Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks

• Published in: Journal of medical genetics Vol. 54; no. 11; pp. 732 - 741
• Main Authors: Decker, Brennan, Allen, Jamie, Luccarini, Craig, Pooley, Karen A, Shah, Mitul, Bolla, Manjeet K, Wang, Qin, Ahmed, Shahana, Baynes, Caroline, Conroy, Don M, Brown, Judith, Luben, Robert, Ostrander, Elaine A, Pharoah, Paul DP, Dunning, Alison M, Easton, Douglas F
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.11.2017; BMJ Publishing Group
• Series: Original article
• Subjects: Age; Ataxia Telangiectasia Mutated Proteins - chemistry; Ataxia Telangiectasia Mutated Proteins - genetics; Breast cancer; Breast Neoplasms - genetics; Cancer Genetics; Cell cycle; Checkpoint Kinase 2 - chemistry; Checkpoint Kinase 2 - genetics; Consortia; Deoxyribonucleic acid; DNA; DNA repair; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; Fanconi Anemia Complementation Group N Protein - chemistry; Fanconi Anemia Complementation Group N Protein - genetics; Female; Genes; Genetic Predisposition to Disease; Genetic Variation; Health risk assessment; Humans; Kinases; Malignancy; Pathogenicity; Population; Proteins; Sequence Analysis, Protein; Studies; Geneticscreening/counselling; Cancer: breast; Evidence Based Practice; Genetic Epidemiology
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2017-104588

BackgroundBreast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK.MethodsGene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms.ResultsTruncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect.ConclusionsTruncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded.