The effect of mismatch repair deficiency on tumourigenesis; microsatelliteinstability affecting genes containing short repeated sequences

We have investigated microsatellite instability (MSI) in colorectal, gastri c, endometrial and ovarian cancer as a result of mismatch repair (MMR) defi ciency. We detected frameshift mutations in several genes that carry short repeated sequences and are important in cell fidelity and growth control; h MSH3, hMSH6, BAX, IGFIIR, TGF beta IIR, E2F4 and BRCA2. Accumulation of mut ations was heterogeneous and mainly restricted to tumours showing MSI at se veral loci (MSI-H). Both insertions and deletions were evident and occasion al intratumour heterogeneity was evident with more than one different addit ional allele in the tumour. Most MSI-H tumours had acquired mutations in mo re than one gene and longer repeated sequences were more frequently targets for mutations. The TGF beta IIR gene was mutated in 62%, the hMSH3 gene in 43%, the E2F4 gene in 35%, the hMSH6 in 32%, the BAX gene in 32%, the IGFI IR gene in 26%, and the BRCA2 gene in 2% of the MSI-H tumours. Homozygous m utations or mutation of both alleles were evident in all genes except BRCA2 , in total 23/105 mutated cases, varying from 7% for BAX to 50% for E2F4. E 2F4 mutations were exclusively found in colon tumours and E2F4 polymorphism s was found in 8% of cases. No difference in mutation prevalence was noted between cancer types apart from TGF beta IIR mutations, which were frequent ly found in colon and gastric tumours but not in endometrial tumours, sugge sting that endometrial tumours progress by a different route where TGF beta IIR mutations are less favourable.