PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
AuthorSouthey, MC; Goldgar, DE; Winqvist, R; Pylkas, K; Couch, F; Tischkowitz, M; Foulkes, WD; Dennis, J; Michailidou, K; van Rensburg, EJ; ...
Source TitleJournal of Medical Genetics
PublisherBMJ PUBLISHING GROUP
University of Melbourne Author/sHopper, John; Campbell, Ian; Milne, Roger; Winship, Ingrid; Southey, Melissa; Tsimiklis, Helen; Dowty, James; Teo, Zhi Ling; Giles, Graham; McLean, Catriona; ...
AffiliationFlorey Department of Neuroscience and Mental Health
Sir Peter MacCallum Department of Oncology
Melbourne School of Population and Global Health
Document TypeJournal Article
CitationsSouthey, M. C., Goldgar, D. E., Winqvist, R., Pylkas, K., Couch, F., Tischkowitz, M., Foulkes, W. D., Dennis, J., Michailidou, K., van Rensburg, E. J., Heikkinen, T., Nevanlinna, H., Hopper, J. L., Doerk, T., Claes, K. B. M., Reis-Filho, J., Teo, Z. L., Radice, P., Catucci, I. ,... Milne, R. L. (2016). PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. JOURNAL OF MEDICAL GENETICS, 53 (12), pp.800-811. https://doi.org/10.1136/jmedgenet-2016-103839.
Access StatusOpen Access
BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
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