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 - Pejovic, Tanja
N1 - Funding Information:
This work was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research and the Ministère de l''Économie, de l''Innovation et des Exportations du Québec through Génome Québec. Amanda Spurdle is supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship, and aspects of this research were funded by Australian NHMRC Project grant ID #1010719. This work was also supported in part by National Institutes of Health (NIH) grants CA128978 and CA116167, an NIH specialized program of research excellence in breast cancer to the Mayo Clinic (P50 CA116201), and the Breast Cancer Research Foundation. The The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) data management and analysis is funded through Cancer Research-UK grant C12292/A11174. Breast Cancer Association Consortium (BCAC) data management was funded by Cancer Research UK (C1287/A10118 and C1287/A12014) and by the European Community''s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175). BCAC meetings have been funded by the European Union COST programme (BM0606). Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute Genetic Associations and Mechanisms in Oncology (GAME-ON) Post-Genome Wide Association Study (GWAS) Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available at http://www.wtccc. org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by the Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute. Funding for the iCOGS infrastructure came from: the European Community''s Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.
Publisher Copyright:
© The Author 2015. Published by Oxford University Press. All rights reserved.
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.
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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 -