G·A·B·B·A

Gastric cancer is one of the major causes of cancer death world-wide: 90% of the cases occur in a sporadic form, about 10% of cases show familial aggregation and an hereditary component was found in a very small proportion of all cases, in approximately 1%.

In sporadic gastric carcinomas, we found that 23% of the cases show global instability at the nucleotide level (MSI phenotype). The MMR defect underlying the MSI phenotype was found to be hMLH1 promoter hypermethylation, leading to absence or decreased expression of this gene. The MSI phenotype was closely associated with a low pTNM stage of the tumours and a significantly better prognosis of the patients. Moreover, it was demonstrated, by multivariate analysis, that the MSI status is an independent prognostic factor in sporadic gastric carcinoma. The particular clinicopathological profile of the MSI tumours was shown to be mediated by mutations in coding repeat sequences of genes that play an important role in MSI carcinogenesis, such as TGFbeta RII, IGFII R and BAX genes. Mutations in TGFbeta RII occurred in 67.9% of the MSI tumours and were significantly associated with the glandular histotype. IGFII R and BAX mutations occurred, respectively, in 25.0% and 32.1% of the cases; there was a trend towards an association between mutations in these genes and decreased nodal metastisation and wall invasiveness, respectively.

Germline E-Cadherin gene mutations have been identified in HDGC kindred. The IGCLC predicted that up to 25.0% of families fulfilling the criteria for HDGC, would harbour germline mutations within CDH1. We validated the IGCLC predictions, since we have found that only families with complete criteria for HDGC display CDH1 germline mutations. The frequency of mutations (33.3%) found in our large series of families, is within the range predicted by the Consortium. Moreover, we found germline CDH1 potentially deleterious sequence alterations in 9.3% of patients with apparently sporadic diffuse gastric cancer occurring in young individuals, probably representing de novo mutations.
In sporadic diffuse gastric carcinomas harbouring CDH1 somatic mutations, we proved that the most common second hit is CDH1 promoter hypermethylation. These two events, mutation and hypermethylation lead to either aberrant or absent expression of E-Cadherin in sporadic diffuse gastric carcinomas.