DNA was analyzed from 57 sporadic gastrointestinal tumors (34 pancreatic cancers, 23 colon tumors) and cognate normal tissues to verify whether mutations at coding sequences were associated with microsatellite instability (MSI). Genomic instability was present in 41% (14/34) of pancreatic samples and in 26% (6/23) of colon cancers previously tested by six microsatellite markers. The tumors included 37 cases showing no MSI; 15 cases with MSI at only 1 locus and 5 cases with MSI at 2 or more loci. All the samples were screened for mutations in genes containing repeated tracts in their coding sequences (TGFbetaRII, IGFRII and bax) and in codon 12 of the K-ras oncogene. Furthermore, loss of heterozygosity (LOH) at NM23.H1 locus was tested, 17/34 (50%) pancreatic tumors and 6/23 (26%) colon cancers showed mutations in codon 12 of K-ras; allelic loss of NM23. H1 locus was found in 6/18 (33%) informative colon tumors and in no pancreatic cancers. The TGFbetaRII, IGFRII and bax genes were altered in 3 (13%), 1 (4%) and 3 (13%) out of 23 colon tumors respectively, but no mutation was detected in pancreatic cancers. Mutations in the repeated nucleotide stretches within the coding sequences of TGFbetaRII, IGFRII and bax genes were found only in colon tumors with a high unstable phenotype (more than 3 microsatellite loci altered).