MICROSATELLITE INSTABILITY IN GASTRIC-CANCER IS ASSOCIATED WITH TUMORLOCATION AND FAMILY HISTORY IN A HIGH-RISK POPULATION FROM TUSCANY

We studied the presence of microsatellite instability (MSI) in a serie s of 108 gastric cancers (GCs) previously identified in an epidemiolog ical study carried out in a high-risk area around Florence, To investi gate associations between MSI and GC family history, 34 cases (31.5%) who had a GC-affected first-degree relative were included in the serie s, A family history positive for colorectal cancer was reported quite rarely (5.6%). The analysis of 6 microsatellite loci in DNA from paire d normal tissue and tumor samples microdissected from paraffin-embedde d specimens revealed varying degrees of instability: 56 cases (51.8%) did not show instability at any of the 6 loci; 19 (17.6%) showed insta bility at 1 locus; 16 (14.8%) showed instability at 2 loci; 11 (10.2%) showed instability at 3 loci; 4 (3.7%) showed instability at 4 loci; and 2 (1.9%) showed instability at 5 loci, The replication error-posit ive (RER+) phenotype, defined as the presence of MSI at 2 or more loci , had a frequency of 30.6% (33 of 108) and tended to be positively ass ociated with female sex, intestinal histological type, advanced tumor stage, vascular invasion, positive GC family history, and blood group of A type, No correlation emerged between age at diagnosis and RER+ ph enotype, whereas a significant association with the RER+ phenotype was shown by the antral location. A multivariate analysis adjusting for a selected group of potential confounding factors confirmed the strong association of the RER+ phenotype with the antral location (P = 0.001) and with a positive GC family history (P < 0.05). Survival analyses a t 5 and 8 years showed no difference between RER+ and RER-patients, ev en when corrected for stage distribution. By the microdissection techn ique, we also used microsatellite allele patterns to investigate intra tumoral heterogeneity and genetic relationships between tumors and adj acent dysplasia and/or intestinal metaplasia. Areas of metaplasia and dysplasia demonstrated MSI only in cases with MSI-positive tumors, In MSI-positive tumors, there was consistent evidence of intratumoral mic rosatellite allele heterogeneity, indicating the presence of genetical ly divergent tumor cell clones within the same neoplasm.