Abstract
Background and aimsCDH1 germline variants have been linked to heritability in diffuse gastric (DGC) and lobular breast cancer (LBC). Studies have not yet assessed whether CDH1 is a cancer-susceptibility gene in other cancers. Herein, we mapped the landscape of pathogenic and likely pathogenic (P/LP) germline variants in CDH1 across various cancers and ethnicities.MethodsWe evaluated CDH1 germline P/LP variants in 212,944 patients at one CLIA-certified laboratory (Invitae) and described their frequency in 7 cancer types. We screened for CDH1 variant enrichment in each cancer relative to a cancer-free population from The Genome Aggregation Database version 3 (gnomADv3).ResultsCDH1 P/LP variants were identified in 141 patients, most commonly in patients with DGC (27/408, 6.6%) followed by colorectal signet-ring cell cancer (CSRCC; 3/79, 3.8%), gastric cancer (56/2756, 2%), and LBC (22/6809, 0.3%). CDH1 P/LP variants were enriched in specific ethnic populations with breast cancer, gastric cancer, CRC, LBC, DGC, and CSRCC compared to matched ethnicities from gnomADv3.ConclusionWe report for the first time the prevalence of P/LP CDH1 variants across several cancers and show significant enrichment in CDH1 P/LP variants for patients with CSRCC, DGC, and LBC across various ethnicities. Future prospective studies are warranted to validate these findings.
Highlights
We report for the first time the prevalence of pathogenic and likely pathogenic (P/LP) CDH1 variants across several cancers and show significant enrichment in CDH1 P/LP variants for patients with colorectal signet-ring cell cancer (CSRCC), diffuse gastric (DGC), and lobular breast cancer (LBC) across various ethnicities
Germline variants in CDH1, which codes for the cell–cell adhesion protein E-cadherin, were first identified in families with hereditary diffuse gastric cancer (HDGC) [1]
Subsequent reports noted that individuals with germline CDH1 pathogenic variants were predisposed to both DGC and lobular breast cancer (LBC) [2]
Summary
Germline variants in CDH1, which codes for the cell–cell adhesion protein E-cadherin, were first identified in families with hereditary diffuse gastric cancer (HDGC) [1]. Subsequent reports noted that individuals with germline CDH1 pathogenic variants were predisposed to both DGC and lobular breast cancer (LBC) [2]. Massari et al reported that 7% of all CDH1 mutations are present in non-gastric tumours with most being identified in patients with breast cancer [3]. A recent study found that among patients not exclusively ascertained based on strict HDGC criteria, the cumulative incidence of gastric cancer for individuals with pathogenic CDH1 variants is significantly lower (42% at age 80 years) than what has been previously reported [6, 7]
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