Frequency of pathogenic germline variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1 and TP53 in sporadic lobular breast cancer

Background: Invasive lobular breast cancer (ILC) accounts for ~15% of invasive breast carcinomas and is commonly associated with lobular carcinoma in situ (LCIS). Both have been shown to have higher familial risks than the more common ductal cancers. However there is little data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in ILC. The aim of this study was to assess the frequency of germline variants in CDH1, BRCA2, BRCA1, CHEK2, PALB2 and TP53 in sporadic ILC and LCIS diagnosed in women aged 60 years or less. Methods: Access Array technology (Fluidigm) was used to amplify all exons of CDH1, BRCA2, BRCA1, TP53, CHEK2 and PALB2 using a custom made targeted sequencing panel in 1,434 cases of ILC and 368 cases of pure LCIS together with 1,611 controls. Results: Case-control analysis revealed an excess of pathogenic variants in BRCA2, CHEK2, PALB2 and CDH1 in women with ILC. CHEK2 was the only gene that showed an association with pure LCIS (OR = 9.90, 95% CI 3.42-28.66, P = 1.4 x10-5) with a larger effect size seen in LCIS compared to ILC (OR = 4.31, 95% CI 1.61-11.58, P = 1.7 x10-3). Conclusions: 11% of patients with ILC aged </= 40 years carried germline variants in known breast cancer susceptibility genes. Impact: Women with ILC aged of 40 years or less should be offered genetic screening using a panel of genes that includes BRCA2, CHEK2, PALB2 and CDH1.