The EPIC-Norfolk Study
Rare, protein-truncating variants in , and , but not , are associated with increased breast cancer risks.
Journal of medical genetics 2017 ; 54: 732-741.
Decker B, Allen J, Luccarini C, Pooley KA, Shah M, Bolla MK, Wang Q, Ahmed S, Baynes C, Conroy DM, Brown J, Luben R, Ostrander EA, Pharoah PD, Dunning AM, and Easton DF
DOI : 10.1136/jmedgenet-2017-104588
PubMed ID : 28779002
PMCID : PMC5740532
URL : https://jmg.bmj.com/content/54/11/732
Abstract
Breast 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 , , and , we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK.
Gene 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 algorithms.
Truncating variants in (OR=4.69, 95% CI 2.27 to 9.68), (OR=3.26; 95% CI 1.82 to 6.46) and (OR=3.11; 95% CI 2.15 to 4.69), but not (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in and were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in were associated with similar risks for both subtypes. There was also some evidence that missense variants in , and may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect.
Truncating variants in are associated with a higher risk of BC than those in or . A substantial risk of BC due to truncating variants can be excluded.