BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Huong D Meeks; Honglin Song; Kyriaki Michailidou; Manjeet K Bolla; Joe Dennis; Qin Wang; Daniel Barrowdale; Debra Frost; Lesley McGuffog; Steve Ellis; Bingjian Feng; Saundra S Buys; John L Hopper; Melissa C Southey; Andrea Tesoriero; Paul A James; Fiona Bruinsma; Ian G Campbell; Annegien Broeks; Marjanka K Schmidt; Frans B L Hogervorst; Matthias W Beckman; Peter A Fasching; Olivia Fletcher; Nichola Johnson; Elinor J Sawyer; Elio Riboli; Susana Banerjee; Usha Menon; Ian Tomlinson; Barbara Burwinkel; Ute Hamann; Frederik Marme; Anja Rudolph; Ramunas Janavicius; Laima Tihomirova; Nadine Tung; Judy Garber; Daniel Cramer; Kathryn L Terry; Elizabeth M Poole; Shelley S Tworoger; Cecilia M Dorfling; Elizabeth J Van Rensburg; Andrew K Godwin; Pascal Guénel; Thérèse Truong; Dominique Stoppa-Lyonnet; Francesca Damiola; Sylvie Mazoyer; Olga M Sinilnikova; Claudine Isaacs; Christine Maugard; Stig E Bojesen; Henrik Flyger; Anne Marie Gerdes; Thomas V O Hansen; Allen Jensen; Susanne K Kjaer; Claus Hogdall; Estrid Hogdall; Inge Sokilde Pedersen; Mads Thomassen; Javier Benitez; Anna González-Neira; Ana Osorio; Miguel De La Hoya; Pedro Perez Segura; Orland Diez; Conxi Lazaro; Joan Brunet; Hoda Anton-Culver; Lee Eunjung; Esther M John; Susan L Neuhausen; Yuan Chun Ding; Danielle Castillo; Jeffrey N Weitzel; Patricia A Ganz; Robert L Nussbaum; Salina B Chan; Beth Y Karlan; Jenny Lester; Anna Wu; Simon Gayther; Susan J Ramus; Weiva Sieh; Alice S Whittermore; Alvaro N A Monteiro; Catherine M Phelan; Mary Beth Terry; Marion Piedmonte; Kenneth Offit; Mark Robson; Douglas Levine; Kirsten B Moysich; Rikki Cannioto; Sara H Olson; Mary B Daly; Katherine L Nathanson; Susan M Domchek; Karen H Lu; Dong Liang; Michelle A T Hildebrant; Roberta Ness; Francesmary Modugno; Leigh Pearce; Marc T Goodman; Pamela J Thompson; Hermann Brenner; Katja Butterbach; Alfons Meindl; Eric Hahnen; Barbara Wappenschmidt; Hiltrud Brauch; Thomas Brüning; Carl Blomqvist; Sofia Khan; Heli Nevanlinna; Liisa M Pelttari; Kristiina Aittomäki; Ralf Butzow; Natalia V Bogdanova; Thilo Dörk; Annika Lindblom; Sara Margolin; Johanna Rantala; Veli Matti Kosma; Arto Mannermaa; Diether Lambrechts; Patrick Neven; Kathleen B M Claes; Tom Van Maerken; Jenny Chang-Claude; Dieter Flesch-Janys; Florian Heitz; Raymonda Varon-Mateeva; Paolo Peterlongo; Paolo Radice; Alessandra Viel; Monica Barile; Bernard Peissel; Siranoush Manoukian; Marco Montagna; Cristina Oliani; Ana Peixoto; Manuel R Teixeira; Anita Collavoli; Emily Hallberg; Janet E Olson; Ellen L Goode; Steven N Hart; Hermela Shimelis; Julie M Cunningham; Graham G Giles; Roger L Milne; Sue Healey; Kathy Tucker; Christopher A Haiman; Brian E Henderson; Mark S Goldberg; Marc Tischkowitz; Jacques Simard; Penny Soucy; Diana M Eccles; Nhu Le; Anne Lise Borresen-Dale; Vessela Kristensen; Helga B Salvesen; Line Bjorge; Elisa V Bandera; Harvey Risch; Wei Zheng; Alicia Beeghly-Fadiel; Hui Cai; Katri Pylkäs; Robert A E M Tollenaar; Ans M W Van Der Ouweland; Irene L Andrulis; Julia A Knight; Steven Narod; Peter Devilee; Robert Winqvist; Jonine Figueroa; Mark H Greene; Phuong L Mai; Jennifer T Loud; Montserrat García-Closas; Minouk J Schoemaker; Kamila Czene; Hatef Darabi; Iain McNeish; Nadeem Siddiquil; Rosalind Glasspool; Ava Kwong; Sue K Park; Soo Hwang Teo; Sook Yee Yoon; Keitaro Matsuo; Satoyo Hosono; Yin Ling Woo; Yu Tang Gao; Lenka Foretova; Christian F Singer; Christine Rappaport-Feurhauser; Eitan Friedman; Yael Laitman; Gad Rennert; Evgeny N Imyanitov; Peter J Hulick; Olufunmilayo I Olopade; Leigha Senter; Edith Olah; Jennifer A Doherty; Joellen Schildkraut; Linetta B Koppert; Lambertus A Kiemeney; Leon F A G Massuger; Linda S Cook; Tanja Pejovic; Jingmei Li; Åke Borg; Anna Öfverholm; Mary Anne Rossing; Nicolas Wentzensen; Karin Henriksson; Angela Cox; Simon S Cross; Barbara J Pasini; Mitul Shah; Maria Kabisch; Diana Torres; Anna Jakubowska; Jan Lubinski; Jacek Gronwald; Bjarni A Agnarsson; Jolanta Kupryjanczyk; Joanna Moes-Sosnowska; Florentia Fostira; Irene Konstantopoulou; Susan Slager; Michael Jones; Antonis C Antoniou; Andrew Berchuck; Anthony Swerdlow; Georgia Chenevix-Trench; Alison M Dunning; Paul D P Pharoah; Per Hall; Douglas F Easton; Fergus J Couch; Amanda B Spurdle; David E Goldgar; kConFab Investigators

doi:10.1093/jnci/djv315

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BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Journal article

Open access

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Huong D Meeks, Honglin Song, Kyriaki Michailidou, Manjeet K Bolla, Joe Dennis, Qin Wang, Daniel Barrowdale, Debra Frost, Lesley McGuffog, Steve Ellis, …

JNCI : Journal of the National Cancer Institute, Vol.108(2), p.djv315

02/01/2016

DOI: https://doi.org/10.1093/jnci/djv315

PMCID: PMC4907358

PMID: 26586665

Abstract

Cancer and Oncology

Cancer och onkologi

Klinisk medicin

Medical and Health Sciences

Medicin och hälsovetenskap

Clinical Medicine

Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1×10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

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Title: BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers
Creators: Huong D Meeks - University of Utah
Honglin Song - University of Cambridge
Kyriaki Michailidou - University of Cambridge
Manjeet K Bolla - University of Cambridge
Joe Dennis - University of Cambridge
Qin Wang - University of Cambridge
Daniel Barrowdale - University of Cambridge
Debra Frost - University of Cambridge
Lesley McGuffog - University of Cambridge
Steve Ellis - University of Cambridge
Bingjian Feng - University of Utah
Saundra S Buys - University of Utah
John L Hopper - University of Melbourne
Melissa C Southey - University of Melbourne
Andrea Tesoriero - University of Melbourne
Paul A James - University of Melbourne
Fiona Bruinsma - Cancer Council Victoria
Ian G Campbell - Peter MacCallum Cancer Centre
Annegien Broeks - Antoni Van Leeuwenhoek Hospital
Marjanka K Schmidt - Antoni Van Leeuwenhoek Hospital
Frans B L Hogervorst - Netherlands Cancer Institute
Matthias W Beckman - Friedrich-Alexander University Erlangen-Nürnberg
Peter A Fasching - University of California, Los Angeles
Olivia Fletcher - Institute of Cancer Research London
Nichola Johnson - Institute of Cancer Research London
Elinor J Sawyer - Guy's and St Thomas' NHS Foundation Trust
Elio Riboli - Imperial College London
Susana Banerjee - Royal Marsden NHS Foundation Trust
Usha Menon - Royal Free Hospital
Ian Tomlinson - University of Oxford
Barbara Burwinkel - German Cancer Research Centre
Ute Hamann - German Cancer Research Centre
Frederik Marme - Heidelberg University
Anja Rudolph - German Cancer Research Centre
Ramunas Janavicius - State Research Institute Centre for Innovative Medicine
Laima Tihomirova - Latvian Biomedical Research and Study Centre
Nadine Tung - Beth Israel Deaconess Medical Center
Judy Garber - Dana-Farber Cancer Institute
Daniel Cramer - Brigham and Women's Hospital / Harvard Medical School
Kathryn L Terry - Brigham and Women's Hospital / Harvard Medical School
Elizabeth M Poole - Harvard University
Shelley S Tworoger - Harvard University
Cecilia M Dorfling - University of Pretoria
Elizabeth J Van Rensburg - University of Pretoria
Andrew K Godwin - University of Kansas Medical Center
Pascal Guénel - University of Paris-Sud
Thérèse Truong - University of Paris-Sud
Dominique Stoppa-Lyonnet - Paris Descartes University
Francesca Damiola - Centre de Recherche en Cancérologie de Lyon
Sylvie Mazoyer - Centre de Recherche en Cancérologie de Lyon
Olga M Sinilnikova - Centre Léon Bérard
Claudine Isaacs - Lombardi Comprehensive Cancer Center
Christine Maugard - CHRU Nouvel Hôpital Civil
Stig E Bojesen - Copenhagen University Hospital
Henrik Flyger - Copenhagen University Hospital
Anne Marie Gerdes - Copenhagen University Hospital
Thomas V O Hansen - Copenhagen University Hospital
Allen Jensen - Danish Cancer Society Research Center
Susanne K Kjaer - University of Copenhagen
Claus Hogdall - University of Copenhagen
Estrid Hogdall - University of Copenhagen
Inge Sokilde Pedersen - Aalborg University Hospital
Mads Thomassen - Odense University Hospital
Javier Benitez - Biomedical Network on Rare Diseases (CIBERER)
Anna González-Neira - Spanish National Cancer Research Center (CNIO)
Ana Osorio - Biomedical Network on Rare Diseases (CIBERER)
Miguel De La Hoya - Hospital Clinico San Carlos de Madrid
Pedro Perez Segura - Hospital Clinico San Carlos de Madrid
Orland Diez - Vall d'Hebron University Hospital
Conxi Lazaro - Bellvitge Biomedical Research Institute
Joan Brunet - Catalan Institute of Oncology
Hoda Anton-Culver - University of California System
Lee Eunjung - University of Southern California
Esther M John - Cancer Prevention Institute of California
Susan L Neuhausen - Beckman Research Institute of City of Hope
Yuan Chun Ding - Beckman Research Institute of City of Hope
Danielle Castillo - City of Hope National Medical Center
Jeffrey N Weitzel - City of Hope National Medical Center
Patricia A Ganz - Jonsson Comprehensive Cancer Center
Robert L Nussbaum - University of California System
Salina B Chan - University of California System
Beth Y Karlan - Cedars-Sinai Medical Center
Jenny Lester - Cedars-Sinai Medical Center
Anna Wu - University of Southern California
Simon Gayther - University of Southern California
Susan J Ramus - University of Southern California
Weiva Sieh - Stanford University
Alice S Whittermore - Stanford University
Alvaro N A Monteiro - H. Lee Moffitt Cancer Center & Research Institute
Catherine M Phelan - H. Lee Moffitt Cancer Center & Research Institute
Mary Beth Terry - Columbia University
Marion Piedmonte - Roswell Park Cancer Institute
Kenneth Offit - Memorial Sloan-Kettering Cancer Center
Mark Robson - Memorial Sloan-Kettering Cancer Center
Douglas Levine - Memorial Sloan-Kettering Cancer Center
Kirsten B Moysich - Roswell Park Cancer Institute
Rikki Cannioto - Roswell Park Cancer Institute
Sara H Olson - Memorial Sloan-Kettering Cancer Center
Mary B Daly - Fox Chase Cancer Center
Katherine L Nathanson - University of Pennsylvania
Susan M Domchek - University of Pennsylvania
Karen H Lu - University of Texas
Dong Liang - Texas Southern University
Michelle A T Hildebrant - University of Texas
Roberta Ness - University of Texas
Francesmary Modugno - Magee-Womens Research Institute
Leigh Pearce - University of Michigan
Marc T Goodman - Cedars-Sinai Medical Center
Pamela J Thompson - Cedars-Sinai Medical Center
Hermann Brenner - German Cancer Research Centre
Katja Butterbach - University of Warwick
Alfons Meindl - Klinikum rechts der Isar
Eric Hahnen - University Hospital of Cologne
Barbara Wappenschmidt - University Hospital of Cologne
Hiltrud Brauch - University of Tübingen
Thomas Brüning - Ruhr-University Bochum
Carl Blomqvist - University of Helsinki
Sofia Khan - University of Helsinki
Heli Nevanlinna - University of Helsinki
Liisa M Pelttari - University of Helsinki
Kristiina Aittomäki - University of Helsinki
Ralf Butzow - University of Helsinki
Natalia V Bogdanova - Hannover Medical School
Thilo Dörk - Hannover Medical School
Annika Lindblom - Karolinska Institutet
Sara Margolin - Karolinska Institutet
Johanna Rantala - Karolinska University Hospital
Veli Matti Kosma - Kuopio University Hospital
Arto Mannermaa - Kuopio University Hospital
Diether Lambrechts - Catholic University of Leuven
Patrick Neven - University Hospitals Leuven
Kathleen B M Claes - Ghent University
Tom Van Maerken - Ghent University
Jenny Chang-Claude - German Cancer Research Centre
Dieter Flesch-Janys - University Medical Center Hamburg-Eppendorf
Florian Heitz - Dr. Horst Schmidt Klinik GmbH
Raymonda Varon-Mateeva - Charité - University Medicine Berlin
Paolo Peterlongo - IFOM - The FIRC Institute of Molecular Oncology
Paolo Radice - Istituto Nazionale dei Tumori
Alessandra Viel - CRO (Centro di Riferimento Oncologico) Aviano National Cancer Institute
Monica Barile - European Institute of Oncology
Bernard Peissel - Istituto Nazionale dei Tumori
Siranoush Manoukian - Istituto Nazionale dei Tumori
Marco Montagna - Veneto Institute of Oncology
Cristina Oliani - ULSS5 Ovest Vicentino
Ana Peixoto - Portuguese Institute of Oncology - Porto
Manuel R Teixeira - University of Porto
Anita Collavoli - University Hospital of Pisa
Emily Hallberg - Mayo Clinic Minnesota
Janet E Olson - Mayo Clinic Minnesota
Ellen L Goode - Mayo Clinic Minnesota
Steven N Hart - Mayo Clinic Minnesota
Hermela Shimelis - Mayo Clinic Minnesota
Julie M Cunningham - Mayo Clinic Minnesota
Graham G Giles - Cancer Council Victoria
Roger L Milne - Cancer Council Victoria
Sue Healey - QIMR Berghofer Medical Research Institute
Kathy Tucker - Prince of Wales Hospital
Christopher A Haiman - University of Southern California
Brian E Henderson - University of Southern California
Mark S Goldberg - McGill University
Marc Tischkowitz - University of Cambridge
Jacques Simard - Laval University
Penny Soucy - Laval University
Diana M Eccles - University of Southampton
Nhu Le - British Columbia Cancer Agency
Anne Lise Borresen-Dale - Oslo university hospital
Vessela Kristensen - Oslo university hospital
Helga B Salvesen - University of Bergen
Line Bjorge - University of Bergen
Elisa V Bandera - Rutgers Cancer Institute of New Jersey
Harvey Risch - Yale University
Wei Zheng - Vanderbilt University
Alicia Beeghly-Fadiel - Vanderbilt University
Hui Cai - Vanderbilt University
Katri Pylkäs - Northern Finland Laboratory Centre
Robert A E M Tollenaar - Erasmus University Medical Center
Ans M W Van Der Ouweland - Erasmus University Medical Center
Irene L Andrulis - University of Toronto
Julia A Knight - University of Toronto
Steven Narod - University of Toronto
Peter Devilee - Leiden University Medical Centre
Robert Winqvist - Northern Finland Laboratory Centre
Jonine Figueroa - National Cancer Institute, USA
Mark H Greene - National Cancer Institute, USA
Phuong L Mai - National Cancer Institute, USA
Jennifer T Loud - National Cancer Institute, USA
Montserrat García-Closas - Institute of Cancer Research London
Minouk J Schoemaker - Institute of Cancer Research London
Kamila Czene - Karolinska Institutet
Hatef Darabi - Karolinska Institutet
Iain McNeish - University of Glasgow
Nadeem Siddiquil - Glasgow Royal Infirmary
Rosalind Glasspool - Cancer Research UK
Ava Kwong - University of Hong Kong
Sue K Park - Seoul National University
Soo Hwang Teo - Cancer Research Initiatives Foundation
Sook Yee Yoon - University of Malaya
Keitaro Matsuo - Aichi Cancer Center Research Institute
Satoyo Hosono - Aichi Cancer Center Research Institute
Yin Ling Woo - University of Malaya
Yu Tang Gao - Shanghai Cancer Institute
Lenka Foretova - Masaryk Memorial Cancer Institute
Christian F Singer - Medical University of Vienna
Christine Rappaport-Feurhauser - Medical University of Vienna
Eitan Friedman - Sheba Medical Center
Yael Laitman - Sheba Medical Center
Gad Rennert - Carmel Medical Center
Evgeny N Imyanitov - N. N. Petrov Institute of Oncology
Peter J Hulick - NorthShore University HealthSystem
Olufunmilayo I Olopade - University of Chicago
Leigha Senter - Ohio State University
Edith Olah - National Institute of Oncology, Budapest
Jennifer A Doherty - Dartmouth College
Joellen Schildkraut - Duke University
Linetta B Koppert - Erasmus University Medical Center
Lambertus A Kiemeney - Radboud University Nijmegen
Leon F A G Massuger - Radboud University Nijmegen
Linda S Cook - University of New Mexico
Tanja Pejovic - Oregon Health & Science University
Jingmei Li - Karolinska Institutet
Åke Borg - Section I
Anna Öfverholm - Sahlgrenska University Hospital
Mary Anne Rossing - Fred Hutchinson Cancer Research Center
Nicolas Wentzensen - National Cancer Institute, USA
Karin Henriksson
Angela Cox - University of Sheffield
Simon S Cross - University of Sheffield
Barbara J Pasini - University of Cambridge
Mitul Shah - University of Cambridge
Maria Kabisch - German Cancer Research Centre
Diana Torres - Pontificia Universidad Javeriana
Anna Jakubowska - Pomeranian Medical University
Jan Lubinski - Pomeranian Medical University
Jacek Gronwald - Pomeranian Medical University
Bjarni A Agnarsson - National University Hospital of Iceland
Jolanta Kupryjanczyk - The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Joanna Moes-Sosnowska - The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Florentia Fostira - National Centre for Scientific Research Demokritos
Irene Konstantopoulou - National Centre for Scientific Research Demokritos
Susan Slager - University Hospital of Pisa
Michael Jones - Institute of Cancer Research London
Antonis C Antoniou - University of Cambridge
Andrew Berchuck - University of Utah
Anthony Swerdlow - Institute of Cancer Research London
Georgia Chenevix-Trench - QIMR Berghofer Medical Research Institute
Alison M Dunning - University of Cambridge
Paul D P Pharoah - University of Cambridge
Per Hall - Karolinska Institutet
Douglas F Easton - University of Cambridge
Fergus J Couch - Mayo Clinic Minnesota
Amanda B Spurdle - Brigham and Women's Hospital / Harvard Medical School
David E Goldgar - University of Utah
kConFab Investigators
Publication Details: JNCI : Journal of the National Cancer Institute, Vol.108(2), p.djv315
Date published: 02/01/2016
Academic Unit: Management Science and Information Systems (RBS); Cancer Epidemiology and Health Outcomes; Plant Biology (SEBS)
Language: English
Resource Type: Journal article
Identifiers: 991031665482504646