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PubMed2003

Radiation-induced transgenerational instability.

To date, the analysis of mutation induction has provided an irrefutable evidence for an elevated germline mutation rate in the parents directly exposed to ionizing radiation and a number of chemical mutagens. However, the results of numerous publications suggest that radiation may also have an indirect effect on genome stability, which is transmitted through the germ line of irradiated parents to their offspring. This review describes the phenomenon of transgenerational instability and focuses on the data showing increased cancer incidence and elevated mutation rates in the germ line and somatic tissues of the offspring of irradiated parents. The possible mechanisms of transgenerational instability are also discussed.

Animals↗
PubMedDate not supplied

Genetic instability and the evolution of angiogenic tumor cell lines (review).

Advanced tumor growth requires the formation of new blood vessels (angiogenesis). Whether new blood vessels are formed or not depends on a balance between angiogenesis inhibitors and promoters. Host tissue, as well as tumor cells, express inhibitory factors preventing angiogenesis. During cancer progression, tumor cell lines evolve which produce factors promoting the angiogenic switch. We use mathematical models in order to examine the conditions required for angiogenic cell lines to emerge and hence for the disease to progress. We find that genetic instability, defined as a much elevated mutation rate of somatic cells, is required for the emergence of angiogenic tumor cells. This is because a high mutation rate ensures that within a short period of time, a sufficiently high number of angiogenic cells are generated. This founder population of mutant cells is large enough to overcome the inhibitory factors produced by the tissue thereby inducing the angiogenic switch through the production of promoters. In the absence of genetic instability, angiogenic cells cannot fix, even if the relevant mutations are generated at low levels in the tumor cell population. This is because angiogenic promoters will not be sufficiently abundant to counter the influence of inhibitory factors. In this context, the inhibition of angiogenesis can be viewed as a host defense ensuring that the tumor need be genetically unstable if it is to grow and progress beyond a certain size limit. We observe that genetic instability is of value early in tumorigenesis but becomes a liability later. This is because instability decreases the fitness of the angiogenic tumor once it has become established.

Animals↗
PubMed2004

Genotoxicity of tobacco smoke and tobacco smoke condensate: a review.

This report reviews the literature on the genotoxicity of mainstream tobacco smoke and cigarette smoke condensate (CSC) published since 1985. CSC is genotoxic in nearly all systems in which it has been tested, with the base/neutral fractions being the most mutagenic. In rodents, cigarette smoke induces sister chromatid exchanges (SCEs) and micronuclei in bone marrow and lung cells. In humans, newborns of smoking mothers have elevated frequencies of HPRT mutants, translocations, and DNA strand breaks. Sperm of smokers have elevated frequencies of aneuploidy, DNA adducts, strand breaks, and oxidative damage. Smoking also produces mutagenic cervical mucus, micronuclei in cervical epithelial cells, and genotoxic amniotic fluid. These data suggest that tobacco smoke may be a human germ-cell mutagen. Tobacco smoke produces mutagenic urine, and it is a human somatic-cell mutagen, producing HPRT mutations, SCEs, microsatellite instability, and DNA damage in a variety of tissues. Of the 11 organ sites at which smoking causes cancer in humans, smoking-associated genotoxic effects have been found in all eight that have been examined thus far: oral/nasal, esophagus, pharynx/larynx, lung, pancreas, myeoloid organs, bladder/ureter, uterine cervix. Lung tumors of smokers contain a high frequency and unique spectrum of TP53 and KRAS mutations, reflective of the PAH (and possibly other) compounds in the smoke. Further studies are needed to clarify the modulation of the genotoxicity of tobacco smoke by various genetic polymorphisms. These data support a model of tobacco smoke carcinogenesis in which the components of tobacco smoke induce mutations that accumulate in a field of tissue that, through selection, drive the carcinogenic process. Most of the data reviewed here are from studies of human smokers. Thus, their relevance to humans cannot be denied, and their explanatory powers not easily dismissed. Tobacco smoke is now the most extreme example of a systemic human mutagen.

DNA Damage↗
PubMed2002

A novel single molecule analysis of spontaneous and radiation-induced mutation at a mouse tandem repeat locus.

Expanded simple tandem repeat (ESTR) loci include some of the most unstable DNA in the mouse genome and have been extensively used in pedigree studies of germline mutation. We now show that repeat DNA instability at the mouse ESTR locus Ms6-hm can also be monitored by single molecule PCR analysis of genomic DNA. Unlike unstable human minisatellites which mutate almost exclusively in the germline by a meiotic recombination-based process, mouse Ms6-hm shows repeat instability both in germinal (sperm) DNA and in somatic (spleen, brain) DNA. There is no significant variation in mutation frequency between mice of the same inbred strain. However, significant variation occurs between tissues, with mice showing the highest mutation frequency in sperm. The size spectra of somatic and sperm mutants are indistinguishable and heavily biased towards gains and losses of only a few repeat units, suggesting repeat turnover by a mitotic replication slippage process operating both in the soma and in the germline. Analysis of male mice following acute pre-meiotic exposure to X-rays showed a significant increase in sperm but not somatic mutation frequency, though no change in the size spectrum of mutants. The level of radiation-induced mutation at Ms6-hm was indistinguishable from that established by conventional pedigree analysis following paternal irradiation. This confirms that mouse ESTR loci are very sensitive to ionizing radiation and establishes that induced germline mutation results from radiation-induced mutant alleles being present in sperm, rather than from unrepaired sperm DNA lesions that subsequently lead to the appearance of mutants in the early embryo. This single molecule monitoring system has the potential to substantially reduce the number of mice needed for germline mutation monitoring, and can be used to study not only germline mutation but also somatic mutation in vivo and in cell culture.

Animals↗
PubMed1998

Eukaryotic mismatch repair: an update.

The discovery that mutations in mismatch repair genes segregate with hereditary nonpolyposis colon cancer has awakened a great deal of interest in the study of the process of postreplicative mismatch repair. The characterisation of the principal players involved in this important metabolic pathway has been greatly facilitated by the amino acid sequence conservation among functional homologues of bacteria, yeast and mammals. The phenotypes of mismatch repair deficient mutants are also similar in many ways. In humans, mismatch repair malfunction demonstrates itself in the form of a mutator phenotype of the affected cells, an instability of microsatellite sequences and increased levels of somatic recombination. Moreover, mismatch repair deficient cells display also varying levels of tolerance to DNA damaging agents and are thought to be involved in the cell killing mediated by these agents. This article discusses some recent developments in this fast-moving field.

Adenosine Triphosphatases↗
PubMed2004

PTEN mutations are common in sporadic microsatellite stable colorectal cancer.

The tumour suppressor gene PTEN, located at chromosome sub-band 10q23.3, encodes a dual-specificity phosphatase that negatively regulates the phosphatidylinositol 3'-kinase (PI3 K)/Akt-dependent cellular survival pathway. PTEN is frequently inactivated in many tumour types including glioblastoma, prostate and endometrial cancers. While initial studies reported that PTEN gene mutations were rare in colorectal cancer, more recent reports have shown an approximate 18% incidence of somatic PTEN mutations in colorectal tumours exhibiting microsatellite instability (MSI+). To verify the role of this gene in colorectal tumorigenesis, we analysed paired normal and tumour DNA from 41 unselected primary sporadic colorectal cancers for PTEN inactivation by mutation and/or allelic loss. We now report PTEN gene mutations in 19.5% (8/41) of tumours and allele loss, including all or part of the PTEN gene, in a further 17% (7/41) of the cases. Both PTEN alleles were affected in over half (9/15) of these cases showing PTEN genetic abnormalities. Using immunohistochemistry, we have further shown that all tumours harbouring PTEN alterations have either reduced or absent PTEN expression and this correlated strongly with later clinical stage of tumour at presentation (P=0.02). In contrast to previous reports, all but one of the tumours with PTEN gene mutations were microsatellite stable (MSI-), suggesting that PTEN is involved in a distinct pathway of colorectal tumorigenesis that is separate from the pathway of mismatch repair deficiency. This work therefore establishes the importance of PTEN in primary sporadic colorectal cancer.

Alleles↗
PubMed1979

Heterogeneous flavonoid glucosyltransferases in purple derivatives from a controlling element-suppressed bronze mutant in maize.

The Ds(Dissociation)-suppressed bronze mutant bz-m2(DI), which is extremely stable in the absence of the regulatory element Ac (Activator), becomes both somatically and germinally unstable when Ac is present. Instability in the germ line may result in the generation of stable (Ac-nonresponding), colored Bz' derivatives. The characterization of several properties of the Bz-controlled enzyme UDPglucose: flavonoid 3-O-glucosyltransferase from mature kernel endosperms of 15 such Bz' derivatives has revealed two distinct groups. The enzyme in group I Bz' derivatives does not differ from the normal enzyme in the Bz progenitor allele of bz-m2(DI). Group II Bz' derivatives, on the other hand, make altered, labile UDPglucose:flavonoid glucosytransferases different from the normal enzyme and probably different from each other. The significance of these two classes of derivatives and possible mechanisms involved in their origin are discussed.

Journal Article↗
PubMed2000

Cytoplasmic dynein-mediated assembly of pericentrin and gamma tubulin onto centrosomes.

Centrosome assembly is important for mitotic spindle formation and if defective may contribute to genomic instability in cancer. Here we show that in somatic cells centrosome assembly of two proteins involved in microtubule nucleation, pericentrin and gamma tubulin, is inhibited in the absence of microtubules. A more potent inhibitory effect on centrosome assembly of these proteins is observed after specific disruption of the microtubule motor cytoplasmic dynein by microinjection of dynein antibodies or by overexpression of the dynamitin subunit of the dynein binding complex dynactin. Consistent with these observations is the ability of pericentrin to cosediment with taxol-stabilized microtubules in a dynein- and dynactin-dependent manner. Centrosomes in cells with reduced levels of pericentrin and gamma tubulin have a diminished capacity to nucleate microtubules. In living cells expressing a green fluorescent protein-pericentrin fusion protein, green fluorescent protein particles containing endogenous pericentrin and gamma tubulin move along microtubules at speeds of dynein and dock at centrosomes. In Xenopus extracts where gamma tubulin assembly onto centrioles can occur without microtubules, we find that assembly is enhanced in the presence of microtubules and inhibited by dynein antibodies. From these studies we conclude that pericentrin and gamma tubulin are novel dynein cargoes that can be transported to centrosomes on microtubules and whose assembly contributes to microtubule nucleation.

Animals↗
PubMed1988

Physical inactivity as a risk factor for primary and secondary coronary events in Göteborg, Sweden.

Physical activity at work and during leisure time were studied by using a questionnaire in a random sample of 7495 middle-aged men from the Primary Prevention Study in Göteborg and in 1273 able-bodied male patients with a first myocardial infarction, registered in the Infarction Register in the same city over the period 1968-84. Data on coronary risk factors and socio-economic factors were recorded in the population sample as were data on risk factors and known somatic predictors for prognosis in the infarction group. An inverse and graded association was found between leisure time physical activity and mean diastolic blood pressure, total cholesterol, body mass index, tobacco smoking, socio-economic status and mental stress in the random sample. During the approximate 12-year follow-up, low physical activity during leisure time, but not at work, was associated with an increased risk of coronary deaths and non-fatal infarctions in univariate analysis. Inactive subjects had twice the incidence of total coronary events (9.4%) as physically active contemporaries (4.2%). After controlling for major coronary risk factors, occupational class, diabetes, family history of coronary heart disease and mental stress in a multivariate logistic regression analysis, the association between leisure time physical activity and total coronary events disappeared. Physical activity at work and during leisure time estimated for the 12-month period preceding the first infarction was not associated with long-term prognosis after infarction. Infarction patients assessed to be in need of additional rehabilitation due to somatic restrictions, work-related factors and emotional instability, resumed work later and had a higher mortality and non-fatal recurrence rate during follow-up than patients not considered to require additional rehabilitation. Physical inactivity was not a risk factor for primary and secondary coronary events in this study. The inverse direction of the association between leisure time physical activity and coronary risk factors suggests that increased physical activity alters the risk factor profile in a favourable direction.

Activities of Daily Living↗
PubMed2006

Quantitative analysis of telomerase activity and telomere length in domestic animal clones.

It has been speculated that incomplete epigenetic reprogramming of the somatic cell genome is the primary reason behind the developmental inefficiencies and postnatal abnormalities observed after nuclear transplantation in domestic animal clones. One chromosome structure that is altered in dividing somatic cells is telomere length-the terminal ends of linear chromosomes capped by repetitive sequences of G-rich noncoding DNA, (TTAGGG)", and specific binding proteins. Telomeres are critical structures that function in maintaining chromosome stability and ensure the full replication of coding DNA by acting as a buffer to terminal DNA attrition due to the end replication problem. Telomere shortening limits cellular proliferation through a DNA damage signal activating permanent cell cycle arrest at a critical telomere length or through structural telomere alterations that prevents effective chromosome capping. Telomere-mediated signaling of cellular senescence has been established for many somatic cell types in vitro, except for germ cells, cancer lines, and regenerative tissues in which telomere length is maintained primarily by the ribonucleoprotein telomerase, a reverse transcriptase that synthesizes TTAGGG repeats de novo onto the chromosome ends. Telomere length discrepancies have been reported in animal clones as being shorter, no different, and even longer than in age-matched control animals, but the etiology is not yet understood. Possible explanations include differences in donor cell type and the efficiency of telomerase reprogramming. This chapter summarizes the conventional protocols and recent advances in telomere length and telomerase activity measurement that will help elucidate the mechanism(s) behind telomere length deregulation in somatic cell clones and its role in chromosomal instability, cellular senescence, and organismal aging in vivo.

Aging↗
PubMed1998

BAX somatic frameshift mutations in endometrioid adenocarcinomas of the endometrium: evidence for a tumor progression role in endometrial carcinomas with microsatellite instability.

Microsatellite instability (MI) has been observed in endometrioid adenocarcinomas of the endometrium, either arising sporadically or in association with the hereditary colon cancer syndrome. Genes known to contain mononucleotide short tracts in their coding sequence are regarded as targets for mutations in these tumors. BAX is a proapoptotic gene that contains a tract of eight consecutive deoxyguanosines in its third coding exon. DNA of 26 patients with endometrial carcinoma was extracted from blood and from fresh-frozen and paraffin-embedded tumor tissue. For MI analysis, microsatellite loci on chromosomes 3, 5, 10, 12, and 18 were amplified by PCR. Frameshift mutations in the (G)8 tract of BAX were detected by single-strand conformation polymorphism (SSCP) analysis. MI at three or more loci was detected in 13 cases. BAX frameshift mutations were detected in seven MI+ tumors (53.8%), but in none of the 13 MI- neoplasms. In two cases, identical BAX frameshift mutations were detected in different areas of the neoplasm, whereas in the other five cases, BAX mutations were heterogeneously distributed throughout the tumor. Immunostaining with antibodies against the carboxy terminus of BAX protein was very useful in assessing the heterogeneous distribution of BAX frameshift mutations in the neoplasms. The results suggest that BAX frameshift mutations are frequent in endometrial carcinomas with MI, probably playing a role in the process of tumor progression of these neoplasms.

Base Sequence↗
PubMed1995

Somatic cell mutation frequency at the HPRT, T-cell antigen receptor and glycophorin A loci in Cockayne syndrome.

Skin fibroblasts of patients with Cockayne syndrome (CS) are hypersensitive to the lethal or mutagenic effect of ultraviolet light, which may cause genetic instability. Up to now, however, no systematic study of in vivo somatic cell mutation in CS cells has been reported. This article describes our investigation of the mutation frequencies (Mfs) at three different loci, i.e. hypoxanthine-guanine phosphoribosyl transferase (HPRT), T-cell antigen receptor (TCR) and glycophorin A (GPA), in six patients with CS. Mfs at the HPRT and TCR loci were found to be within the normal range as determined in age-matched controls. In the GPA locus of two patients, there was a slight increase, but it was much smaller than that reported in other DNA repair deficient syndromes. The frequency of spontaneous HPRT mutation in Epstein-Barr virus transformed B-lymphoblastoid cells derived from CS patients was similar to that in cells from normal children. The molecular characterization of the representative HPRT mutant T cell clones from CS patients did not show any structural alterations. These results may explain, at least in part, why CS is not associated with predisposition to cancer.

Adolescent↗
PubMed2026

Distinct mutational landscapes for germline and somatic cancer variants in forty tumor suppressor genes.

Germline and somatic cancer variants in tumor suppressor genes (TSGs) share loss-of-function mechanisms, but studies of a few genes (DICER1 and CEBPA) have demonstrated differences in variant consequence and location. To systematically assess whether TSGs display distinct mutational patterns, we leveraged large public genetic databases and compared 32,941 high-quality pathogenic/likely pathogenic (P/LP) germline variants in ClinVar, with 12,907 oncogenic/likely oncogenic (O/LO) somatic tumor variants from cBioPortal across 40 TSGs. Only 3,863 (9.2%) variants were shared. Eighteen TSGs showed significantly different distributions of variant occurrences by molecular consequence, replicated with non-overlapping somatic data from the COSMIC database (chi-squared tests, false discovery rate = 5%). DICER1, TP53, and SMAD4 displayed excess somatic missense events, while nine TSGs (e.g., RB1 and APC) contained excess somatic stop-gain events throughout the coding sequence. Analysis by tumor type revealed excess stop-gain events in tissues exposed to environmental mutagens with corresponding mutation signatures. For several TSGs (WT1), germline variants predispose to tumors (Wilms' tumor) distinct from the majority source of somatic data (myeloid leukemia). Germline and somatic events are also distributed unevenly across cDNA locations, with 103 regions of preferential clustering in 39 TSGs (78 somatic and 25 germline). Twenty somatic clusters contained recurring frameshifts in homopolymer runs, many in tumors with microsatellite instability. Germline clusters contain more germline-exclusive variants, some driving non-cancer phenotypes reflecting genetic pleiotropy. Altogether, germline and somatic variants of TSGs represent unique sets with substantially different patterns shaped by selection pressures from gene-specific and somatic mutational mechanisms. Characterizing these distinctions enables more accurate clinical interpretation of TSG variants.

Humans↗
PubMed1998

Genetic alterations in a patient with Turcot's syndrome.

Turcot's syndrome (TS) is a rare disorder associated with the development of both brain and colon neoplasms. Because of the very low incidence of the disease, its molecular basis remains unclear. Presented is a TS case of a 30-year-old Japanese male with a histopathologically confirmed diagnosis of both brain tumor (glioblastoma multiforme) and colon tumor (well-differentiated adenocarcinoma). Germline mutations of the p53 gene, somatic mutations of the Ki-ras, p53 and APC genes, and microsatellite instability (MSI) was examined using polymerase chain reaction (PCR)-single strand conformation polymorphism analysis, followed by PCR-direct sequencing, and sequencing after subcloning. No germline mutations of the p53 gene were found. Somatic mutations of Ki-ras and APC genes were found in the colon adenocarcinoma but not in the brain tumor. No somatic mutation of the p53 gene was present in either colon or brain tumors. Microsatellite instability of both colon and brain tumors was positive in two of four loci. These results indicate that the colon tumor of the TS patient carries the Ki-ras and APC gene mutations. The finding of MSI in both the brain and the colon tumors may support the hypothesis that alterations of DNA repair genes are involved in the tumor development of the TS patient.

Adenomatous Polyposis Coli↗
PubMed1999

[The study of quantitative karyotypic variability by induction of chromosomal instability in cultured cells of the Indian muntjac skin fibroblasts].

The influence of mycoplasmal contamination and somatic cell hybridization on the character of karyotypic variability in cell cultures of Indian muntjac skin fibroblasts has been investigated. Mycoplasma arginini and Acholeplasma laidlawii, used as factors inducing chromosomal instability, do not break the main regulations peculiar to intact control. They regulations are: 1) nonrandom character of cell distribution according to the number of chromosomal deviations from MSVK; 2) specific character of deviations of each chromosome from MSVK; 3) presence of significant connections between separate chromosomes by simultaneous mainly single directed numeral deviations. However, mycoplasmal contamination promotes the increase in the number of deviations in the direction of a decreasing chromosomes number. There is a breach of some connections between chromosomes by simultaneous deviations. They are chromosomes with broken connections according to the number of deviations which form telomeric associations (dicentrics). The number of these associations excel essentially intact control. The formation of new MSVK in subline M2 cells of the Indian muntjac in the process of chromosomal segregation in cell hybrid (M2 x clone of JF1 rat Jensen sarcoma) depends on the presence of significant connections between chromosomes by simultaneous numerical deviations in direction of MSVK formation. They are chromosomes that take part in the formation of new MSVK which form telomeric associations. These associations can be observed till stabilization of new MSVK. Probably, the support of the balance of karyotypic structure by factors inducing chromosomal instability is connected with change of some connections between chromosomes according to the number by simultaneous deviations as well as with the formation of dicentrics.

Acholeplasma↗
PubMed2005

Somatic evolution of cancer cells.

Cancers develop through a process called genomic instability, which generates diversity, from which clonal evolution may occur. In colorectal cancers, this process has been extensively studied, and there are three identifiable processes involved in generating diversity at the genetic or epigenetic level. Colorectal cancers may have chromosomal instability (CIN), microsatellite instability (MSI), or the CpG island methylator phenotype (CIMP). Each of these processes is associated with a unique mutational or epigenetic "signature" identifiable in the tumor cells, and there are important conceptual and clinical implications of each.

Adenoma↗
PubMed2005

Somatic acquisition and signaling of TGFBR1*6A in cancer.

CONTEXT: TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. OBJECTIVES: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. DESIGN, SETTING, AND PATIENTS: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. MAIN OUTCOME MEASURES: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation. RESULTS: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. CONCLUSIONS: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.

Activin Receptors, Type I↗
PubMed1995

Microsatellite instability in gynecological sarcomas and in hMSH2 mutant uterine sarcoma cell lines defective in mismatch repair activity.

We have examined a panel of gynecological sarcomas for microsatellite instability. The genomic DNA from 11 of 44 sarcomas contained somatic alterations in the lengths of one or more di-, tri-, tetra-, or pentanucleotide microsatellite sequence markers, and 6 of these cases had alterations in two or more markers. In addition, di-, tri-, and tetranucleotide microsatellites were found to be highly unstable in single cell clones of two cell lines derived from a uterine mixed mesodermal tumor. Since such instability is characteristic of cells defective in postreplication mismatch repair, we examined mismatch repair activity in extracts made from these lines. Both extracts were repair deficient, while an extract of another gynecological sarcoma cell line not exhibiting microsatellite instability was repair proficient. The repair deficiency was complemented by a colon tumor cell extract that was defective in the hMLH1 protein but not by an extract defective in hMSH2 protein. This suggested that the defect in the uterine sarcoma line could be in hMSH2. Subsequent analysis of the gene revealed a 2-bp deletion in exon 14, leading to premature truncation of the hMSH2 protein at codon 796 and no detectable wild-type gene present. These data suggest that the microsatellite instability observed in these cell lines, and possibly in a significant number of gynecological sarcomas, is due to defective postreplication mismatch repair. There was no apparent correlation with microsatellite instability and clinical outcome.

DNA Repair↗