Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival

Summary Gastric cancer is one of the leading causes of cancer death worldwide, and although the incidence has decreased in Western countries, specific high-risk areas are present in Italy. Gastric cancer with high-level microsatellite instability (MSI-H) represents a well-defined subset of carcinomas showing distinctive clinicopathologic features. We examined clinicopathologic associations and long-term survival in a series of 159 gastric cancer cases from a high-risk population in Tuscany (central Italy). MSI-H was associated with antral location of the tumor ( P = .001), intestinal type according to Lauren classification ( P = .002), expanding type according to Ming classification ( P = .0001), and mucinous histologic type according to the Japanese Research Society for Gastric Cancer classification ( P = .002). In addition, MSI-H was strongly associated with a higher survival at 15 years ( P = .01) and with loss of hMLH1 expression, evaluated by immunohistochemistry ( P = .001). Multivariate analyses showed a significant association between the absence of hMLH1 reactivity and the expanding tumor type ( P = .002). We also investigated the MSI-H–related genetic changes by analyzing coding repeats within target genes involved in pathways that control cell growth ( TGFβRII , IGFIIR , RIZ , TCF4 , DP2 ), apoptosis ( BAX , BCL10 , FAS , CASPASE5 , APAF1 ), and DNA repair genes ( hMSH6 , hMSH3 , MED1 , RAD50 , BLM , ATR , BRCA2 , MRE11 ). Gastric cancer cases with MSI-H were found to accumulate heterozygous mutations affecting multiple molecular pathways and multiple genes within each pathway. Intriguingly, in this subset, TGFβRII mutations appeared to be inversely related to BLM mutations ( P = .006), whereas RAD50 mutation carriers showed significantly reduced survival ( P = .03).