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

EMBRACE, 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 BroeksMarjanka 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, Jonine Figueroa

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalJNCI: Journal of the National Cancer Institute
Issue number2
Publication statusPublished - Feb 2016


  • Adult
  • Aged
  • BRCA2 Protein
  • Breast Neoplasms
  • Codon, Terminator
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Logistic Models
  • Lysine
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Odds Ratio
  • Ovarian Neoplasms
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms
  • Risk Assessment
  • Risk Factors


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