Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival.
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 (TGFbetaRII, 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, TGFbetaRII mutations appeared to be inversely related to BLM mutations (P = .006), whereas RAD50 mutation carriers showed significantly reduced survival (P = .03).
Falchetti
Mario
M
Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy.
Saieva
Calogero
C
Lupi
Ramona
R
Masala
Giovanna
G
Rizzolo
Piera
P
Zanna
Ines
I
Ceccarelli
Ketty
K
Sera
Francesco
F
Mariani-Costantini
Renato
R
Nesi
Gabriella
G
Palli
Domenico
D
Ottini
Laura
L
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000368:Aged; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D015996:Survival Rate
D005819:Genetic Markers; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II