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PubMed2001

Isolation and characterization of point mutations in mismatch repair genes that destabilize microsatellites in yeast.

The stability of simple repetitive DNA sequences (microsatellites) is a sensitive indicator of the ability of a cell to repair DNA mismatches. In a genetic screen for yeast mutants with elevated microsatellite instability, we identified strains containing point mutations in the yeast mismatch repair genes, MSH2, MSH3, MLH1, and PMS1. Some of these mutations conferred phenotypes significantly different from those of null mutations in these genes. One semidominant MSH2 mutation was identified. Finally we showed that strains heterozygous for null mutations of mismatch repair genes in diploid strains in yeast confer subtle defects in the repair of small DNA loops.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Absence of mutations in the analysis of coding sequences of the entire transforming growth factor-beta type II receptor gene in sporadic human breast cancers.

The transforming growth factor-beta (TGFbeta) binds the type II TGFbeta growth factor receptor (TGFbetaRII) to inhibit the growth of most epithelial tissues. Most human colon and gastric cancers with microsatellite instability (MI) have frameshift mutations in polynucleotide repeats within the TGFbetaRII coding region; these mutations truncate the receptor protein and disable the serine/threonine kinase to produce TGF-beta resistance. To further investigate the type, frequency and tissue distribution of TGFbetaRII gene mutations, in this study, we examined 36 sporadic breast cancers. We previously produced eight intron based primer pairs for mutational analysis of the entire coding region of the TGFbetaRII gene. Using these primers, we developed protocols for polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of PCR products from genomic DNA samples of 36 breast cancer patients and we tested them for microsatellite instability (MI) at eight microsatellite loci. One case demonstrated MI (2.8%) and we found no mutations. These and other recent data indicate that TGFbetaRII mutations are essentially confined to colon and gastric cancers with MI. The narrow spectrum of tissues containing RII mutations illustrates the complexity of genetic checkpoints in human carcinogenesis.

Base Sequence↗

PubMed1997

The Muir-Torre syndrome in a black patient with AIDS: histopathology and molecular genetic studies.

In 1981, a black man had adenocarcinoma of the colon. In 1986, he had a sebaceous adenoma and the diagnosis of the Muir-Torre syndrome was established. The patient was found to be HIV sero-positive in 1986, and 8 years later fulfilled the CDC criteria for AIDS. During 1989 to 1993 the CD4 count was > 200 cells/ml and the patient had 2 sebaceous tumors, 1 basal cell carcinoma and 1 keratoacanthoma. In 1994 to 1996, the CD4 count was < 200 cells/ml and the patient developed 18 sebaceous tumors and a poorly differentiated adenocarcinoma of the finger which metastasized to axillary lymph nodes. Microsatellite analysis of tumor DNA from a sebaceous adenoma and adenocarcinoma of the finger revealed widespread microsatellite instability. The interaction of AIDS with the behavior of the tumors in the Muir-Torre syndrome has not previously been reported. Although our patient had an increase in the number of new sebaceous tumors at the same time he experienced deterioration of the immune system, he is doing well 15 years after resection of adenocarcinoma of the colon and 16 months after metastatic poorly differentiated adenocarcinoma of the skin. This follows the previously observed tendency for cancers of the Muir-Torre syndrome, especially those displaying widespread microsatellite instability, to be less lethal than their histologically similar counterparts in people without Muir-Torre syndrome.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Analysis of microsatellite instability in sporadic parathyroid adenomas.

Microsatellite instability (MSI) is the form of genomic instability associated with defective DNA mismatch repair (MMR) in human tumorigenesis. Recent reports have suggested a role for MSI in the pathogenesis of sporadic parathyroid adenomas. However, because of their small sample sizes and/or lack of systematic analysis of genome-wide MSI, these studies have not provided conclusive evidence that MMR defects are a common occurrence in parathyroid neoplasia. To further investigate whether MSI plays an important role in parathyroid tumorigenesis, we analyzed 49 sporadic parathyroid adenomas for MSI using a panel of 5 microsatellite DNA markers that has been recommended for sensitive detection of MSI by the NCI Workshop and validated in other tumor types. These microsatellite loci were amplified by PCR using fluorescent-labeled primers from the 49 samples of template tumor DNA and matching normal DNA isolated from the same patients' peripheral blood leukocytes. None of the 49 tumors showed evidence of MSI at any of the analyzed loci of the NCI marker panel. These observations strongly suggest that defective DNA MMR plays a minor role, if any, in the pathogenesis of sporadic parathyroid adenomas.

Adenoma↗

PubMed2002

Microsatellite instability is not a common feature in medullary breast cancer.

Microsatellite instability (MSI) is a form of genomic instability associated with defective DNA mismatch repair in tumors. MSI is found in 85-90% of hereditary nonpolyposis colorectal cancer cases; however, its occurrence in breast carcinogenesis still remains to be clarified. In addition, data are limited on the incidence of MSI in the medullary subtype. The purpose of this study was to investigate the occurrence of MSI in medullary breast cancer (MBC). The study included a total of 16 patients with MBC, nine with typical and seven with atypical histology. The incidence of MSI in five microsatellite loci (D2S123, D3S1611, D17S807, D17S796 and Xq11-12) was determined by comparing paired normal and tumor tissue DNA after PCR amplification from paraffin-embedded tissues. All 16 tumors showed stability at five loci. Although the number of microsatellite markers and DNA samples may limit the value of our results, we conclude that the MSI phenotype is uncommon in human MBC.

Journal Article↗

PubMed2004

Promotion of microsatellite instability by hepatitis C virus core protein in human non-neoplastic hepatocyte cells.

Hepatitis C virus proteins exert an effect on a variety of cellular functions, including gene expression, signal transduction, and apoptosis, and because they possess oncogenic potentials, they have also been suggested to play an important role in hepatocarcinogenesis. Although the mechanisms of hepatocarcinogenesis remain poorly understood, we hypothesized that the disease may arise because of a disturbance of the DNA repair system by hepatitis C virus proteins. To test this hypothesis, we developed a reproducible microsatellite instability assay system for mismatch-repair using human-cultured cells transducted with pCXpur retrovirus expression vector, in which the puromycin resistance gene was rendered out-of-frame by insertion of a (CA)(17) dinucleotide repeat tract immediately following the ATG start codon. Using several human cancer cell lines known to be replication error positive or negative, we demonstrated that this assay system was useful for monitoring the propensity for mismatch-repair in the cells. This assay system was applicable to non-neoplastic human PH5CH8 hepatocytes, which could support hepatitis C virus replication. Using PH5CH8 cells, in which hepatitis C virus proteins were stably expressed by the retrovirus-mediated gene transfer, we found that the core protein promoted microsatellite instability in PH5CH8 cells. Interestingly, such promotion by the core protein only occurred in cells having the core protein belonging to genotype 1b or 2a and did not occur in cells having the core protein belonging to genotype 1a, 2b, or 3a. This is the first report to demonstrate that the core protein may disturb the DNA repair system.

Adaptor Proteins, Signal Transducing↗

PubMed1995

DNA mismatch binding defects, DNA damage tolerance, and mutator phenotypes in human colorectal carcinoma cell lines.

DNA mismatch binding in vitro, resistance to DNA methylation damage, and spontaneous mutation rates were examined in human colorectal adenocarcinoma cell lines. Of 11 cell lines, 3 (DLD1, HCT15, and LoVo) were defective in mismatch binding. All three lines had a mutator phenotype. These properties indicate that DLD1 and HCT15 may, like LoVo, carry mutations in the mismatch recognition protein hMSH2. Mismatch binding was normal in the remaining eight lines, including HCT116 in which a second mismatch repair protein, hMLH1, is defective. Two lines, SW620 and SW48, did not express detectable levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. SW620 exhibited the expected sensitivity to N-methyl-N-nitrosourea. In contrast, SW48 cells were highly resistant to N-methyl-N-nitrosourea and also slightly to methyl methanesulfonate, indicating that they are tolerant to DNA methylation damage. SW48 exhibited the spontaneous mutator phenotype and microsatellite instability that are hallmarks of a defect in mismatch repair. This cell line provides evidence for the association between methylation tolerance and defective mismatch correction in human colorectal carcinoma cells. The properties of methylation-tolerant, mismatch repair-defective cells identify possible selective pressures that might facilitate the natural selection of mismatch repair-defective tumors.

Adenocarcinoma↗

PubMed2002

Microsatellite instability as a marker in predicting metachronous multiple colorectal carcinomas after surgery: a cohort-like study.

PURPOSE: In case-control studies, it was reported that microsatellite instability might be helpful in predicting the development of metachronous multiple colorectal cancers. The purpose of this cohort-like study was to determine whether microsatellite instability is a novel independent marker in predicting metachronous colorectal carcinomas after colorectal cancer surgery. METHODS: Three hundred twenty-eight colorectal carcinoma patients were surveyed by periodic colonoscopy for at least three years after surgery. Among these, DNA from paraffin-embedded sections was available for 272 cases. DNA of these cases was studied for six microsatellite markers (five dinucleotide repeats, one mononucleotide repeat). Microsatellite instability phenotype was defined as alterations in one or more loci. RESULTS: Median follow-up period was 74 months, and the median number of colonoscopies was 4.6. The percentage of microsatellite instability-positive cases was 26.4 percent (72/272). Seventeen metachronous colorectal carcinomas were detected during the follow-up period. Incidences of metachronous colorectal carcinomas in microsatellite instability-positive and microsatellite instability-negative cases were 15.3 and 3 percent, respectively (P < 0.001). The cumulative five-year incidence of metachronous colorectal carcinomas was significantly higher in microsatellite instability-positive cases than in microsatellite instability-negative cases (12.5 vs. 2.5 percent, P < 0.0001). Logistic regression analysis of the relationship between incidence of metachronous colorectal carcinomas and possible risk factors (namely, coexistence of adenoma at the time of surgery, family history of colorectal carcinoma, history of extracolonic malignancy, and microsatellite instability status) showed that microsatellite instability and coexistence of adenoma were significant independent risk factors for the occurrence of metachronous colorectal carcinomas, with values of P = 0.001 and 0.02, respectively. CONCLUSION: These data indicate that microsatellite instability can be regarded as a novel independent and important marker for predicting the development of metachronous colorectal carcinoma after surgery.

Carcinoma↗

PubMed1999

Frequent aberration of the transforming growth factor-beta receptor II gene in cell lines but no apparent mutation in pre-invasive and invasive carcinomas of the uterine cervix.

The type II transforming growth factor-beta (TGF-beta) receptor (RII) gene located at 3p22 plays an important role in regulating growth and differentiation of epithelium, including that of the uterine cervix. Loss-of-function mutations of RII have frequently been found in gastrointestinal cancers, with a replication-error (RER) phenotype characterized by the presence of microsatellite instability (MI). In this study, genomic PCR, SSCP and DNA sequencing were conducted to investigate the coding sequences of the RII gene in cell lines (n = 5) and tissues (n = 15) of squamous carcinomas of the uterine cervix. Intragenic deletions were noted in 2 of 5 cervical-cancer cell lines (ME180 and HeLa cells). However, no mutation, other than DNA polymorphisms, was found in 15 cervical cancers with either alleleic loss at 3p22 (n = 11) or MI (n = 4). Further analysis of squamous intraepithelial lesions (SIL) with (n = 12) or without (n = 4) MI for the (A)10 change, a prototypic mutation found in over 90% of RER-positive colon cancers, also showed no aberration. Our study concludes that the RII gene is frequently disrupted in cervical-cancer cell lines, but is rarely mutated in CC and SIL tissues, including those showing MI or alleleic loss at 3p22. The underlined mechanism of genomic instability in CC and SIL may thus differ from that of colorectal cancer. The allelic loss at 3p22-24 in CC does not involve the coding sequence of the RII gene. The non-coding sequence of RII or an unidentified gene may be responsible for it.

Carcinoma, Squamous Cell↗

PubMed1997

Frequent gains on chromosome arms 1q and/or 8q in human endometrial cancer.

Comparative genomic hybridization (CGH) was employed to survey genomic regions with increased and decreased copy number of the DNA sequence in 15 endometrial cancers [10 cases with microsatellite instability positive (MI+) and 5 cases with MI-]. Twelve of these 15 tumors (80%) showed abnormalities in copy number at one or more of the chromosomal regions. There were no regions with frequent chromosomal losses. Conversely, 11 of 15 cases (73%) showed gains on chromosome arms 1q (8/15; 53%) and/or 8q (6/15; 40%). Concordant gains of both chromosome arms 1q and 8q were observed in all three endometrial cancers of histological grade 3. These results suggest that these two chromosomal regions may contain genes whose increased expression contributes to development and/or progression of endometrial carcinogenesis. Two cases were further analyzed by fluorescence in situ hybridization (FISH) using three probes on chromosome 1 and two probes on chromosome 8 to more accurately determine increases in copy number. We found gains of chromosome 1q to 2.9-3.6 copies per cell and on 8q to 4.4 copies per cell.

Chromosome Aberrations↗

PubMed2006

Muir-Torre syndrome: Diagnostic and screening guidelines.

A 65-year-old man presented with a history of multiple skin coloured papules on his face that were asymptomatic. He had an adenocarcinoma resected from his proximal colon 12 years prior to presentation as well as a family history of colon cancer on the maternal side. Diagnostic biopsies showed the lesions to be sebaceous adenomas and epitheliomas and the diagnosis of Muir-Torre syndrome was made. The sebaceous tumour tissue showed microsatellite instability and immunohistochemical staining indicated diminished expression in the DNA mismatch-repair protein complex MSH2/MSH6. Genetic analysis showed a germline mutation in the MSH2 gene confirming the diagnosis of Muir-Torre syndrome. The patient and his first-degree relatives have been referred for genetic counselling and screening. We review the diagnostic criteria in this syndrome and review the recommended screening guidelines.

Aged↗

PubMed2000

Ageing and the mismatch repair system.

Age-related accumulation of mutations has been extensively documented, and it has been proposed as one of the prominent causes of malignancies in old age. The present review is focused on the particular case of DNA mismatch repair system (MMR), that has drawn increased attention for its possible relevance to malignancy. We also report on our own observations on an age-associated genomic instability that develops with age in the MMR system. Our study was performed on DNA samples that were prepared from peripheral blood cells, obtained at a 10-year interval from young and old human subjects. The two DNA samples from each individual were examined comparatively. The older individuals showed a significantly higher rate of microsatellite instability (MSI) in several loci examined, whereas no difference was found between the paired samples of any of the young subjects. We suggest that this increase in MSI with age may indicate an overall genomic instability in the elderly.

Aging↗

PubMed2003

Tissue microarray immunohistochemical expression analysis of mismatch repair (hMLH1 and hMSH2 genes) in endometrial carcinoma and atypical endometrial hyperplasia: relationship with microsatellite instability.

Alterations in the mismatch repair genes (hMLH1 and hMSH2) play an important role in the development of microsatellite instability in sporadic endometrial cancer. Tissue microarray technology allows molecular profiling of tumor samples at the DNA, RNA, and protein levels. We analyzed hMLH1 and hMSH2 expression by immunohistochemistry in a group of atypical endometrial hyperplasias (n = 10), endometrioid endometrial carcinomas (n = 58), and nonendometrioid endometrial carcinomas (n = 27) on tissue microarray. The results were correlated with microsatellite instability status as evaluated by BAT-25 and BAT-26. Overall, 29.4% of lesions showed microsatellite instability. Loss of nuclear hMLH1 and hMSH2 protein expression was seen in 22.3% and 6.5% of cases, respectively. Immunohistochemistry for hMLH1 and hMSH2 showed lack of protein expression in 64% and 16.6% of microsatellite instability-positive endometrial lesions, respectively. Taken together, hMLH1 or hMSH2 protein expression was absent in 18 of 24 microsatellite instability-positive cases (75% sensitivity). A high level of concordance was found between immunohistochemistry for hMLH1 and hMSH2 and microsatellite instability status evaluated by BAT-25 and BAT-26 (kappa value of 0.7). Of the 57 cases found to be microsatellite instability negative, 53 showed normal expression of both proteins (93% specificity). The observed predictive value of absence of expression of hMLH1 for predicting microsatellite instability-positive status was 82%. The predictive value of normal expression of both proteins for predicting microsatellite instability-negative status was 90%. These results are consistent with those previously reported in whole tissue sections. Therefore, immunohistochemical analysis of hMLH1 and hMSH2 expression on tissue microarray provides an accurate technique for screening for tumors with microsatellite instability. Tissue microarrays represent an ideal approach for comparing different diagnostic or predictive markers with one another in consecutive tissue microarray sections.

Adaptor Proteins, Signal Transducing↗

PubMed2005

High-throughput scanning of breast tumor surgical specimens for low-level mutations.

Large numbers of mutations are postulated to occur as early events in carcinogenesis. For certain types of human tumors (mutator phenotypes) these mutations can be a driving force in generating clonogenic, causative genetic changes leading to multistage carcinogenesis. These low-level mutational events are highly significant due to their potential use as molecular markers for early identification of genomic instability that can lead to cancer and to their potential influence on the ability of tumors to resist drug treatment and/or metastasize. Detecting the presence and diversity of such genetic changes in human tumors is desirable due to their potential prognostic value. However, identification of these low-frequency genetic changes is difficult, since most mutations exist at mutant/wild-type ratios of <10(-3). We recently developed inverse PCR-based amplified restriction fragment-length polymorphism (iFLP), a new technology that combines inverse PCR, RFLP, and denaturing HPLC to allow scanning of the genome at several thousand positions per experiment for low-level point mutations. Using iFLP we previously demonstrated low-level mutations (mutation frequency <10(-3)) in human colon cancer cells that harbor mismatch repair deficiency and in sporadic colon cancer surgical specimens. In the present work we investigated whether low-level mutations are also present in sporadic breast cancer surgical specimens. Using iFLP we identified widespread low-level mutations in two out of ten surgical specimens examined (20%). Examination of the microsatellite instability status of these samples demonstrated that the samples are stable (MSI-S). We conclude that low-level mutations are less frequent in breast cancer than in colon cancer; however, single nucleotide instability that generates such mutations may still be present in a fraction of breast cancers.

Base Sequence↗

PubMed2002

Frameshift mutations of RIZ, but no point mutations in RIZ1 exons in malignant melanomas with deletions in 1p36.

Recently, the retinoblastoma protein interacting zinc finger gene RIZ has been proposed as a candidate for the tumor suppressor locus on 1p36, because of the common loss of RIZ1 RNA in human tumors. In addition, frameshift mutations of this gene have been demonstrated in a variety of tumors with microsatellite instability. Since alterations in this region have been described in malignant melanomas, we investigated DNA of paraffin-embedded sections from 16 typical naevi, 19 atypical naevi, 33 primary melanoma lesions and 25 metastases and DNA from four melanoma cell lines by PCR and direct sequencing analysis of RIZ. Frameshift mutations in the RIZ gene were found in 17% of melanoma samples and 8.6% of naevi, but we could not demonstrate any missense mutations in the exons of RIZ1. No LOH of the RIZ gene nor any microsatellite instability in six dinucleotide markers or in the mononucleotide repeats IGRIIR, hMSH3, and hMSH6 could be demonstrated in the samples with RIZ frameshift mutations. Although our results do not explain the high rate of deletions in 1p36 found in this tumor, they assign RIZ a potential role in the multi-step tumor forming process of malignant melanoma of the skin.

Cell Transformation, Neoplastic↗

PubMed2003

An intron splice acceptor polymorphism in hMSH2 and risk of leukemia after treatment with chemotherapeutic alkylating agents.

PURPOSE: We sought to determine whether the -6 exon 13 T>C polymorphism in the DNA mismatch repair gene hMSH2 modulates susceptibility to acute myeloid leukemia after therapy and particularly after O(6)-guanine alkylating chemotherapy. We also determined the extent of microsatellite instability (MSI) in therapy-related acute myeloid leukemia (t-AML) as a marker of dysfunctional DNA mismatch repair. EXPERIMENTAL DESIGN: Using a novel restriction fragment length polymorphism, verified by direct sequencing, we have genotyped 91 t-AML cases, 420 de novo acute myeloid leukemia cases, and 837 controls for the hMSH2 -6 exon 13 polymorphism. MSI was evaluated in presentation bone marrow from 34 cases using the mononucleotide microsatellite markers BAT16, BAT25, and BAT26. RESULTS: Distribution of the hMSH2 -6 exon 13 polymorphism was not significantly different between de novo acute myeloid leukemia cases and controls, with heterozygotes and homozygotes for the variant (C) allele representing 12.2 and 1.6%, respectively, of the control population. However, the variant (C) hMSH2 allele was significantly overrepresented in t-AML cases that had previously been treated with O(6)-guanine alkylating agents, including cyclophosphamide and procarbazine, compared with controls (odds ratio, 4.02; 95% confidence interval, 1.40-11.37). Thirteen of 34 (38%) t-AML cases were MSI positive, and 2 of these 13 cases were homozygous for the variant (C) allele, a frequency substantially higher than in the control population. CONCLUSIONS: Association of the hMSH2 -6 exon 13 variant (C) allele with leukemia after O(6)-guanine alkylating agents implicates this allele in conferring a nondisabling DNA mismatch repair defect with concomitant moderate alkylation tolerance, which predisposes to the development of t-AML via the induction of DNA mismatch repair-disabling mutations and high-grade MSI. Homozygosity for the hMSH2 variant in 2 of 13 MSI-positive t-AML cases provides some support for this model.

Adolescent↗

PubMed2001

DNA mismatch repair enzyme hMSH2 in malignant melanoma: increased immunoreactivity as compared to acquired melanocytic nevi and strong mRNA expression in melanoma cell lines.

Mutations in the mismatch DNA repair gene human MutS homologen 2 (hMSH2) are causative for microsatellite instability and carcinogenesis in various human tumours, including hereditary nonpolyposis colorectal cancer. Because microsatellite instability has been detected in malignant melanoma, we have investigated hMSH2 in melanocytic tumours. We found strong nuclear immunoreactivity for hMSH2 that was elevated in malignant melanoma and melanoma metastases as compared to acquired nevi. These findings suggest that increased genomic instability in malignant melanoma is associated with elevated protein levels of this DNA repair enzyme. hMSH2 is not exclusively regulated by proliferative activity in melanocytes, because there was no correlation between staining patterns of hMSH2 and the proliferation marker Ki-67. In contrast, immunoreactivity scores for hMSH2 and p53 were both upregulated in malignant melanocytic tumours. These findings support the concept that hMSH2 gene expression may be regulated in melanocytes by the p53 protein, as has been reported previously in other tissues. Using the reverse transcription-polymerase chain reaction, we detected strong hMSH2 mRNA expression in each of 8 melanoma cell lines analysed (highest amounts in SK-MEL-25 cells, lowest amounts in MML-I cells). In conclusion, our findings indicate that hMSH-2 may be of importance for genetic stability, tumorigenesis and progression of malignant melanoma.

Base Pair Mismatch↗

PubMed1999

Clinical and pathologic significance of microsatellite instability in endometrial cancer.

Microsatellite instability (MSI) is identified as electrophoretic shifts in allele sizes of microsatellite DNA sequences. It is characteristic of a subset of sporadic colorectal tumors as well as hereditary nonpolyposis colorectal cancer (HNPCC). The cells that display MSI are thought to be susceptible to increased mutability. MSI has been detected in a wide variety of human tumors, but the influence of this form of genetic instability on disease initiation and progression remains unclear. Using a polymerase chain reaction (PCR)-based method we screened 50 sporadic primary endometrial carcinomas to characterize the prevalence of MSI in these tumors and analyze the correlation of MSI with clinicopathologic parameters in this malignancy. Fifteen cases (30%) displayed low frequency of MSI (MSI-L) showing MSI at one locus in 5 loci examined. Two cases (4%) showed high frequency of MSI (MSI-H) having MSI at 2 or more loci. Taking MSI-L and MSI-H cases together as MSI-positive, statistical analysis of patient age, tumor grade, and stage failed to disclose significant differences or trends between cases with MSI-positive and MSI-negative (P > 0.05). No significant relationship was observed between patients with MSI and without MSI (P > 0.05), however, the MSI exhibited only in those cases without evidence of disease at the 24th month after treatment. The difference is statistically significant when compared with patients who are alive with disease or died of disease (P < 0.01). However, the overall survival curves were not statistically different. We conclude that MSI is present in a subgroup of endometrial cancer.

Journal Article↗