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

Australia Ovarian Cancer Study Group; EMBRACE; OCGN; PRostate cancer Asso Ciation group To Investigate Cancer Associated aLterations in the genome; GEMO Study Collaborators; HEBON

doi:10.1093/jnci/djv315

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

Australia Ovarian Cancer Study Group
, EMBRACE
, OCGN
, PRostate cancer Asso Ciation group To Investigate Cancer Associated aLterations in the genome
, GEMO Study Collaborators
, HEBON

Institute of Human Genetics

Huntsman Cancer Institute
University of Cambridge
Melbourne School of Population and Global Health
University of Melbourne
Peter Maccallum Cancer Centre
Cancer Council Victoria
Antoni van Leeuwenhoek Hospital
Netherlands Cancer Institute
University Hospital Erlangen
University of California at Los Angeles
Institute of Cancer Research
Guy’s Hospital
Imperial College London
Department of Breast Surgery
University College London
University of Oxford
German Cancer Research Center
Heidelberg University
State Research Institute Centre for Innovative Medicine
Latvian Biomedical Research and Study Centre
Beth Israel Deaconess Medical Center
Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Harvard Medical School
Harvard T.H. Chan School of Public Health
University of Pretoria
University of Kansas
National Institute of Health Bogotá
APHP – Paris Saclay University
Institut Curie
INSERM U830
Université Paris Descartes
Centre de Recherche en Cancérologie de Lyon
Centre for Cancer Genetic Epidemiology
Department of Tumour Biology
Centre Léon Bérard
Georgetown University
CHRU Nouvel Hôpital Civil
University of Copenhagen
Copenhagen University Hospital – Herlev and Gentofte
Rigshospitalet
Danish Cancer Society
Aalborg University
Odense University Hospital
Centro de Investigación en Red de Enfermedades Raras
Centre for Biomedical Research on Rare Diseases (CIBERER)
IdISSC (El Instituto de Investigación Sanitaria del Hospital Clnico San Carlos)
Hospital Clinico San Carlos
Vall d'Hebron University Hospital
Barcelona University/Oral Health and Masticatory System Group (Bellvitge Biomedical Research Institute)
Institute Catala Oncologia
University of California-Irvine
Keck School of Medicine of USC
Cancer Prevention Institute of California
Beckman Research Institute of City of Hope
University of California at San Francisco
Cedars-Sinai Medical Center
Stanford University School of Medicine
H. Lee Moffitt Cancer Center & Research Institute
Mailman School of Public Health
Roswell Park Cancer Institute
Memorial Sloan-Kettering Cancer Center
Fox Chase Cancer Center
University of Pennsylvania Health System
MD Anderson Cancer Center
Texas Southern University
University of Texas Health Science Center at Houston
University of Pittsburgh
University of Pittsburgh Cancer Institute
University of Michigan, Ann Arbor
University of Warwick
Klinikum Rechts der Isar
Center for Integrated Oncology
University of Cologne
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
University of Tübingen
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA)
University of Helsinki
Hannover Medical School
Karolinska Institutet
Karolinska University Hospital
University of Eastern Finland
Kuopio University Hospital
VIB Department of Molecular Microbiology
KU Leuven
University Hospitals Leuven
Ghent University Hospital
University of Hamburg
Kliniken Essen-Mitte
Dr. Horst Schmidt Klinik GmbH
Charité Universitätsmedizin
FIRC Institute of Molecular Oncology
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
IRCCS Centro di Riferimento Oncologico - Aviano PN
European Institute of Oncology
Istituto Oncologico Veneto – IRCCS
U.O.C. di Oncologia
Portugese Oncology Institute
University of Porto
University Hospital of Pisa
Mayo Clinic Rochester, MN
QIMR Berghofer Medical Research Institute
Prince of Wales Hospital
McGill University Health Centre, Royal Victoria Hospital
McGill University
School of Clinical Medicine
Research Center
University of Southampton, Faculty of Medicine
BC Cancer
Oslo University Hospital-Radiumhospitalet
University of Oslo
Oslo University Hospital
Haukeland University Hospital
University of Bergen
Rutgers - The State University of New Jersey, New Brunswick
Yale University
Vanderbilt-Ingram Cancer Center
University of Oulu
Northern Finland Laboratory Centre NordLab
Erasmus MC
Mount Sinai Hospital of University of Toronto
University of Toronto
Leiden University
National Cancer Institute (NCI)
University of Glasgow
Glasgow Royal Infirmary
Cancer Research UK
Hong Kong Sanatorium & Hospital
The University of Hong Kong
Seoul National University
Sime Darby Medical Centre
University of Malaya
Aichi Cancer Center Hospital and Research Institute
Shanghai Cancer Institute
Masaryk Memorial Cancer Institute
Medical University of Vienna
The Gertner Institute
Carmel Medical Center and Technion Faculty of Medicine
N.N. Petrov Institute of Oncology
NorthShore University HealthSystem
The University of Chicago
Ohio State University
National Institute of Oncology
Dartmouth College
Duke University
Duke Cancer Institute
Radboud University Nijmegen
Radboud Institute for Molecular Life Sciences
University of New Mexico
Oregon Health and Science University
Lund University
Sahlgrenska University Hospital
Fred Hutchinson Cancer Research Center
Skane University Hospital
University of Sheffield
Pomeranian Medical University in Szczecin
Department of Pathology
M.Sklodowska-Curie Cancer Centre
Demokritos National Centre for Scientific Research

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

Abstract

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 (OR_w) 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 (OR_w = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10^-6) and invasive ovarian cancer (OR_w = 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 (OR_w = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10^-5 and OR_w = 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.

Original language	English
Journal	Journal of the National Cancer Institute
Volume	108
Issue number	2
DOIs	https://doi.org/10.1093/jnci/djv315
State	Published - 01 Feb 2016

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10.1093/jnci/djv315

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@article{f21fd1a5038944be94aff3b5fa2cac58,

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

abstract = "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.",

author = "\{Australia Ovarian Cancer Study Group\} and EMBRACE and OCGN and \{PRostate cancer Asso Ciation group To Investigate Cancer Associated aLterations in the genome\} and \{GEMO Study Collaborators\} and HEBON and Meeks, \{Huong D.\} and Honglin Song and Kyriaki Michailidou and Bolla, \{Manjeet K.\} and Joe Dennis and Qin Wang and Daniel Barrowdale and Debra Frost and Lesley McGuffog and Steve Ellis and Bingjian Feng and Buys, \{Saundra S.\} and Hopper, \{John L.\} and Southey, \{Melissa C.\} and Andrea Tesoriero and James, \{Paul A.\} and Fiona Bruinsma and Campbell, \{Ian G.\} and Annegien Broeks and Schmidt, \{Marjanka K.\} and Hogervorst, \{Frans B.L.\} and Beckman, \{Matthias W.\} and Fasching, \{Peter A.\} and Olivia Fletcher and Nichola Johnson and Sawyer, \{Elinor J.\} and Elio Riboli and Susana Banerjee and Usha Menon and Ian Tomlinson and Barbara Burwinkel and Ute Hamann and Frederik Marme and Anja Rudolph and Ramunas Janavicius and Laima Tihomirova and Nadine Tung and Judy Garber and Daniel Cramer and Terry, \{Kathryn L.\} and Poole, \{Elizabeth M.\} and Tworoger, \{Shelley S.\} and Dorfling, \{Cecilia M.\} and \{Van Rensburg\}, \{Elizabeth J.\} and Godwin, \{Andrew K.\} and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Dominique Stoppa-Lyonnet and Francesca Damiola and Diana Torres",

year = "2016",

month = feb,

day = "1",

doi = "10.1093/jnci/djv315",

language = "English",

volume = "108",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "2",

}

Australia Ovarian Cancer Study Group, EMBRACE, OCGN, PRostate cancer Asso Ciation group To Investigate Cancer Associated aLterations in the genome, GEMO Study Collaborators & HEBON 2016, 'BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers', Journal of the National Cancer Institute, vol. 108, no. 2. https://doi.org/10.1093/jnci/djv315

TY - JOUR

T1 - BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

AU - Australia Ovarian Cancer Study Group

AU - EMBRACE

AU - OCGN

AU - PRostate cancer Asso Ciation group To Investigate Cancer Associated aLterations in the genome

AU - GEMO Study Collaborators

AU - HEBON

AU - Meeks, Huong D.

AU - Song, Honglin

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K.

AU - Dennis, Joe

AU - Wang, Qin

AU - Barrowdale, Daniel

AU - Frost, Debra

AU - McGuffog, Lesley

AU - Ellis, Steve

AU - Feng, Bingjian

AU - Buys, Saundra S.

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Tesoriero, Andrea

AU - James, Paul A.

AU - Bruinsma, Fiona

AU - Campbell, Ian G.

AU - Broeks, Annegien

AU - Schmidt, Marjanka K.

AU - Hogervorst, Frans B.L.

AU - Beckman, Matthias W.

AU - Fasching, Peter A.

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Sawyer, Elinor J.

AU - Riboli, Elio

AU - Banerjee, Susana

AU - Menon, Usha

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Hamann, Ute

AU - Marme, Frederik

AU - Rudolph, Anja

AU - Janavicius, Ramunas

AU - Tihomirova, Laima

AU - Tung, Nadine

AU - Garber, Judy

AU - Cramer, Daniel

AU - Terry, Kathryn L.

AU - Poole, Elizabeth M.

AU - Tworoger, Shelley S.

AU - Dorfling, Cecilia M.

AU - Van Rensburg, Elizabeth J.

AU - Godwin, Andrew K.

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Stoppa-Lyonnet, Dominique

AU - Damiola, Francesca

AU - Torres, Diana

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84962488384

U2 - 10.1093/jnci/djv315

DO - 10.1093/jnci/djv315

M3 - Article

C2 - 26586665

AN - SCOPUS:84962488384

SN - 0027-8874

VL - 108

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 2

ER -

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

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