智利早发胃癌患者的种系致病性变异

Aim: This study aims to identify and describe the pathogenic/likely pathogenic (P/LP) germline variants found in 159 Chilean patients with early-onset gastric cancer (EOGC). Introduction: Early-onset gastric cancer (EOGC), diagnosed before the age of 45 or 50, is increasingly recognized as a distinct clinical entity. Familial gastric cancer, which clusters within families often with early onset, is associated with specific genetic syndromes. Hereditary gastric cancer (HGC) accounts for about 10% of all gastric cancer cases, with mutations in the CDH1 gene being the most frequently observed in HGC. A previous report from our group described a Chilean family with hereditary diffuse gastric cancer (HDGC) harboring a pathogenic CDH1 variant, suggesting a lower frequency of pathogenic variants in this population. Methods: Gene panel analysis was performed on 124 patients, and whole-exome sequencing (WES) was conducted on 35 patients using the Agilent SureSelect Human All Exome V7 kit. Alignment and variant calling were performed using Dragen v3.8, and variants were annotated with Illumina Nirvana and Annovar. Genotyping of index patients and their relatives was done using PCR and Sanger sequencing. Results: Nine P/LP germline variants were identified across five genes in 11 patients. No P/LP pathogenic variants were found in the CDH1 gene, consistent with prior findings. A P/LP variant in the CTNNA1 gene (c.531T>G, p.Tyr177Ter) was found in one patient. Additionally, a high CAAD score variant of uncertain significance (VUS) (c.293G>A, p.Arg98Gln) was found in a large HDGC family. Two BRCA2 P/LP variants were identified: c.4740_4741dupTG (p.Glu1581fs) in two unrelated patients and c.5439delT (p.Leu1813_Val1814insTer) in one patient, both variants having been previously described in Chilean hereditary breast cancer patients. Three ATM P/LP variants were identified, including c.3381_3384del (p.Gln1128fs) in a family with three affected individuals, and c.3894dup (p.Ala1299fs) and c.8122G>A (p.Asp2708Asn) in other unrelated patients. A RUNX1 variant (c.1270T>G, p.Ser424Ala) was found in three independent cases, and a POT1 variant (c.1087C>T, p.Arg363Ter) was identified in a family with multiple gastric cancer cases. Conclusion: These families exhibited incomplete penetrance and multi-organ cancers. This is the first report of P/LP variants in the RUNX1 and POT1 genes in hereditary gastric cancer. RUNX1 is associated with hereditary myeloid malignancies, and POT1 with hereditary colorectal cancer. This study provides new insights into the genetic basis of early-onset gastric cancer in the Chilean population, highlighting the need for further investigation of these variants in familial gastric cancer syndromes. Funding: Beca Chile Postdoctorado 74190063, CONICYT-FONDAP 15130011 /ANID-FONDAP apoyo 1523A0008, FONDECYT 1231773, NIH R01CA223978, R21CA199631, U54CA233306, and P30CA093373.