Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer.

M Aronson,C Forster-Gibson,S Brar,Z Cohen,A Govindarajan,W.S Meschino,P Kaurah,R.H Kim,A Blumenthal,I Ambus,K Buckley,C Swallow,L Velsher,K Semotiuk

doi:10.3747/co.27.5663

Abstract

CDH1 pathogenic variants (pvs) cause most cases of inherited diffuse gastric cancer (dgc), but have low detection rates and vary geographically. In the present study, we examined hereditary causes of dgc in patients in Ontario. CDH1 testing through single-site or multi-gene panels was conducted for patients with dgc meeting the 2015 International Gastric Cancer Linkage Consortium (igclc) criteria, or with isolated dgc at less than 50 years of age, or with a strong family history of cancer identified at the Zane Cohen Centre (zcc). All CDH1-positive patients at zcc, regardless of cancer history, were summarized. In 15 of 85 patients with dgc (17.6%), a pv or likely pv was identified through CDH1 single-site (n = 43) or multi-gene panel (n = 42) testing. The detection rate was 9.4% overall (8 of 85) and 11% using igclc criteria (7 of 65). No CDH1 pvs were identified in patients with isolated dgc at less than 40 years of age, but 1 pv was identified in a patient with isolated dgc at less than 50 years of age. Multi-gene panels identified 9 pvs (21.4%), including CDH1, STK11, ATM, BRCA2, MLH1, and MSH2. Review of 81 CDH1 carriers identified 10% with dgc (median age: 48 years; range: 38-59 years); 41% were unaffected (median age: 53 years; range: 26-89 years). Observed malignancies other than dgc or lobular breast cancer (lbc) included colorectal, gynecologic, kidney or bladder, prostate, testicular, and ductal breast cancers. Lobular-breast cancer was seen only in 3 families. In Ontario, the detection rate of CDH1 pvs in patients with dgc was low: no pvs were identified in patients with isolated dgc at less than 40 years of age, and 1 was identified in a patient with isolated dgc at less than 50 years of age. Isolated lbc with no dgc was observed in CDH1-positive families, as were pathology-confirmed nondgc or non-lbc malignancies, which had not previously been reported. Given a phenotype that overlaps with other hereditary conditions, multi-gene panels are recommended for all patients with dgc at less than 50 years of age and for those meeting igclc criteria.

Highlights

Gastric cancer arises in 1 of 3500 Canadians yearly[1]
No CDH1 pvs were identified in patients with isolated dgc at less than 40 years of age, but 1 pv was identified in a patient with isolated dgc at less than 50 years of age
In Ontario, the detection rate of CDH1 pvs in patients with dgc was low: no pvs were identified in patients with isolated dgc at less than 40 years of age, and 1 was identified in a patient with isolated dgc at less than 50 years of age

Summary

Introduction

Hereditary gastric cancer is rare: 10% of individuals with gastric cancer have a positive family history, but only 1%–3% are found to have a hereditary condition[2]. The most common hereditary condition associated with diffuse-type gastric cancer (dgc) is hereditary diffuse gastric cancer syndrome (hdgc), which is caused by a heterozygous germline pathogenic or likely pathogenic variant (pv) in the CDH1 gene. The syndrome is associated with a lifetime risk for dgc of 70% in men and 56% for women, and a risk for lobular breast cancer (lbc) in women of 42%3. CDH1 pathogenic variants (pvs) cause most cases of inherited diffuse gastric cancer (dgc), but have low detection rates and vary geographically. We examined hereditary causes of dgc in patients in Ontario

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