UBIQUITOUS SOMATIC MUTATIONS IN SIMPLE REPEATED SEQUENCES REVEAL A NEW MECHANISM FOR COLONIC CARCINOGENESIS

SPONTANEOUS errors in DNA replication have been suggested to play a si gnificant role in neoplastic transformation and to explain the chromos omal alterations seen in cancer cells1. A defective replication factor could increase the mutation rate in clonal variants arising during tu mour progression, but despite intensive efforts, increases in tumour c ell mutation rates have not been unambiguously shown2. Here we use an unbiased genomic fingerprinting technique3 to show that 12 per cent of colorectal carcinomas carry somatic deletions in poly(dA . dT) sequen ces and other simple repeats. We estimate that cells from these tumour s can carry more than 100,000 such mutations. Only tumours with affect ed poly(dA . dT) sequences carry mutations in the other simple repeats examined, and such mutations can be found in all neoplastic regions o f multiple tumours from the same patient, including adenomas. Tumours with these mutations show distinctive genotypic and phenotypic feature s. We conclude that these mutations reflect a previously undescribed f orm of carcinogenesis in the colon (predisposition to which may be inh erited) mediated by a mutation in a DNA replication factor resulting i n reduced fidelity for replication or repair (a 'mutator mutation').