Abstract
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.
Highlights
Gastric cancer (GC) is one of the most common cancers worldwide, ranking fifth for incidence and third for mortality [1]
All carriers of CDH1 pathogenic/likely-pathogenic variants fell within the patient group selected according to criteria I-IV, i.e., criteria established by the international gastric cancer linkage consortium (IGCLC) for HDGC [13]
Regarding the 11 loss-of-function variants we found in genes other than CDH1, six were in genes associated with hereditary breast and ovarian cancer (HBOC), including BRCA1, BRCA2, ATM, and PALB2
Summary
Gastric cancer (GC) is one of the most common cancers worldwide, ranking fifth for incidence and third for mortality [1]. The gene most frequently associated with hereditary cases is CDH1 (OMIM *192090) [6], pathogenic variants of which are causative of the hereditary diffuse gastric cancer syndrome (HDGC, OMIM #137215), a dominant condition predisposing to both DGC and breast cancer of lobular histotype (LBC). By following guideline criteria for genetic testing, the detection rate of CDH1 pathogenic variants is 30–50% in selected patients from populations with low GC incidence, while it drops down to. We aimed at identifying, by multigene panel (MGP) testing, genetic variants associated with GC and/or LBC in patients with suspected cancer predisposition. To our knowledge, this is the first NGS-based analysis on a large cohort of Italian patients
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