Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Abstract

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS 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). RESULTS 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. CONCLUSION 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.

Detection of Structural Variations and Fusion Genes in Breast Cancer Samples Using Third-Generation Sequencing

“…By the combination of a full-length panel approach and long-read sequencing tools, it was possible to explore not only SNPs but also most SVs within these genes, regardless of their locations at either exons or introns. The panel in our study focuses on two gene types: twenty genes associated with a high risk of breast cancer and also participated in homologous recombination repair (HRR) ( Breast Cancer Association et al, 2021 ; Hu et al, 2021 ; Yadav et al, 2021 ), and eight genes involved in the precision medicine during breast cancer treatment ( Harbeck et al, 2019 ; Sparano et al, 2019 ; Waks and Winer, 2019 ) ( Supplementary Table S1 ). Probes were designed to cover the whole genome regions of these genes, which are about 5 M bases.…”

Pleiotropic cancer manifestations of germline CDH1 mutations: Risks and management

“…Mutation rate detection in LBC is increasing 22,30,32 . It is interesting to note that the majority of the screened LBC families were not associated with the DGC spectrum.…”

“…For HLBC, the panel established the following criteria: (a) bilateral LBC with or without family history of LBC, with age at onset <50 years; and (b) unilateral LBC with family history of LBC, with age at onset <45 years. When adopting these criteria, the probability to identify germline CDH1 mutations is estimated to be around 3% in high‐risk LBC patients, 21 and 0.5% in unselected LBCs 22 …”

“…When adopting these criteria, the probability to identify germline CDH1 mutations is estimated to be around 3% in high-risk LBC patients, 21 and 0.5% in unselected LBCs. 22 4 | DIFFUSE GASTRIC CANCER…”

Clinical outcomes and Oncotype DX Breast Recurrence Score® in early‐stageBRCA‐associated hormone receptor‐positive breast cancer

“… 4 , 6 , 8 Women with BRCA2 mutations have an increased risk of invasive lobular breast cancer, as opposed to BRCA1 mutation carriers. 9 While the observations would be expected to have strong implications on prognosis, data on BRCA‐associated ( BRCAm ) breast cancers are inconsistent. 10 Most studies describing characteristics of BRCAm cancers are small and descriptive involving data from multiple institutions.…”