further downstream signaling activation. Secondly, analysis of ALKF1174S in Drosophila models confirms that the mutation mediates a strong rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALKF1174S mutation, which displays ligand independent activity in vivo, correlating with rapid and treatment resistant tumor growth. The study also shows that initial screening in the first tumor biopsy of a patient may not be sufficient and that further molecular analyses in particular in tumor progression and/or tumor relapse is warranted for better understanding of the treatment of neuroblastoma patients.

  • 33. Michels, Judith
    et al.
    Vitale, Ilio
    Galluzzi, Lorenzo
    Adam, Julien
    Olaussen, Ken Andre
    Kepp, Oliver
    Senovilla, Laura
    Talhaoui, Ibtissam
    Guegan, Justine
    Enot, David Pierre
    Talbot, Monique
    Robin, Angelique
    Girard, Philippe
    Orear, Cedric
    Lissa, Delphine
    Sukkurwala, Abdul Qader
    Garcia, Pauline
    Behnam Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kohno, Kimitoshi
    Wu, Gen Sheng
    Brenner, Catherine
    Dessen, Philippe
    Saparbaev, Murat
    Soria, Jean-Charles
    Castedo, Maria
    Kroemer, Guido
    Cisplatin Resistance Associated with PARP Hyperactivation2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 7, p. 2271-2280Article in journal (Refereed)
    Abstract [en]

    Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7); 2271-80.

  • 34. Nap, M
    et al.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Börmer, O
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Wagener, C
    Handt, S
    Schreyer, M
    Mach, J P
    Buchegger, F
    von Kleist, S
    Specificity and affinity of monoclonal antibodies against carcinoembryonic antigen.1992In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 52, no 8, p. 2329-39Article in journal (Refereed)
    Abstract [en]

    The binding specificities of 52 well-characterized monoclonal antibodies (Mabs) against carcinoembryonic antigen (CEA) from 12 different research groups were studied by immunohistochemistry and immuno flow cytometry. In addition, the binding constant for the interaction between Mab and CEA was determined by a solution-phase assay. Cryostat sections of colon carcinoma and normal colon, stomach, liver, pancreas, and spleen were studied by immunohistochemistry. Peripheral blood granulocytes, monocytes, and lymphocytes were assayed by immuno flow cytometry. The Mabs used here have previously been classified into five essentially nonoverlapping epitope groups (GOLD 1-5) (Cancer Res., 49: 4852-4858, 1989). Most Mabs cross-reacted with different normal tissues, ranging from highly cross-reactive Mabs (positive reaction with 8 of 9 discriminating tissues) to relatively specific Mabs (positive reaction with 1 of 9 discriminating tissues). Five Mabs (10%) were specific, reacting only with colon carcinoma, normal colon mucosa, and normal gastric foveola. There was a correlation between epitope group and binding specificity. Mabs with a high degree of CEA specificity almost exclusively belonged to epitope groups 1, 2, and 3, while highly cross-reactive Mabs belonged to epitope groups 4 and 5. There was no correlation between antibody specificity and affinity for CEA. Specific Mabs with high as well as low affinity were found.

  • 35. Nilchian, Azadeh
    et al.
    Johansson, Joel
    Ghalali, Aram
    Travica Asanin, Sandra
    Santiago, Ana
    Rosencrantz, Oskar
    Vincent, C Theresa
    Sollerbrant, Kerstin
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Stenius, Ulla
    Fuxe, Jonas
    CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 1, p. 47-60Article in journal (Refereed)
    Abstract [en]

    Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie- and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyper-activation of AKT and sensitized cells to TGF-β1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer.

  • 36. Ose, Jennifer
    et al.
    Poole, Elizabeth M.
    Schock, Helena
    Lehtinen, Matti
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    Visvanathan, Kala
    Helzlsouer, Kathy
    Buring, Julie E.
    Lee, I-Min
    Tjonneland, Anne
    Dossus, Laure
    Trichopoulou, Antonia
    Masala, Giovanna
    Onland-Moret, N. Charlotte
    Weiderpass, Elisabete
    Duell, Eric J.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Travis, Ruth C.
    Rinaldi, Sabina
    Merritt, Melissa A.
    Trabert, Britton
    Wentzensen, Nicolas
    Tworoger, Shelley S.
    Kaaks, Rudolf
    Fortner, Renee T.
    Androgens Are Differentially Associated with Ovarian Cancer Subtypes in the Ovarian Cancer Cohort Consortium2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 14, p. 3951-3960Article in journal (Refereed)
    Abstract [en]

    Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case–control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens [testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)], sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, ORlog2 = 1.12; 95% confidence interval 1.02–1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors [e.g., testosterone, endometrioid tumors, ORlog2 = 1.40 (1.03–1.91)], but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors [ORlog2 = 0.76 (0.60–0.96)]. Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.

  • 37. Ostrom, Quinn T.
    et al.
    Egan, Kathleen M.
    Nabors, L. Burt
    Gerke, Travis
    Thompson, Reid C.
    Olson, Jeffrey J.
    LaRocca, Renato
    Chowdhary, Sajeel
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina
    Wiencke, John K.
    Amos, Christopher I.
    Bernstein, Jonine L.
    Claus, Elizabeth B.
    Il'yasova, Dora
    Johansen, Christoffer
    Lachance, Daniel H.
    Lai, Rose
    Merrell, Ryan T.
    Olson, Sara H.
    Sadetzki, Siegal
    Schildkraut, Joellen
    Shete, Sanjay
    Houlston, Richard S.
    Jenkins, Robert B.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine.
    Bondy, Melissa L.
    Barnholtz-Sloan, Jill S.
    Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13Article in journal (Other academic)
    Abstract [en]

    Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with >50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1).

  • 38. Peña, Cristina
    et al.
    Céspedes, María Virtudes
    Lindh, Maja Bradic
    Kiflemariam, Sara
    Mezheyeuski, Artur
    Edqvist, Per-Henrik
    Hägglöf, Christina
    Karolinska Institutet, Stockholm, Sweden.
    Birgisson, Helgi
    Bojmar, Linda
    Jirström, Karin
    Sandström, Per
    Olsson, Eleonor
    Veerla, Srinivas
    Gallardo, Alberto
    Sjöblom, Tobias
    Chang, Andy C-M
    Reddel, Roger R
    Mangues, Ramón
    Augsten, Martin
    Ostman, Arne
    STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 4, p. 1287-97Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis.

  • 39. Santucci-Pereira, Julia
    et al.
    O'Malley, Colleen
    de Cicco, Ricardo Lopez
    Kirma, Nameer B.
    Huang, Tim H.
    Liu, Joseph
    Ross, Eric A.
    Slifker, Michael
    Peri, Suraj
    Russo, Irma H.
    Bordas, Pal
    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. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Russo, Jose
    Pregnancy changes the DNA methylation profile of the breast in postmenopausal women2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 40. Santucci-Pereira, Julia
    et al.
    Zeleniuch-Jacquotte, Anne
    Afanasyeva, Yelena
    Zhong, Hua
    Ross, Eric A.
    Slifker, Michael
    Peri, Suraj
    de Cicco, Ricardo Lopez
    Zhai, Yubo
    Russo, Irma H.
    Nguyen, Theresa
    Sheriff, Fathima
    Arslan, Alan A.
    Bordas, Pal
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ahman, Janet
    Eriksson, Anna-Stina L.
    Johansson, Robert
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Russo, Jose
    Gene expression profile induced by pregnancy in the breast of premenopausal women2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 41. Shete, Sanjay
    et al.
    Lau, Ching C
    Houlston, Richard S
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill
    Lai, Rose
    Il'yasova, Dora
    Schildkraut, Joellen
    Sadetzki, Siegal
    Johansen, Christoffer
    Bernstein, Jonine L
    Olson, Sara H
    Jenkins, Robert B
    Yang, Ping
    Vick, Nicholas A
    Wrensch, Margaret
    Davis, Faith G
    McCarthy, Bridget J
    Leung, Eastwood Hon-Chiu
    Davis, Caleb
    Cheng, Rita
    Hosking, Fay J
    Armstrong, Georgina N
    Liu, Yanhong
    Yu, Robert K
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L
    Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the gliogene consortium2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 24, p. 7568-7575Article in journal (Refereed)
    Abstract [en]

    Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568-75. (C) 2011 AACR.

  • 42.
    Späth, Florentin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krop, Esmeralda J. M.
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Vermeulen, Roel
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 6, p. 1408-1415Article in journal (Refereed)
    Abstract [en]

    The B-cell activation markers CXCL13, sCD23, (S)CD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of markerdisease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lympho-ma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope - 28, Ptrend(-)7.279 x 10 (-10)). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. 

  • 43.
    Svenson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length in peripheral blood predicts survival in clear cell renal cell carcinoma2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 7, p. 2896-2901Article in journal (Refereed)
    Abstract [en]

    Telomeres are repetitive structures located at chromosome ends. Previous studies have indicated that blood cell telomeres may serve as a biomarker for cancer risk. In addition, we recently reported that blood telomere length predicted survival in patients with breast cancer. In the present study, we examined whether blood telomere length may act as a predictor for survival in newly diagnosed patients with clear cell renal cell carcinoma. Furthermore, we analyzed telomere length in tumor samples and corresponding kidney cortex. Relative telomere length (RTL) was measured on extracted DNA using real-time PCR. Interestingly, and in line with our previous findings in breast cancer, patients with the longest blood telomeres (fourth quartile) had a significantly worse prognosis compared with patients with shorter blood RTL (P=0.005). A highly significant association was found between long blood telomeres and a poor outcome in patients with nonmetastatic disease (P<0.001), whereas patients with distant metastases had a poor survival regardless of blood RTL (P=0.432). No correlations were found between blood RTL and various clinical variables, such as erythrocyte sedimentation rate, hemoglobin, and thrombocyte count. Multivariate Cox regression analysis verified long blood RTL as an independent negative prognostic marker. In contrast, telomere length in kidney cortex and tumor tissue did not predict survival. In conclusion, our results indicate that blood RTL may predict kidney cancer survival, with implications for future treatment strategies.

  • 44.
    Svenson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nordfjäll, Katarina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Manjer, Jonas
    Nilsson, Peter
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Breast cancer survival is associated with telomere length in peripheral blood cells2008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 10, p. 3618-3623Article in journal (Refereed)
    Abstract [en]

    Telomeres are essential for maintaining chromosomal stability. Previous studies have indicated that individuals with shorter blood telomeres may be at higher risk of developing various types of cancer, such as in lung, bladder, and kidney. We have analyzed relative telomere length (RTL) of peripheral blood cells in relation to breast cancer incidence and prognosis. The study included 265 newly diagnosed breast cancer patients and 446 female controls. RTL was measured by real-time PCR, and our results show that the patient group displayed significantly longer telomeres compared with controls (P < 0.001). Age-adjusted odds ratios (OR) for breast cancer risk increased with increasing telomere length, with a maximal OR of 5.17 [95% confidence interval (95% CI), 3.09-8.64] for the quartile with the longest telomeres. Furthermore, RTL carried prognostic information for patients with advanced disease. Node positive (N+) patients with short telomeres (</=median) showed an increased survival compared with N+ patients with long telomeres (P = 0.001). For patients with ages <50 years with tumors >16 mm (median tumor diameter), short telomeres were associated with a significantly better outcome than longer telomeres (P = 0.006). Cox regression analysis showed that long RTL was a significant independent negative prognostic factor (hazards ratio, 2.92; 95% CI, 1.33-6.39; P = 0.007). Our results indicate that blood RTL may serve as a prognostic indicator in breast cancer patients with advanced disease.

  • 45. Thompson, Patricia A.
    et al.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tsavachidis, Spyros
    Brewster, Abenaa
    Sahin, Aysegul
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Loss of LRIG1 Locus Increases Risk of Early and Late Relapse of Stage I/II Breast Cancer2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 11, p. 2928-2935Article in journal (Refereed)
    Abstract [en]

    Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse >= 5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients.

  • 46.
    Thysell, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bovinder Ylitalo, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    A Systems Approach to Prostate Cancer Classification: Letter2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 24, p. 7131-7132Article in journal (Refereed)
  • 47.
    Thysell, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bovinder Ylitalo, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Clinically relevant molecular subgroups of prostate cancer bone metastases2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 123-123Article in journal (Other academic)
  • 48. Toniolo, Paolo
    et al.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chen, Tianhui
    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.
    Lehtinen, Matti
    Kaaks, Rudolf
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Zeleniuch-Jacquotte, Anne
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lukanova, Annekatrin
    Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 17, p. 6779-6786Article in journal (Refereed)
    Abstract [en]

    Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy.

  • 49. Travis, Ruth C.
    et al.
    Appleby, Paul N.
    Martin, Richard M.
    Holly, Jeff M. P.
    Albanes, Demetrius
    Black, Amanda
    Bueno-de-Mesquita, H. Bas
    Chan, June M.
    Chen, Chu
    Chirlaque, Maria-Dolores
    Cook, Michael B.
    Deschasaux, Melanie
    Donovan, Jenny L.
    Ferrucci, Luigi
    Galan, Pilar
    Giles, Graham G.
    Giovannucci, Edward L.
    Gunter, Marc J.
    Habel, Laurel A.
    Hamdy, Freddie C.
    Helzlsouer, Kathy J.
    Hercberg, Serge
    Hoover, Robert N.
    Janssen, Joseph A. M. J. L.
    Kaaks, Rudolf
    Kubo, Tatsuhiko
    Le Marchand, Loic
    Metter, E. Jeffrey
    Mikami, Kazuya
    Morris, Joan K.
    Neal, David E.
    Neuhouser, Marian L.
    Ozasa, Kotaro
    Palli, Domenico
    Platz, Elizabeth A.
    Pollak, Michael N.
    Price, Alison J.
    Roobol, Monique J.
    Schaefer, Catherine
    Schenk, Jeannette M.
    Severi, Gianluca
    Stampfer, Meir J.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Univ Uppsala Hosp, Dept Surg Sci, Uppsala, Sweden.
    Tamakoshi, Akiko
    Tangen, Catherine M.
    Touvier, Mathilde
    Wald, Nicholas J.
    Weiss, Noel S.
    Ziegler, Regina G.
    Key, Timothy J.
    Allen, Naomi E.
    A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 8, p. 2288-2300Article in journal (Refereed)
    Abstract [en]

    The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (P-trend all <= 0.005), and IGFBP-1 was inversely associated weakly with risk (P-trend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (P-heterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, P-heterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. 

  • 50. Tuomisto, Anne
    et al.
    Sund, Malin
    Tahkola, Jenni
    Latvanlehto, Anne
    Savolainen, Eeva-Riitta
    Autio-Harmainen, Helena
    Liakka, Annikki
    Sormunen, Raija
    Vuoristo, Jussi
    West, Anne
    Lahesmaa, Riitta
    Morse, Herbert C
    Pihlajaniemi, Taina
    A mutant collagen XIII alters intestinal expression of immune response genes and predisposes transgenic mice to develop B-cell lymphomas2008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 24, p. 10324-10332Article in journal (Refereed)
    Abstract [en]

    Epithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1(del) expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII-positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII-dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility.

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