Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes

Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS. •Whist bona fide genes that predispose t