CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation

Abstract

Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking.

CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer

“…Histology-specific enrichment analysis validated prior associations between CDH1 germline variants in LBC and DGC and identified a novel association with CSRCC [ 9 ]. CSRCC is an aggressive adenocarcinoma subtype with a poor prognosis overall and thus determining cancer-risk susceptibility genes presents an unmet need.…”

“…In one study, colon cancer was reported in 3 of 238 (1%) CDH1 pathogenic variant carriers, with 1 case of SRCC. Most recently, Benesch et al postulated through clinical observation and data from SEER that SRCC might be enriched among CDH1 variant carriers with signet ring cell gastric cancer [ 9 ]. Notably, there was no increased risk of colon cancer in CDH1 carriers compared to that of the SEER population [ 6 ].…”

The Autophagic Route of E-Cadherin and Cell Adhesion Molecules in Cancer Progression

“…Somatic CDH1 mutations in these tumors are also common [ 72 , 73 , 74 , 75 ]. CDH1-associated lobular breast and diffuse gastric cancers are characterized by small, non-cohesive epithelial cells individually dispersed or organized in a single-file linear pattern in a fibrous stroma [ 76 , 77 ]. Although most data support the notion that CDH1 is a tumor suppressor, Kleer and coworkers have shown that in inflammatory breast cancers, E-cadherin seems to exert an opposite role [ 78 ].…”

Gastric Signet-Ring-Cell Adenocarcinoma with Delayed Retroperitoneal Metastasis and Fibrosis

“…Gastric SRCCs share no risk factors with conventional intestinal gastric cancers such as Helicobacter pylori infection [ 2 ]. Some gastric SRCCs arise from germline mutations in CDH1 , termed as hereditary diffuse gastric cancers (HDGCs); however, an increasing array of genes are now implicated including CTNNA1 , BRCA2 , S TK11 , SBHB , PRSS1 , ATM , MSR1 , and PALB2 [ 3 , 4 ]. HDGC however comprises only 1–3% of all gastric cancers, leaving the pathogenesis behind most gastric SRCCs unknown and understudied [ 5 ].…”

“…If detected prior to submucosal invasion, prognosis is equivalent or better than that of intestinal gastric adenocarcinomas [ 2 ]. However, the diffuse nature of the disease usually results in detection at advanced stages [ 1 , 4 ]. There remains considerable debate from numerous retrospective epidemiological studies whether SRCC histology is an independent prognostic factor [ 2 ].…”