Background:
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.
Methods:
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.
Results: 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.
Conclusions: 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 non-
dgc 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.
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