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 significant role in neoplastic transformation and to explain the chromosomal alterations seen in cancer cells. A defective replication factor could increase the mutation rate in clonal variants arising during tumour progression, but despite intensive efforts, increases in tumour cell mutation rates have not been unambiguously shown. Here we use an unbiased genomic fingerprinting technique to show that 12 per cent of colorectal carcinomas carry somatic deletions in poly(dA.dT) sequences and other simple repeats. We estimate that cells from these tumours can carry more than 100,000 such mutations. Only tumours with affected poly(dA.dT) sequences carry mutations in the other simple repeats examined, and such mutations can be found in all neoplastic regions of multiple tumours from the same patient, including adenomas. Tumours with these mutations show distinctive genotypic and phenotypic features. We conclude that these mutations reflect a previously undescribed form of carcinogenesis in the colon (predisposition to which may be inherited) mediated by a mutation in a DNA replication factor resulting in reduced fidelity for replication or repair (a 'mutator mutation').
California Institute of Biological Research, La Jolla 92037.
Y
Y
Ionov
M A
MA
Peinado
S
S
Malkhosyan
D
D
Shibata
M
M
Perucho
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000235:genetics*; D016172:DNA Fingerprinting; D004273:DNA, Neoplasm; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011067:Poly dA-dT / Q000235:genetics; D016133:Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D017384:Sequence Deletion
D004273:DNA, Neoplasm; D011067:Poly dA-dT