Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer
CDH1 pathogenic variants (PV) cause the majority of inherited diffuse-gastric cancer (DGC), but have low detection rates and vary geographically. This study examines hereditary causes of DGC in patients from Ontario, Canada.
Eligible DGC cases at the Zane Cohen Centre (ZCC) underwent multi-gene panel or CDH1 single-site testing if they met 2015 International Gastric Cancer Linkage Consortium (IGCLC) criteria, isolated DGC <50 or family history suggestive of an inherited cancer syndrome. A secondary aim was to review all CDH1 families at the ZCC to assess cancer penetrance.
85 DGC patients underwent CDH1 (n=43) or multi-gene panel testing (n=42), and 15 (17.6%) PV or likely PV were identified. CDH1 detection rate was 9.4% (n=8/85), and 11% (n=7/65) using IGCLC criteria. No CDH1 PV identified in isolated DGC <40, but one PV identified in isolated DGC<50. Multi-gene panel from 42 individuals identified 9 PV (21.4%) including CDH1, STK11, ATM, BRCA2, MLH1 and MSH2. Review of 81 CDH1 carriers revealed that 10% had DGC (median age:48, range:38-59), 41% were unaffected (median age:53, range:26-89). Three families had lobular-breast cancer (LBC) only. Non-DGC/LBC malignancies included colorectal, gynecological, kidney/bladder, prostate, testicular and ductal breast.
Low detection rate of CDH1 in Ontario DGC patients. No CDH1 PV found in isolated DGC <40, but identified in isolated DGC<50. Multi-gene panels are recommended for all DGC under age 50, and those meeting the IGCLC criteria, given overlapping phenotype with other hereditary conditions. HDGC phenotype is evolving with a spectrum of non-DGC/LBC cancers.