Abstract

Background and aims: Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Since gastric cancer is relatively common in the general population as well it is unsettled whether or not gastric cancer is a true HNPCC spectrum malignancy.

Subjects and methods: To this end, the molecular and clinicopathological profiles of gastric cancers (N=13) from HNPCC mutation carriers were evaluated and compared to sporadic gastric cancers (N=46) stratified by histology and microsatellite instability (MSI) status.

Results: Our study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the APC region was associated with intestinal histology regardless of MSI (P=0.0070). KRAS mutations (P=0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (P<0.0001) were associated with MSI tumors being absent in MSS tumors. The average number of methylated tumor suppressor gene loci among 24 genes studied (methylation index) was higher in MSI vs. microsatellite-stable (MSS) tumors regardless of histology (P<0.0001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (P=0.00049) and the general methylation index lower (P=0.038), suggesting similar but not identical developmental pathways. All lacked the mismatch repair protein corresponding to the germline mutation and displayed MSI-high.

Conclusion: The present molecular evidence combined with the previous demonstration of increased incidence relative to the general population make it justified to consider gastric cancers as true HNPCC spectrum malignancies.