Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA

Os portadores das mutações de alto risco da linha germinal nos genes BRCA1 e BRCA2 apresentam penetrância incompleta, assim como variabilidade na idade de manifestação, indicando a existência de moduladores genéticos e não-genéticos. Nos últimos anos os estudos de associação genómicos têm identificado com sucesso novas variantes genéticas associadas à susceptibilidade para o cancro da mama.

Este estudo aliou estas duas frentes e foram analisadas mais de 3000 variantes candidatas em cerca de 445 loci, no âmbito do projecto iCOGS. Os resultados obtidos não evidenciam o envolvimento de qualquer destas variantes no aumento de risco de cancro da mama. A procura continua para identificar novos modificadores. O consórcio iCOGS visa melhorar o nosso conhecimento sobre a susceptibilidade genética de três cancros: mama, ovário e próstata. Este consórcio reúne os esforços de
167 grupos de investigação espalhados pelo mundo.

Autores e Afiliações:

Paolo Peterlongo1,2, Jenny Chang-Claude3, Kirsten B. Moysich4, Anja Rudolph3, Rita K. Schmutzler5,6,7, Jacques Simard8, Penny Soucy8, Rosalind A. Eeles9, Douglas F. Easton10, Ute Hamann11, Stefan Wilkening12, Bowang Chen13, Matti A. Rookus14, Marjanka K Schmidt15, Frederieke H. van der Baan14, Amanda B. Spurdle16, Logan C. Walker17, Felicity Lose16, Ana-Teresa Maia18, Marco Montagna19, Laura Matricardi19, Jan Lubinski20, Anna Jakubowska20, Encarna B. Gómez Garcia21, Olufunmilayo I. Olopade22, Robert L. Nussbaum23, Katherine L. Nathanson24, Susan M. Domchek24, Timothy R. Rebbeck25, Banu K. Arun26, Beth Y. Karlan27, Sandra Orsulic27, Jenny Lester27, Wendy K. Chung28, Alex Miron29, Melissa C. Southey30, David E. Goldgar31, Saundra S. Buys32, Ramunas Janavicius33, Cecilia M. Dorfling34, Elizabeth J. van Rensburg34, Yuan Chun Ding35, Susan L. Neuhausen35, Thomas V. O. Hansen36, Anne-Marie Gerdes37, Bent Ejlertsen38, Lars Jønson36, Ana Osorio39,40, Cristina Martínez-Bouzas41, Javier Benitez39,42, Edye E. Conway43, Kathleen R. Blazer44, Jeffrey N. Weitzel45, Siranoush Manoukian46, Bernard Peissel46, Daniela Zaffaroni46, Giulietta Scuvera46, Monica Barile47, Filomena Ficarazzi1,48, Frederique Mariette1,48, Stefano Fortuzzi1,48, Alessandra Viel49, Giuseppe Giannini50, Laura Papi51, Aline Martayan52, Maria Grazia Tibiletti53, Paolo Radice46, Athanassios Vratimos54, Florentia Fostira54, Judy E. Garber55; Alan Donaldson56, Carole Brewer57, Claire Foo58, D. Gareth R. Evans59, Debra Frost10, Diana Eccles60, Angela Brady61, Jackie Cook62, Marc Tischkowitz63, Julian Adlard64, Julian Barwell65, Lisa Walker66, Louise Izatt67, Lucy E. Side68, M. John Kennedy69,70, Mark T. Rogers71, Mary E. Porteous72, Patrick J. Morrison73, Radka Platte10, Rosemarie Davidson74, Shirley V. Hodgson75, Steve Ellis10 and Trevor Cole76 on behalf of EMBRACE10; Andrew K. Godwin77, Kathleen Claes78, Tom Van Maerken78, Alfons Meindl79, Andrea Gehrig80, Christian Sutter81, Christoph Engel82, Dieter Niederacher83, Doris Steinemann84, Hansjoerg Plendl85, Karin Kast86, Kerstin Rhiem5,6,87, Nina Ditsch88, Norbert Arnold89, Raymonda Varon-Mateeva90, Barbara Wappenschmidt5,6,87, Shan Wang-Gohrke91; Brigitte Bressac-de Paillerets92,93, Bruno Buecher94, Capucine Delnatte95, Claude Houdayer94,96, Dominique Stoppa-Lyonnet94,96,97, Francesca Damiola98, Isabelle Coupier99,100, Laure Barjhoux100, Laurence Venat-Bouvet101, Lisa Golmard94, Nadia Boutry-Kryza102, Olga M. Sinilnikova98,102, Olivier Caron103, Pascal Pujol99,104, Sylvie Mazoyer98 and Muriel Belotti94 on behalf of GEMO Study Collaborators105; Marion Piedmonte106, Michael L. Friedlander107, Gustavo C. Rodriguez108, Larry J Copeland109, Miguel de la Hoya110, Pedro Perez Segura111, Heli Nevanlinna112,113, Kristiina Aittomäki114; Theo A.M. van Os115, Hanne E.J. Meijers-Heijboer116, Annemarie H. van der Hout117, Maaike P.G. Vreeswijk118, Nicoline Hoogerbrugge119, Margreet G.E.M. Ausems120, Helena C. van Doorn121 and J. Margriet Collée122 on behalf of HEBON14; Edith Olah123, Orland Diez124,125,126,127, Ignacio Blanco128, Conxi Lazaro129, Joan Brunet130, Lidia Feliubadalo131, Cezary Cybulski20, Jacek Gronwald20, Katarzyna Durda20, Katarzyna Jaworska-Bieniek20, Grzegorz Sukiennicki20, Adalgeir Arason131,132, Jocelyne Chiquette133, Manuel R. Teixeira134,135, Curtis Olswold136, Fergus J. Couch137, Noralane M. Lindor138, Xianshu Wang139, Csilla I. Szabo140, Kenneth Offit141, Marina Corines142, Lauren Jacobs142, Mark E. Robson141, Liying Zhang143, Vijai Joseph141, Andreas Berger144, Christian F. Singer144, Christine Rappaport144, Daphne Geschwantler Kaulich144, Georg Pfeiler144, Muy-Kheng M. Tea144, Catherine M. Phelan145, Mark H. Greene146, Phuong L. Mai146, Gad Rennert147, Anna Marie Mulligan148,149, Gord Glendon150, Sandrine Tchatchou151, Irene L. Andrulis151,152, Amanda Ewart Toland153, Anders Bojesen154, Inge Sokilde Pedersen155, Mads Thomassen156, Uffe Birk Jensen157, Yael Laitman158, Johanna Rantala159, Anna von Wachenfeldt160, Hans Ehrencrona161,162, Marie Stenmark Askmalm163, Åke Borg164, Karoline B. Kuchenbaecker10, Lesley McGuffog10, Daniel Barrowdale10, Sue Healey16, Andrew Lee10, Paul D.P. Pharoah165; Georgia Chenevix-Trench16 on behalf of KConFab Investigators166, Antonis C. Antoniou10, Eitan Friedman158.

1IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan,Italy. 2Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 4Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA. 5Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Germany. 6Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany. 7Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany, on behalf of the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC). 8Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Canada. 9Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK. 10Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK. 11Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. 12Genomic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 13Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 14Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 15Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands 16Department of Genetics and Computational Biology, QIMR Berghofer, Brisbane, Australia. 17Department of Pathology, University of Otago, Christchurch, New Zealand. 18Department of Biomedical Sciences and Medicine, Gambelas Campus, University of Algarve, Portugal. 19Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto  IOV - IRCCS, Padua, Italy. 20Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 21Department of Clinical Genetics, MUMC, Maastricht, The Netherlands. 22Center for Clinical Cancer Genetic, Department of Medicine and Human Genetics, University of Chicago Medical Center, Chicago, USA. 23Department of Medicine and Institute for Human Genetics, University of California, San Francisco, USA. 24Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, USA. 25Department of Epidemiology and Biostatistics, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, USA. 26University of Texas MD Anderson Cancer Center, Houston, TX, USA. 27Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA. 28Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA. 29Department of Genetics and Genomics at Case Western Reserve Medical School, Cleveland, Ohio, USA. 30Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia. 31Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA. 32Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA. 33Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology and Transfusion Medicine Center, Dept. of Molecular and Regenerative Medicine; State Research Institute Centre for Innovative medicine, Vilnius, Lithuania. 34Department of Genetics, University of Pretoria, Pretoria, South Africa. 35Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA. 36Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 37Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 38Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 39Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. 40Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain. 41Molecular Genetics Laboratory, Department of Biochemistry, Cruces Hospital Barakaldo, 48903-Barakaldo-Bizkaia, Spain. 42Human Genetics Group and Genotyping Unit, Spanish National Cancer Centre (CNIO), Madrid, Spain. 43Saint Alphonsus Regional Medical Center, care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California 91010, USA. 44Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California 91010 USA. 45Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California 91010 USA (for the City of Hope Clinical Cancer Genetics Community Research Network). 46Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 47Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy. 48Cogentech Cancer Genetic Test Laboratory, Milan, Italy. 49Division of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano (PN), Italy. 50Department of Molecular Medicine, Sapienza University, Rome, Italy. 51Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy. 52Unit of Genetic Counseling, Medical Oncology Department, Nazionale Tumori Regina Elena, Rome, Italy. 53UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria Varese, Italy. 54Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Aghia Paraskevi Attikis, Athens, Greece. 55Dana-Farber Cancer Institute, Boston, MA, USA. 56Clinical Genetics Department, St Michael’s Hospital, Bristol, UK. 57Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK. 58Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK. 59Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. 60University of Southampton, Faculty of Medicine, Southampton University Hospitals NHS Trust, Southampton, UK. 61North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK. 62Sheffield Clinical Genetics Service, Sheffield Children’s Hospital, Sheffield, UK. 63Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, UK. 64Yorkshire Regional Genetics Service, Leeds, UK. 65Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, UK. 66Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK. 67Clinical Genetics, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK. 68North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK. 69Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin, Eire. 70St James's Hospital, Dublin, Eire. 71All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK. 72South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK. 73Centre for Cancer Research and Cell Biology, Queens University of Belfast, Department of Medical Genetics, Belfast HSC Trust, Belfast, UK. 74Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK. 75Medical Genetics Unit, St George's, University of London, UK. 76West Midlands Regional Genetics Service, Birmingham Women’s Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK. 77Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA. 78Center for Medical Genetics, Ghent University, Ghent, Belgium. 79Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Germany.  80Institute of Human Genetics, University Würzburg, Wurzburg, Germany. 81University Heidelberg, Heidelberg, Germany. 82Institute for Medical Informatics, Statistics and Epidemiology University of Leipzig, Leipzig, Germany. 83University Düsseldorf, Dusseldorf, Germany. 84Hannover Medical School, Hanover, Germany. 85Institute of Human Genetics, University Hospital of Schleswig-Holstein/University Kiel, Kiel, Germany. 86University Dresden, Dresden, Germany. 87Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany. 88Department of Gynaecology and Obstetrics, University Munich, Munich, Germany. 89University Hospital of Schleswig-Holstein/University Kiel, Kiel, Germany. 90Institute of Human Genetics, Charite Berlin, Germany. 91Department of Gynaecology and Obstetrics, University Hospital Ulm, Germany. 92INSERM U946, Fondation Jean Dausset, Paris, France. 93Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France. 94Institut Curie, Department of Tumour Biology, Paris, France. 95Centre René Gauducheau, Nantes, France. 96Université Paris Descartes, Sorbonne Paris Cité, France. 97Institut Curie, INSERM U830, Paris, France. 98INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 99Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France. 100Unité d'Oncogénétique, CRLCC Val d'Aurelle, Montpellier, France. 101Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren, Limoges, France. 102Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon – Centre Léon Bérard, Lyon, France. 103Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France. 104INSERM 896, CRCM Val d'Aurelle, Montpellier, France. 105GEMO study: National Cancer Genetics Network «UNICANCER Genetic Group», France. 106Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA. 107Australia New Zealand Gynaecological Oncology Group (ANZGOG), Coordinating Centre, Camperdown, Australia. 108Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, USA. 109Ohio State University, Department of Obstetrics and Gynecology, Hilliard, OH, USA. 110Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 111Department of Oncology, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 112Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. 113University of Helsinki, Helsinki, Finland. 114Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland. 115Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 116Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. 117Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands. 118Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands. 119Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. 120Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 121Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Erasmus University MC Cancer Institute, Rotterdam, The Netherlands. 122Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 123Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 124Oncogenetics Group, University Hospital Vall d’Hebron, Barcelona, Spain. 125Universitat Autònoma de Barcelona, Barcelona, Spain. 126Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. 127Vall d’Hebron Research Institute (VHIR), Barcelona, Spain. 128Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 129Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 130Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI-Catalan Institute of Oncology, Girona, Spain. 131BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 132Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland. 133Unité de Recherche en Santé des Populations, Centre des Maladies du Sein Deschênes-Fabia, Centre de Recherche FRSQ du Centre Hospitalier Affilié Universitaire de Québec, Québec, QC, Canada. 134Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. 135Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. 136Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 137Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 138Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA. 139Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 140National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 141Clinical Genetics Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 142Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 143Diagnostic Molecular Genetics Laboratory, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 144Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 145Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA. 146Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA. 147Clalit National Cancer Control Center, Haifa, Israel. 148Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 149Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. 150Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 151Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 152Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. 153Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. 154Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark. 155Section of Molecular Diagnostics, Department of Biochemistry, Aalborg University Hospital, Aalborg, Denmark. 156Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark. 157Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 158Sheba Medical Center, Tel Aviv, Israel. 159Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 160Department of Oncology, Karolinska University Hospital, Stockholm, Sweden. 161Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. 162Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 163Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping,
Sweden. 164Department of Oncology, Lund University, Lund, Sweden. 165Department of Oncology, University of Cambridge, Cambridge, UK. 166kConFab: Kathleen Cuningham Consortium for Research into Familial Breast Cancer – Peter MacCallum Cancer Center, Melbourne, Australia.

Abstract:

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
 

Revista: CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION

Link: http://cebp.aacrjournals.org/content/early/2014/10/21/1055-9965.EPI-14-0532.full.pdf+html?sid=2ed3f8e0-4e6d-4136-aaed-19815b92d7