Abstract
To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.
Highlights
Invasive lobular carcinoma (ILC) of the breast accounts for approximately 10%-15% of all invasive breast carcinomas.[1]
In case-control analysis, CDH1 and BRCA2 pathogenic variant (PV) were associated with high risks of ILC and CHEK2, ATM, and PALB2 PVs were associated with moderate risks
The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not
Summary
Invasive lobular carcinoma (ILC) of the breast accounts for approximately 10%-15% of all invasive breast carcinomas.[1]. The risk of ILC among carriers of PVs in other genes from multigene hereditary cancer testing panels has not been adequately defined. Some studies have reported that PVs in BRCA1 and TP53 do not predispose to ILC,[5,6] whereas PVs in BRCA2 7 and the CHEK2 I157T missense variant have been associated with ILC.[8,9,10] previous studies have primarily evaluated the frequency of germline PVs in CDH1 and other genes among high-risk women with family history of breast cancer or young age at diagnosis. In one of the largest studies of ILC involving population-based and clinical testing cohorts, we describe the frequency of germline PVs in cancer predisposition genes in women with ILC and estimate the magnitude of risk of ILC in PV carriers
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