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 - Moysich, Kirsten B.
N1 - 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.
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 -