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BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

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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 hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 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 = 5.9x10(-6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-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 = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-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.
Keywords
GERM-LINE MUTATION, SINGLE-NUCLEOTIDE POLYMORPHISMS, PANCREATIC-CANCER, SUSCEPTIBILITY GENE, DNA RECOMBINATION, ESTROGEN-RECEPTOR, FAMILY-HISTORY, FANCONI-ANEMIA, LOCI, CONSORTIUM

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Chicago
Meeks, Huong D, Honglin Song, Kyriaki Michailidou, Manjeet K Bolla, Joe Dennis, Qin Wang, Daniel Barrowdale, et al. 2016. “BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.” Jnci-journal of the National Cancer Institute 108 (2).
APA
Meeks, H. D., Song, H., Michailidou, K., Bolla, M. K., Dennis, J., Wang, Q., Barrowdale, D., et al. (2016). BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 108(2).
Vancouver
1.
Meeks HD, Song H, Michailidou K, Bolla MK, Dennis J, Wang Q, et al. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE. 2016;108(2).
MLA
Meeks, Huong D, Honglin Song, Kyriaki Michailidou, et al. “BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.” JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 108.2 (2016): n. pag. Print.
@article{7158225,
  abstract     = {Background: The K3326X variant in BRCA2 (BRCA2*c.9976A{\textrangle}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 hormone-related cancers. 
Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 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 = 5.9x10(-6)) and invasive ovarian cancer (ORw = 1.26, 95\% CI = 1.10 to 1.43, P = 3.8x10(-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 = 3.4x10(-5) and ORw = 1.50, 95\% CI = 1.28 to 1.76, P = 4.1x10(-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.},
  articleno    = {djv315},
  author       = {Meeks, Huong D and Song, Honglin and Michailidou, Kyriaki and Bolla, Manjeet K and Dennis, Joe and Wang, Qin and Barrowdale, Daniel and Frost, Debra and McGuffog, Lesley and Ellis, Steve and Feng, Bingjian and Buys, Saundra S and Hopper, John L and Southey, Melissa C and Tesoriero, Andrea and James, Paul A and Bruinsma, Fiona and Campbell, Ian G and Broeks, Annegien and Schmidt, Marjanka K and Hogervors, Frans BL and Beckman, Matthias W and Fasching, Peter A and Fletcher, Olivia and Johnson, Nichola and Sawyer, Elinor J and Riboli, Elio and Banerjee, Susana and Menon, Usha and Tomlinson, Ian and Burwinkel, Barbara and Hamann, Ute and Marme, Frederik and Rudolph, Anja and Janavicius, Ramunas and Tihomirova, Laima and Tung, Nadine and Garber, Judy and Cramer, Daniel 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 Guenel, Pascal and Truong, Therese and Stoppa-Lyonnet, 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  issn         = {0027-8874},
  journal      = {JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE},
  keyword      = {GERM-LINE MUTATION,SINGLE-NUCLEOTIDE POLYMORPHISMS,PANCREATIC-CANCER,SUSCEPTIBILITY GENE,DNA RECOMBINATION,ESTROGEN-RECEPTOR,FAMILY-HISTORY,FANCONI-ANEMIA,LOCI,CONSORTIUM},
  language     = {eng},
  number       = {2},
  pages        = {10},
  title        = {BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers},
  url          = {http://dx.doi.org/10.1093/jnci/djv315},
  volume       = {108},
  year         = {2016},
}

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