Prevalence of Pathogenic Germline Variants in Patients With Gastric Cancer Ascertained Through Multigene Panel Testing.

Purpose: The prevalence of pathogenic/likely pathogenic germline variants (PGVs) in gastric cancer (GC) predisposition genes is not well understood. We aimed to determine this in patients with GC undergoing germline genetic testing at a large commercial laboratory.

Methods: This was a cross-sectional study. Retrospective review of genetic testing in patients with GC at a commercial laboratory (Invitae Corp) from March 2015 to July 2023 was performed. Prevalence of PGVs was determined and compared with a control cohort of 20,139 individuals unaffected by cancer. Data were abstracted from test requisition forms.

Results: In total, 3,706 patients with GC underwent genetic testing, of which 494 (13.3%) patients carried PGVs, 1,200 (32.4%) had variants of uncertain significance, and 1,890 (51%) had negative testing. PGVs were identified in 38 genes, of which 385 of 494 (77.9%) were in a gene previously associated with GC, including 35% in homologous recombination repair genes (BRCA1, BRCA2, PALB2, and ATM), 19.5% in Hereditary Diffuse GC genes (CDH1 and CTNNA1), and 17.4% in Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). Comparing the GC cohort with the unaffected cohort, it was found that there was significant enrichment of PGVs in most GC-associated genes, except for APC, EPCAM, MUTYH, and PMS2. Odds of carrying a PGV was increased significantly in males and patients with a personal history of another cancer with odds ratio (OR) of 1.3 (95% CI, 1.1 to 1.6) and OR, 1.4 (95% CI, 1.1 to 1.7), respectively.

Conclusion: In this large study of genetic testing in patients with GC, more than one in eight patients referred for germline testing was found to harbor a PGV in a cancer predisposition gene, which is higher than previous estimates. Most PGVs were identified in genes previously associated with GC.