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

  • M. Aronson Sinai Health System, Zane Cohen Centre for Digestive Diseases
  • C. Swallow Sinai Health System, University of Toronto
  • A. Govindarajan Sinai Health System, University of Toronto
  • K. Semotiuk Sinai Health System, Zane Cohen Centre for Digestive Diseases
  • Z. Cohen Sinai Health System, Zane Cohen Centre for Digestive Diseases, Sinai Health System, University of Toronto
  • P. Kaurah BC Cancer
  • L. Velsher North York General Hospital
  • I. Ambus North York General Hospital
  • K. Buckley Grand River Hospital
  • C. Forster-Gibson Trillium Health Partners
  • W.S. Meschino Porcupine Health Unit
  • A. Blumenthal Lakeridge Health
  • R.H. Kim Sinai Health System, University of Toronto
  • S. Brar Sinai Health System, University of Toronto
Keywords: CDH1, Hereditary diffuse gastric cancer, HDGC, early-onset, lobular breast cancer

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Author Biographies

C. Swallow, Sinai Health System, University of Toronto

Department of Surgery

A. Govindarajan, Sinai Health System, University of Toronto

Department of Surgery

Z. Cohen, Sinai Health System, Zane Cohen Centre for Digestive Diseases, Sinai Health System, University of Toronto

Department of Surgery

R.H. Kim, Sinai Health System, University of Toronto

Department of Medicine, Division of Medical Oncology

S. Brar, Sinai Health System, University of Toronto

Department of Surgery

Published
2019-12-10
How to Cite
Aronson, M., Swallow, C., Govindarajan, A., Semotiuk, K., Cohen, Z., Kaurah, P., Velsher, L., Ambus, I., Buckley, K., Forster-Gibson, C., Meschino, W., Blumenthal, A., Kim, R., & Brar, S. (2019). Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer. Current Oncology, 27(2). https://doi.org/10.3747/co.27.5663
Section
Cancer Genetics