Ionov, Y., Peinado, M. A., Malkhosyan, S., Shibata, D. & Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic neoplasia. Nature 363, 558-561
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').
- SourceAvailable from: PubMed Central
[Show abstract] [Hide abstract]
- "The microsatellite sequence mutation rate due to MMR of tumor cells is 100–1,000 fold higher than that of normal cells. Furthermore, the MSI in colorectal tumors caused by aberrant MMR gene expression is ~15% (17). Therefore, detecting MSI is of high value. "
ABSTRACT: Mismatch repair (MMR) genes play an important role in the occurrence and development of sporadic colorectal cancer; however, the effect of MMR genes on clinicopathological features and prognosis remains unclear. The aim of the present study was to observe the clinical significance of MMR gene expression in sporadic colorectal cancer. Clinicopathological data and postoperative samples from 404 patients with sporadic colorectal cancer were obtained from the Affiliated Tumor Hospital of Xinjiang Medical University. The immunohistochemistry PV-9000 two-step method was performed to measure the protein expression of human mutL homolog 1 (hMLH1), human mutS homolog (hMSH) 2, human postmeiotic segregation increased 2 (hPSM2) and hMSH6. Differences in clinicopathological features, family history and survival time subsequent to surgery between groups with normal and aberrant MMR protein (MMRP) expression were compared. A total of 27.23% of all patients showed aberrant nuclear staining of MMRP. Among the patients with aberrant MMRP expression, a higher proportion of patients showed aberrant expression of more than one type of MMRP than aberrant expression of only one type of MMRP. Aberrant expression of hMLH1/hPSM2 was most commonly observed (29/404). In addition, aberrant MMRP expression in colorectal cancer was indicated predominantly in the right hemicolon. Histological type primarily showed mucinous adenocarcinoma. In addition, with increasing body mass index (BMI), the MMRP deficiency rate was also shown to increase gradually. There was a close association between MMRP expression deficiency and family history of cancer (P<0.05). For TNM stage III patients, the Kaplan-Meier survival curve showed that the aberrant MMRP expression group had a three-year disease-free survival (DFS) rate of 66.67%, which was longer than the DFS rate of the normal group (55.41%), with no statistical difference (P>0.05). In conclusion, the immunohistochemistry PV-9000 two-step method can be used to measure MMRP expression in colorectal cancer. Aberrant MMRP expression is closely correlated with tumor location, histological type, BMI and tumor family history in sporadic colorectal cancer. Aberrant MMRP expression may have an effect on the prognosis of stage III patients.Experimental and therapeutic medicine 11/2014; 8(5):1416-1422. DOI:10.3892/etm.2014.1927 · 0.94 Impact Factor
[Show abstract] [Hide abstract]
- "The leap from describing a mutational signature to a mechanistic understanding of its etiology is challenging. For several, we have a reasonably complete picture: C>T mutations at CpG dinucleotides are due to spontaneous deamination of methylated cytosine (Waters and Swann 2000); C>T substitutions in skin cancers result from the failure to repair UV-induced cyclobutane pyrimidine dimers (Pfeifer et al. 2005; Pleasance et al. 2010a); and microsatellite instability arises in cells with loss of the mismatch repair pathway (Aaltonen et al. 1993; Ionov et al. 1993; Thibodeau et al. 1993). For the majority of mutational signatures, however, we have limited insights into their etiology, resulting in a proliferation of neologisms that describe their genomic manifestations rather than the underlying (and unknown) mechanisms. "
ABSTRACT: Mutation is associated with developmental and hereditary disorders, aging and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used C. elegans whole genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds, propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was ~1/genome/generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage-fusion-bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. Aflatoxin-B1 induced substitutions of guanines in GpC context, as observed in aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions and rearrangements. Strikingly, both agents induced clustered rearrangements resembling 'chromoanasynthesis,' a replication-based mutational signature seen in constitutional genomic disorders, suggesting interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease.Genome Research 07/2014; 24(10). DOI:10.1101/gr.175547.114 · 13.85 Impact Factor
[Show abstract] [Hide abstract]
- "During the replication of DNA, short segments of the repeated bases of DNA, which are found throughout the human genome (as microsatellites) are the subject of insertion or deletion types mutations that can change the length of these microsatellites. Most of these errors are corrected by polymerase enzymes, but a small number of these errors cannot be corrected by MMR system. Almost all the MSI negative tumors are with known features including being less invasive, having better prognosis and showing little changes compared with MSI positive tumors. "
ABSTRACT: Background: Microsatellites or simple sequence repeats are repeating sequences of deoxyribonucleic acid (DNA). Mutation in mismatch repair (MMR) genes can cause microsatellites instability (MSI) in some tumors. In familial disorder of hereditary non-polyposis colorectal cancer (HNPCC), there is a defect in the mechanism of MMR and clearly defective MMR cause unstable microsatellites. This study has been conducted for investigating the instability of microsatellites in alleles of BAT-26 of MSH2 gene in patients with HNPCC in Isfahan, which is an important prognostic biomarker for the prediction of the treatment outcome. Materials and Methods: DNA extraction from forty HNPCC patients peripheral blood samples were performed by using the DNA extraction kit. The polymerase chain reaction (PCR) reaction to amplify BAT-26 was performed. The PCR products were studied by electrophoresis on agarose gel. Results: The size of specific band was 121 bp out of 40 HNPCC samples and based on the above method, it was shown that 12 cases (30%) demonstrated MSI. Chi-square test showed this difference is statistically significant (P < 0.05). Conclusions: The present study was conducted to evaluate the MSI in HNPCC patients. It was determined that the polymorphisms in BAT-26 of MSH2 gene could detect MSI with high sensitivity. Previous reports as well as our results have shown that the use of BAT-26 alone would be sufficient to identify HNPCC-associated MSH2 gene. Identifying MSI in these genes as a marker for prognosis, according to the present study and other researches is important to predict the treatment outcomes.06/2014; 3:145. DOI:10.4103/2277-9175.135162