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PubMed2004

Mutation rates in the complex microsatellite MYCL1 and related simple repeats in cultured human cells.

Microsatellite instability is a phenotype observed in tumors cells that have defects in DNA mismatch repair (MMR). Most markers used for detecting microsatellite instability are mono- and dinucleotide repeats, but one tetranucleotide repeat (MYCL1) has been reported to be useful for this purpose. The MYCL1 repeat is actually a complex repeat, made up of approximately 14 GAAA tetranucleotides plus various other GA-rich repeats. In order to determine the nature of the instability of the this sequence, we have used a frameshift-reversion assay in MMR-proficient and -deficient human cells to compare the mutation rates and the types of mutation of MYCL1 to those of the related simple repeats (GAAA)17, (GA)17, and (CA)17. We found that the complex repeat was the most stable of the repeats examined in cells deficient in MMR; the tetranucleotide was less stable, while the dinucleotides were the least stable. In MMR-proficient cells, the relative rates were reversed; the MYCL1 repeat was the least stable, the tetranucleotide was more stable, and the dinucleotides were the most stable. These results suggest that MYCL1 and the pure tetranucleotide have relatively low rates of errors during replication, but that the errors in these repeats are corrected less efficiently than those in the smaller repeats. Because of their high rate of instability in MMR-proficient cells, MYCL1 and other tetranucleotide repeats appear to lack specificity for detection of tumors with defective MMR.

Base Sequence↗
PubMed1999

Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer.

BACKGROUND: The incidence of colorectal cancer in persons under 46 years of age is substantially higher in Hong Kong than in Scotland and many other countries. Consequently, we examined whether there is a hereditary predisposition for colorectal cancer in this Southern Chinese population. METHODS: We investigated the incidence of microsatellite instability (MSI) at 10 DNA sites in 117 colorectal cancer specimens from Chinese patients of various ages. Those tumors with new alleles at 40% or more of the sites investigated were identified as highly unstable MSI (MSI-H). In young patients, we also searched for germline mutations in three mismatch repair genes (hMSH2, hMLH1, and hMSH6). RESULTS: The incidence of MSI-H varied statistically significantly with age, being observed in more than 60% of those younger than age 31 years at diagnosis and in fewer than 15% of those age 46 years or older. In 15 patients (<46 years old) whose colorectal cancers showed MSI-H, eight possessed germline mutations in either hMSH2 or hMLH1. When mutations in hMSH6 were included, more than 80% of Chinese colorectal cancer patients younger than 31 years had germline mutations in mismatch repair genes. We found a novel germline missense mutation in hMSH6 in a 29-year-old man whose tumor showed no MSI. Two patients had a 4-base-pair insertion in exon 10 causing a truncated protein; this insertion is a common polymorphism with a population allele frequency in Chinese of 5.6%. CONCLUSIONS: Our results indicate that germline mutations in mismatch repair genes contribute substantially to the pathogenesis and high incidence of colorectal cancer in young Hong Kong Chinese. However, because young Chinese and Caucasians show similar proportions of colorectal cancers with MSI-H, despite the higher incidence in the former, additional factors may underlie the high susceptibility of young Chinese to colorectal cancer.

Adenocarcinoma↗
PubMed1998

Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites.

Microsatellite instability (MI) characterizing tumors with replication errors (RER+ tumors) was first described in colorectal tumors from hereditary non-polyposis colorectal cancer (HNPCC) patients as well as in sporadic cases. It has also been observed in subgroups of extracolonic sporadic tumors, but there is no consensus as to the number of microsatellite loci to examine, and the threshold percentage of unstable loci required to classify a tumor as RER+. We have recently shown that BAT-26, a mononucleotide repeat microsatellite, was quasi-monomorphic in DNA from normal individuals and from colorectal RER- samples, and showed important size variations in RER+ samples. In the present work, we analyzed BAT-26 allelic profiles in tumors of the breast (n = 107), brain (n = 78), stomach (n = 59), prostate (n = 49), esophagus (n = 36), thyroid (n = 31), endometrium (n = 12), and cervix (n = 10) whose RER status was already known, thus extending BAT-26 analysis to a total of 542 human solid tumors. BAT-26 alleles were quasi-monomorphic in RER- samples (475/481) and shortened in RER+ tumors (57/61), including four tumors shown to have been misclassified on the basis of dinucleotide repeat microsatellite analysis. In 3/481 RER- and 4/61 RER+ cases, BAT-26 size variation was important enough to attract attention, but not sufficient to establish the RER status of the corresponding tumors. In these cases, the analysis of BAT-25 and BAT-34C4, two other mononucleotide repeat microsatellites, was necessary to resolve the ambiguity. There were only 3 false positive cases. In conclusion, BAT-26 was able to identify the RER status of 539 out of 542 tumors from various origins (99.5% efficiency) in a single-step experiment without the requirement for matching normal DNA.

Breast Neoplasms↗
PubMed2004

Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches.

Both the availability of multiple treatment modalities and novel therapeutic targets make the correct prognostic stratification and the identification of truly predictive factors an issue of major debate in gastric cancer. Along with "classic" prognostic factors such as those related to the diffusion of the tumour at diagnosis (i.e., depth of gastric wall infiltration, locoregional lymph nodes or distant metastases) or those concerning the pathologic characteristics of the tumour, other, innovative, factors should be considered if a better definition of the characteristics of the tumour is to be given. These biological factors are often derived from the genetic process, which is thought to represent a crucial step to gastric cancer (DNA copy number changes, microsatellite instability, thymidilate synthase, E-cadherin, beta-catenin, mucin antigen, p53, c-erb B-2, COX-2, matrix metalloproteinases, VEGFR and EGFR). Some of those putative prognostic indicators can also be considered predictive of response to therapy as they are a molecular target either to chemotherapeutics (i.e., thymidilate synthase that is targeted by 5FU) or to a new class of antineoplastic molecules (i.e., c-erb B-2 targeted by trastuzumab, COX-2 by NSAIDs, matrix metalloproteinases, EGFR and VEGFR by specific inhibitors).

Apoptosis↗
PubMed2002

Variation in the vasopressin V1a receptor promoter and expression: implications for inter- and intraspecific variation in social behaviour.

Instability in highly repetitive microsatellite DNA located in the regulatory regions of genes may be a major factor producing diversity in both region-specific gene expression and the resulting phenotypes. Polymorphisms in promoter regions affecting expression of genes involved in regulating behaviour may play a role in generating individual variation in behaviour, including psychopathologies in humans, and probably are also important for the evolution of behaviour. Here we discuss the prairie vole vasopressin V1a receptor gene as a model that may be useful for understanding the evolution of promoter sequences and the relationship between gene sequence, expression and behavioural phenotype.

Animals↗
PubMedDate not supplied

MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial pneumonia limited to the lung and characterized by a fibroproliferative response with only minor signs of inflammation, which almost always causes rapid fibrotic destruction of the lung. In this study, we investigated genomic instability in IPF, using microsatellite DNA analysis, aiming to detect any specific genetic alterations for this disease. We used 40 highly polymorphic microsatellite DNA markers, in multiplex PCR assays, to examine 52 sputum specimens from IPF patients versus correspondent venous blood. Loss of heterozygosity (LOH) was found in 20 (38.5%) patients in at least one locus. These alterations were found on markers previously associated with lung cancer located on 1p34.3, 3p21.32-p21.1, 5q32-q33.1, 9p21 and 17p13.1 where MYCL1, FHIT, SPARC, p16(Ink4) and TP53 genes have been mapped respectively. These data provide new insights into IPF pathogenesis and a new perspective for its correlation with lung cancer.

Acid Anhydride Hydrolases↗
PubMedDate not supplied

[Etiopathogenic factors in colorectal cancer. Genetic and clinical features (first of 2 parts)].

INTRODUCTION: Colorectal Cancer (CRC) is the second cause of death in Spain, reaching the first place in non-smoking population. It is also the tumour with the greatest one-year incidence. The last few years some reduction in its incidence along with a greater 5-year average survival has been observed. PATHOGENESIS: Most CRCs develop from benign polyps. Vogelstein's hypothesis suggests an orderly progression from normal mucosa, to a small polyp, to a large polyp and finally to a CRC. In this progression transforming cells will be increasingly charged with molecular alterations. GENETIC FACTORS: 20% of CRCs have a genetic background although only a fourth of these are genetically based. The APC (or FAP) gene mutation is one of the earlier events that can be seen in tumour progression. When this mutation appears in the germ line it renders Familial Adenomatose Polyposis Syndrome (that evolves to CRC in a 100% of cases) or to the Gardner Syndrome (if it has extracolonic expressions). The p53 mutation is a late event in cellular transformation but it makes a rapid accumulation of mutations an easier process and it confers advantages for survival of the tumour cells. Mutations in the genes implicated in microsatellite instability are related to DNA error repair; their clinical correlates are the Lynch I and II syndromes. Other important genes related to CRC are DCC and ras. CLINICAL FACTORS: Inflammatory Bowel Disease (particularly Crohn's disease) is the most important clinical factor, it may enhance basal risk 30 times. Other risk factors are: previous malignant conditions, pelvic irradiation and previous surgery (cholecystectomy and ureterosigmoidostomy). The endocrinologic factors have a rising importance and so hormonal substitution therapy for menopause and multiparity can provide some protection. The use of NSAIDs can also be protective (specially COX-2 inhibitors). CONCLUSIONS: It is important that people who are identified as having a high risk for developing a CRC are subjected to a strict clinical and endoscopic follow-up in order to be able to identify an incipient tumour or to practice prophylactic surgery. The use of hormonal substitution therapy or anti COX-2 NSAIDs can be future useful chemoprophylactic agents.

Colorectal Neoplasms↗
PubMed2005

Microsatellite instability (MSI) analysis in patients with endometrial cancer.

Microsatellite instability (MSI) seems to be important for the development of various human cancers including sporadic endometrial cancer. The aim of this study was evaluation of microsatellite instability in 20 postmenopausal women with endometrial adenocarcinoma in DNA samples obtained from cancer tissue and blood of the same patients. Control DNA was obtained from normal endometrial tissue (n=25). MSI was studied at five loci containing single- or dinucleotide repeat sequences and mapping to different chromosomal locations: BAT-25 (at locus 4q12), BAT-26 (2pl6), D2S123 (2pl6-p21), D5S346 (5q21-q22) and D17S250 (17q11.2-q12). No differences in the MSI frequencies between blood and cancer tissue obtained from patients were detected. The microsatellite instability status was significantly higher in endometrial cancer tissue [5/20 (25%)] as compared to control [3/25 (12%)] (p < 0.05). There were no significant differences between MSI presence in the subgroups assigned to the histological grades (p > 0.05). The results suggest that the microsatellite instability seems to be important in the development of sporadic endometrial cancer.

Adenocarcinoma↗
PubMed1997

Rarity of microsatellite genomic instability in B-cell non-Hodgkin's lymphomas in hepatitis C virus-infected patients.

Several groups have emphasized the likely implication of the hepatitis C virus (HCV) in a fraction of B-cell non-Hodgkin's lymphomas. Since only a minority of patients with HCV infection and monoclonal mixed cryoglobulinaemia develop overt lymphoma, the identification of predisposing factors has relevant clinical implications. The replication error phenotype (RER+), as revealed by widespread microsatellite instability, is caused by defects in DNA mismatch repair genes, and has been frequently disclosed in subsets of B-cell lymphomas with underlying infection and chronic inflammation. We therefore investigated the occurrence of the RER+ phenotype in a series of eight consecutive B-cell NHLs in patients with chronic infection by HCV. A polymerase chain reaction-based assay was used to analyse an extended panel of 15 microsatellite loci. Microsatellite instability was not observed in six tumour samples in any locus; the two remaining cases showed instability at only one locus. Therefore genetic instability by defects in DNA mismatch repair genes should not represent the general mechanism predisposing to overt lymphoma in HCV-infected patients. Although a clearer definition of HCV-related B-cell disorders should better address future studies on genetic instability in larger series, we recommend additional oncogenetic pathways as the target of further research.

Adult↗
PubMed2000

Microsatellite instability in primary brain tumors.

Microsatellite instability has been reported in hereditary colorectal cancer syndrome and in various kinds of human sporadic tumors. It has also been shown in brain tumors, although with conflicting results. In the present study, DNA samples obtained from 20 primary brain tumors (10 glioblastomas, three astrocytomas, five meningiomas, one ependymoma, one hemangiopericytoma) were analyzed to detect microsatellite instability. Nine microsatellites, mono, di-, tri- and tetranucleotide repeat markers, located on nine different chromosomes, were used. Four of the 20 neoplasias (20%) showed microsatellite alterations in tumor DNA with respect to normal DNA. Two glioblastomas and one atypical meningioma (15%) showed additional bands or bands with shift of electrophoretic mobility, whereas allelic loss was observed in two glioblastomas (10%). In one glioblastoma, one allelic loss and one extra allele were observed at two different loci. These data indicate that in primary brain tumors there is not a high genetic instability. Although we used markers with inherently high levels of instability, only sporadic microsatellite alterations were found. Consequently, alterations in the mechanisms of DNA mismatch-repair, the most important cause of replication errors in hereditary and sporadic colorectal cancers, do not seem to play a major role in the oncogenesis of primary brain tumors.

Adult↗
PubMed2003

Expression of the DNA mismatch repair proteins (hMLH1 and hMSH2) in infiltrating pancreatic cancer and its relation to some phenotypic features.

UNLABELLED: DNA mismatch repair system defects cause microsatellite instability (MSI) and form an alternative pathway in cancer development. Germline mutations of DNA mismatch repair genes account for hereditary nonpolyposis colorectal cancer, which has a different morphology and biology than sporadic cancers. MSI has also been found in sporadic neoplasms and some inflammatory conditions (chronic pancreatitis, ulcerative colitis). The purpose of the present study was to evaluate the expression of hMLH1 and hMLH2 proteins in infiltrating pancreatic cancer and to find out whether there is a relationship between some phenotypic manifestations and expression of MMR genes. We studied 30 cases of infiltrating pancreatic cancer and apart from hMLH1 and hMLH2 expression cytokeratin 7 and chromogranin were measured as markers of ductal and endocrine differentiation, respectively. All ductal pancreatic cancers expressed cytokeratin 7. In most cases the expression was strong, present in 50-100% of cells in moderately differentiated cancers and in 80-100% of cells in poorly differentiated cancers. Chromogranin expression was seen in 5 moderately differentiated cancers and in 6 poorly differentiated cancers (up to 20% of positive cells). In all cases DNA mismatch repair genes expression was present. CONCLUSION: Ductal pancreatic carcinomas express hMLH1 and hMLH2 proteins irrespective of their differentiation. The expression of cytokeratin 7 is typical of ductal pancreatic carcinoma and its level is related to cancer differentiation. Some ductal pancreatic carcinomas irrespective of their differentiation show the expression of chromogranin, which is associated with the expression of hMSH2 gene.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens.

Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2.1-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-1) frameshift mutation in the TGFbetaIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.

Amino Acid Sequence↗
PubMed1995

Microsatellite instability in primary neoplasms from HIV + patients.

AIDS is associated with a high risk of certain malignancies, notably Kaposi's sarcoma (KS) and B-cell non-Hodgkin's lymphoma (NHL). The pathogenesis of these malignancies is not fully understood. One mechanism of malignant transformation recently described in colon tumorigenesis results from defects in DNA mismatch repair, manifest as widespread microsatellite instability. We demonstrate a high rate of microsatellite instability in KS and aggressive lymphomas obtained from HIV-infected patients, whereas there is no evidence of instability in similar lesions from HIV-negative patients. Further elucidation of the underlying mechanisms responsible for HIV-associated instability in primary tumours may provide insight into the pathogenesis of these AIDS-related neoplasms.

DNA Repair↗
PubMed2004

Detection of microsatellite alterations in bronchial washings in squamous cell lung cancer: the first study from India.

BACKGROUND: In recent times, the possibility of detecting lung cancer using microsatellite alterations (microsatellite instability and loss of heterozygosity) in DNA of bronchial washings has been explored. However, no data regarding the presence of microsatellite alterations in lung cancer are available from India, a country which contributes significantly to the lung cancer burden of the world. METHODS: Bronchial washings as well as tumor specimens obtained on bronchoscopy were analyzed for the presence of loss of heterozygosity (LOH) and microsatellite instability (MSI) using the D3S1300 microsatellite marker on chromosome 3p and the TP53 marker on chromosome 17p. RESULTS: The sensitivities of the TP53 and D3S1300 loci in bronchial washings were 35% and 45% (combined 50%), respectively, which was significantly better than conventional cytology (positive for malignant cells in 15%). The presence of these microsatellite alterations was not related to the age, cumulative smoking exposure or smoking status (current or former) of patients. CONCLUSION: Microsatellite alterations, particularly LOH, occur in a significant proportion of Indian patients with squamous cell carcinoma of the lung.

Acid Anhydride Hydrolases↗
PubMed2001

Frequent allelic imbalance at the ATM locus in DNA multiploid colorectal carcinomas.

DNA multiploidy may involve specific DNA ploidy states with respect to genetic alterations such as oncogenes, tumor suppressor gene mutation and microsatellite instability. To clarify the role of DNA multiploidy in colorectal cancer, we analysed allelic imbalance involving the ATM gene, localized to chromosome 11q22-23 and thought to be involved in genetic stability, in a series of multiploid colorectal carcinomas. In addition, p53 gene mutation (exons 5-8) and allelic imbalance at 11q24 loci distal to the ATM locus were also examined. The crypt isolation technique coupled with DNA cytometric sorting and polymerase chain reaction assay using 10 microsatellite markers tightly linked to the ATM gene were used to study ATM allelic imbalance in 55 colorectal carcinomas (15 diploid, 13 aneuploid, 27 multiploid). While allelic imbalance at the ATM locus was rarely observed in diploid and aneuploid carcinomas, multiploid carcinomas exhibited a high frequency of ATM allelic imbalance. In multiploid carcinoma samples, diploid subpopulations showed a smaller range of allelic imbalance at the loci tested compared to aneuploid subpopulations that demonstrated allelic imbalance over a relatively large region. Also, the frequency of AI at 11q24 showed a similar tendency to that at the ATM locus for each DNA ploidy state. An association between p53 gene mutation and ATM allelic imbalance in multiploid carcinoma was also observed. Our results suggest that ATM allelic imbalance and p53 gene mutations occur during the progression from diploid to aneuploid cell populations in multiploid colorectal carcinomas.

Allelic Imbalance↗
PubMed2000

Microsatellite instability is associated with genetic alteration but not with low levels of expression of the human mismatch repair proteins hMSH2 and hMLH1.

Mutational inactivation of hMSH2 or hMLH1 has been known to be responsible for microsatellite instability and cellular resistance to DNA-damaging alkylating agents. However, the effects of altered expression of hMSH2 or hMLH1 on microsatellite stability and cellular response to alkylating agents has not been well investigated. Previously, we have reported that downregulation of the hMLH1 protein was a frequent event and was closely associated with cellular resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in human gastric carcinoma cell lines. Therefore, to investigate the relationship between microsatellite instability and quantitative changes in hMSH2 and hMLH1, we compared the genetic status and expression levels of hMSH2 and hMLH1 with microsatellite instability in 11 human gastric carcinoma cell lines. Five cell lines contained wild-type hMSH2 and hMLH1 and expressed adequate levels of hMSH2 and hMLH1 proteins. In three cell lines, genetic alterations such as mutation in the hMLH1 gene (SNU-1) or the hMSH2 gene (SNU-638), or hypermethylation in the promoter region of the hMLH1 gene (SNU-520) were observed. Microsatellite instability assays revealed that only these three cell lines exhibited microsatellite instability. Three cell lines (SNU-216, -484, and -668) containing wild-type hMSH2 and hMLH1 genes produced significantly downregulated hMSH2 and/or hMLH1 proteins. In spite of the substantial decrease in the protein levels, these cell lines did not show microsatellite instability. Together with our previous report, this study suggests that: microsatellite instability of cells is associated only with genetic alteration of the mismatch repair genes; relatively low levels of the hMSH2 and hMLH1 proteins may be sufficient to retain the microsatellite stable phenotype; and the cellular response to alkylating agents is associated with genetic alteration and decreased expression of the mismatch repair genes in human gastric carcinoma cell lines.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Genomic stability in malignant melanoma of Xiphophorus.

Microsatellite instability is a feature of many tumours and is indicative of a generalized genomic instability of cancer cells. Whether this phenomenon is essential for tumorigenesis and whether it is an early or late step is still a matter of debate. In the Xiphophorus melanoma model, the primary steps leading to tumour formation are known and include overexpression of a mutationally altered epidermal growth factor receptor and the resulting defects in signalling. We have analysed the late stages of melanoma progression for microsatellite instability. Although several types of microsatellite allele alteration in DNA from tumours relative to DNA from non-tumour tissue were found, the frequency was rather low (7.6%). Thus, although the tumours show a wide range of malignancy and aggressiveness, genomic instability that becomes apparent as microsatellite instability does not appear to be an obligatory step for melanoma progression.

Animals↗