Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis

Abstract

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').

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

“…It is well established that tumours exhibiting MSI have a better prognosis in older patient cohorts than tumours that are microsatellite stable. [1][2][3][4]6 However, our findings that MSI is not associated with good prognosis in young patients are novel and are of practical as well as biological importance.…”

“…[1][2][3][4][5][6] However, the age distribution of the cohorts analysed in many of these studies reflects the fact that the majority of patients with colorectal cancer are elderly, with the highest age-specific incidence in the oldest age groups. 7,8 Most tumours exhibiting the MSI phenotype are in older patients, very few of whom carry germline MMR gene mutations.…”

“…Around 50% of all tumours in patients Ͻ 30 years old exhibit MSI, 9,15 whereas only 7-15% of tumours are MSI in older cohorts. [1][2][3][4][5][6] Hence, there is reason to question the validity of applying survival data from MSI analysis of older patient cohorts to estimation of prognosis for younger patients.…”

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

“…1 A classic example of this is the biallelic promoter methylation of the mismatch repair gene, MLH1, which accounts for B70% of sporadic colorectal cancers that exhibit microsatellite instability as a direct consequence of impaired mismatch repair activity. [2][3][4][5] MLH1 methylation occurs in close association with the presence of the oncogenic BRAF V600E mutation in sporadic colorectal cancer. 6 The c.-93G4A SNP (rs1800734) within the MLH1 promoter has been associated with an increased risk of microsatellite instability or MLH1 methylation in some colorectal and endometrial cancer populations, but not in others.…”

Variable mutation frequencies in coding repeats of TCF-4 and other target genes in colon, gastric and endometrial carcinoma showing microsatellite instability

“…They accumulate frequent deletions and insertions in microsatellite DNA sequences due to de®cient repair of spontaneous errors which occur during the replication of these repetitive DNA sequences Thibodeau et al, 1993;Ionov et al, 1993). The MSI-H phenotype is associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome as a result of predisposing constitutional mutations in genes involved in DNA mismatch repair (Bronner et al, 1994;Papadopoulos et al, 1994;Fishel et al, 1993;Leach et al, 1993).…”