Journal
CANCERS
Volume 11, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/cancers11091340
Keywords
stomach neoplasms; cancer predisposition; CDH1 gene; next-generation sequencing
Categories
Funding
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
- Italian Ministry of Education, University and Research (MIUR)-Dipartimenti di Eccellenza Program (2018-2022)-Department of Biology and Biotechnology L. Spallanzani, University of Pavia
- Dunia Beam Erasmus Mundus project
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The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10-50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.
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