Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “somatic instability”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources
PubMed1991

Instability of immunoglobulin genes in S107 cell line.

Somatic mutation occurs frequently in rearranged and expressed immunoglobulin variable region genes in vivo. In contrast, V region hypermutation seldom occurs in antibody-forming cells in culture. The S107 mouse myeloma cell line is one of the few cell lines that has been observed to generate V region mutations frequently and spontaneously in vitro. Detailed examination reveals that both the S107 tumor and the cell line derived from it contain and express a duplicated heavy-chain gene. In culture, only one of the two heavy-chain genes undergoes both V and C region mutation, and variants with complex phenotypes and genotypes arise as a result of mutation and segregation of these duplicated genes.

Animals↗
PubMed2000

Somatic alterations of the androgen receptor CAG repeat in human colon cancer delineate a novel mutation pathway independent of microsatellite instability.

The human androgen receptor gene contains a polymorphic CAG repeat region ranging from 8 to about 35 repeats in the normal human population. The repeat length is inversely related to the transactivation potential of the receptor. We have analyzed the repeat length in 50 sporadic colon cancer samples in comparison to surrounding healthy mucosa and have found somatic reductions of up to 10 repeats in 5 cases (10%), 3 of which were complex, probably involving both alleles. Alterations occurred in tumors with and without microsatellite instability indicating that they follow an independent mutation pathway. The similar repeat of the huntingtin gene did not show any somatic alterations in the same cases. No correlation to sex, tumor stage, location, or histology was evident. In the tumors that showed somatic reductions, the reduced allele was present in at least half of the cells and thus in most, if not all, of the tumor component of the sample. Somatic reductions of the androgen receptor CAG repeat thus occur frequently, through a pathway distinct from microsatellite instability and early during colon carcinogenesis. The receptor is expressed in most normal and neoplastic tissue samples analyzed. Apparent growth selection of cells bearing shortened AR alleles suggests that androgens contribute to colon carcinogenesis in a yet unknown way.

Alleles↗
PubMed1992

Evolutionary somatic cell changes in cervical tumour progression quantitatively evaluated with morphological, histochemical and kinetic parameters.

The somatic cell changes which characterise malignancy evolution in human cervical preneoplastic and neoplastic lesions have been assessed on histological sections by means of a computerised image analyser. Many features have been simultaneously measured on each cell of the lesions studied, and the following results have been obtained: Some features, mainly kinetic, show continuously increasing values which express changes correlated to the increasing malignancy; other features, especially related to nuclear atypia, cellular heterogeneity and the degree of aneuploidy, have values dropping at the level of early stromal infiltration, which can be morphometrically characterised as composed of relatively homogeneous phenotypes; these features seem to express the degree of genetic instability and relate to the evolutionary somatic cell changes; tumour progression evolves through sequential discontinuous steps, each of them characterised by specific phenotypical features of the neoplastic cell population; the neoplastic cells in the foci of early stromal infiltration and vascular invasion, phenotypically more homogeneous than the parent cell populations of carcinoma in situ and infiltrating carcinoma, seem to possess a greater genetic stability.

Aneuploidy↗
PubMed2003

In vivo somatic microsatellite mutations identified in non-malignant human tissue.

Microsatellite instability (MSI) has been described in cancer cells and in vitro cell lines, and meiotic changes in repeat length have also been documented. We report the novel observation of somatic microsatellite mutation (SMM) in normal human somatic cells in vivo, detected while genotyping 5767 prenatal samples (4640 amniotic fluid samples and 1127 chorionic villus biopsies) as a diagnostic test for exclusion of trisomy 13, 18 or 21. Quantitative fluorescence-PCR using a multiplex of 12 primer pairs, for four loci on each of the three chromosomes, was followed by fragment analysis on a capillary-based genetic analyser. Forty-seven (4.2%) chorionic villus samples and six (0.1%) amniotic fluid samples showed allelic mosaicism, interpreted as SMM. In four cases, analysis of parental blood samples confirmed the presence of a de novo allele. SMM was detected at all but two of the 12 loci tested, and the incidence of mutation increased with repeat length. Detection of SMM in chorionic villus samples may imply less rigorous correction of replication errors in these extra-embryonic tissues, and is likely to have been facilitated by clonal expansion in the small samples of tissue tested. The presence of the same phenomenon in six amniotic fluid samples would imply that in these pregnancies, the instability event had occurred early in embryogenesis. The results suggest that defective proof reading during DNA replication may be more common in non-malignant human somatic tissue than previously recognised.

Alleles↗
PubMed2006

Gene expression analysis of tumor infiltrating lymphocyte markers in endometrial cancers indicates no significant increases in those cases with microsatellite instability.

Microsatellite instability (MSI) is seen in many cancers and is the result of either a germline or somatic defect in the DNA mismatch repair system. Microsatellite instability is common in endometrial cancers occurring in about 25% of cases with endometrioid histology. Tumor infiltrating lymphocytes (TIL) are more prominent in colorectal cancer cases with MSI. The presence of increased TIL is associated with increased survival in these colorectal cancers, and is suggested as one possible mechanism to explain the increased survival rates in colorectal cancer patients with MSI positive cancers. Some degree of evidence indicates that increased TIL is also predictive of increased survival in endometrial cancer. The relative levels and states of activation of TIL in endometrial cancers with and without MSI has not been explored. Our previous data indicates that global gene expression patterns from MSI and non-MSI endometrial cancers are distinct, however TIL markers were not over-represented on statistically relevant gene lists that distinguish these groups. We further examined these pre-existing microarray data by directly querying transcripts present in the T-cell gene ontology (GO) group. No significant differences were observed between MSI and microsatellite stable (MSS) groups. Finally we directly examined a set of T-cell marker transcripts previously utilized to define increased activated and cytotoxic TIL in MSI positive colorectal cancers. Whereas colorectal cancers with MSI have been previously demonstrated to contain higher ratios of CD8/CD3 message levels we observed no difference in endometrial cancers. In addition, levels of CD3 indicated no increases in TIL in MSI positive cases and 2 markers of activation, granzyme B and IL-2R were not different in MSI positive and negative cancers. These data indicate that significant differences in TIL derived transcripts do not occur between endometrioid endometrial cancers with and without microsatellite instability.

Biomarkers, Tumor↗
PubMed1999

Genetic instability did not lead to p53 mutations in an extremely early-onset breast cancer in a cancer-prone family.

BACKGROUND: A positive family history is a major contributor to risk of development of breast cancer. METHODS: Somatic and germ line mutations of p53 and genetic instability were evaluated for an extremely early-onset breast cancer case in a cancer-prone family. RESULTS: The mode of inheritance in this case was clearly autosomal dominant. DNA replication error was recognized by detecting microsatellite allelic alterations. However, mutations of p53 were not found at either somatic or germ-line level. CONCLUSION: These genetic studies suggest that an increased genetic instability did not lead to p53 gene mutations in this breast cancer patient.

Adult↗
PubMed1999

Rapid structural and epigenetic changes in polyploid and aneuploid genomes.

Recent work with plants has demonstrated that genome instability can be triggered by a change in chromosome number arising from either whole genome duplications (polyploidy) or loss/gain of individual chromosomes (aneuploidy). This genome instability is manifested as rapid structural and epigenetic alterations that can occur somatically or meiotically within a few generations after heteroploid formation. The intrinsic instability of newly formed polyploid and aneuploid genomes has relevance for genome evolution and human carcinogenesis, and points toward recombinational and epigenetic mechanisms that sense and respond to chromosome numerical changes.

Aneuploidy↗
PubMedDate not supplied

On some technical aspects of direct DNA diagnosis of the fragile X syndrome.

Direct DNA analysis of fragile X [Fra(X)] mutations has already shown its clear superiority for postnatal and prenatal diagnosis of the disorder and for carrier detection. However, it is of great importance to have conditions which guarantee optimal reliability and sensitivity. Some mutations may be more difficult to detect, especially in female carriers: this is the case for small amplifications of the CGG repeat (premutations) or for smears which can be generated by the instability of the full mutation in somatic tissues. We present the various alternatives (probe/enzymes combinations) for Southern blot based diagnosis, the possible artefacts and our detailed experimental protocol, which has given excellent results on a large number of families. While detection of amplification, using for instance EcoRI, appears sufficient for initial testing of mentally retarded patients, once the fra(X) diagnosis has been established, we favor the use of an EcoRI+EagI digest, which detects both amplification and abnormal methylation, for analysis of the family, including carrier detection and prenatal diagnosis. We discuss the place of proposed PCR based techniques for detection of mutations, or for indirect tracking using polymorphic microsatellites in the immediate vicinity of the fra(X) locus.

DNA Mutational Analysis↗
PubMed1983

Somatic variation of H-2Kk expression and structure in a T-cell lymphoma: instability, stabilization, high production and structural mutation.

In the heterozygous T lymphoma line LDHB, variants which have lost the expression of individual H-2 class I genes are spontaneously generated in vitro at a frequency of 10(-1)-10(-2). A cell line (HK13) in which the class I gene Kk is stably expressed (frequency of loss variants less than 10(-4) was selected from LDHB cells by fluorescence activated cell sorting. Further selection of HK13 cells for high Kk expression led to the isolation of the HK22 line which expresses twice as much Kk as HK13. From HK13 and HK22 cells, spontaneous structural variants of Kk having lost individual serological determinants of the Kk wild-type molecule, were isolated by fluorescence activated cell sorting. Such variants occur at a frequency of 10(-6)-10(-7) per cell per generation. The analysis of these variants indicates that they carry mutations in the Kk structural gene and that HK13 cells express a single Kk gene which appears to be duplicated in HK22 cells. We did not find evidence for the generation of variants expressing 'alien' class I products in the LDHB cell line. The instability of class I gene expression in LDHB cells and the transition to stable expression may represent steps of T-cell differentiation in the thymus.

Animals↗
PubMed2005

Low-frequency common fragile sites: link to neuropsychiatric disorders?

Common fragile sites are unstable chromosomal regions that predispose chromosomes to breakage and rearrangements. Recombinogenic DNA sequences encompassing these sites may contribute to both germinal and somatic genomic mutations, and the genomic instability at these regions might cause severe inherited disorders or predispose to cancer. In this review, we discuss the characterization of common fragile site FRA13A within the neurobeachin gene, which is involved in development and function of the central nervous system. We raise the possibility of an implication of common fragile sites in neuropsychiatric disorders and overview previous and recent reports concerning individual variability of expression of common fragile sites in human populations.

Carrier Proteins↗
PubMed2000

Beta-catenin and adenomatous polyposis coli (APC) mutations in adenomas from hereditary non-polyposis colorectal cancer patients.

To clarify the roles of the adenomatous polyposis coli (APC) and beta-catenin genes in hereditary nonpolyposis colorectal cancer (HNPCC) tumorigenesis, we searched for their mutations in 14 HNPCC adenomas with microsatellite instability (MSI). Seven (50%) adenomas exhibited somatic APC mutations, five of which were frameshift mutations and the other two nonsense ones. However, the APC mutational spectrum of these adenomas was similar to that of sporadic colorectal tumors. Two adenomas (14.3%) with undetectable APC alterations showed missense mutations at codon 45 (TCT to TTT or to CCT) in beta-catenin. The MSI frequency in adenomas with beta-catenin mutations was significantly higher than that with APCones (P<0.001), indicating that mutations of beta-catenin rather than APC are strongly associated with MSI. These data suggest that adenomas with beta-catenin activating mutations and some with APC inactivating mutations may be precursors of HNPCC colorectal cancers.

Adenoma↗
PubMed2000

Transcription-induced cleavage of immunoglobulin switch regions by nucleotide excision repair nucleases in vitro.

Immunoglobulin (Ig) heavy chain class switch recombination (CSR) mediates isotype switching during B cell development. CSR occurs between switch (S) regions that precede each Ig heavy chain constant region gene. Various studies have demonstrated that transcription plays an essential role in CSR in vivo. In this study, we show that in vitro transcription of S regions in their physiological orientation induces the formation of stable R loops. Furthermore, we show that the nucleotide excision repair nucleases XPF-ERCC1 and XPG can cleave the R loops formed in the S regions. Based on these findings, we propose that CSR is initiated via a mechanism that involves transcription-dependent S region cleavage by DNA structure-specific endonucleases that function in general DNA repair processes. Such a mechanism also may underlie transcription-dependent mutagenic processes such as somatic hypermutation, and contribute to genomic instability in general.

DNA Repair↗
PubMed1978

Antibody diversity.

Three important aspects of immunoglobulin gene organization and structure have emerged from studies of cloned immunoglobulin kappa chain genes. (i) Multiple variable genes are encoded separately in the genome of both immunoglobulin-producing and uncommitted (embryonic) cells, thereby establishing the evolutionary base for generating immunoglobulin diversity. (ii) These genes exist as many small, closely related families (subgroups) that share close sequence homology largely within their own subgroup. (iii) Comparison of two cloned variable gene segments derived from a single subgroup reveals a feature of their structure that distinguishes them from fixed genes (that is, globin genes) and provides, through extensive surrounding sequence homology, a large target for intergenic recombination. This last observation suggests that a simple recombination mechanism may account for their genetic instability in both germ line and somatic cells.

Animals↗
PubMedDate not supplied

Micronuclei level in exfoliated buccal mucosa cells of patients with benign and malignant tumors of female reproductive organs and breast.

Micronucleus (MN) levels in exfoliated buccal mucosa cells of primary breast, cervix and corpus uteri cancer patients, and patients with benign tumors of uterus (myoma) and breast (fibroadenoma) were studied. Significantly increased number of MN in cells of cancer patients was observed compared to both healthy persons and patients with benign tumors. In patients with benign tumors no increase in MN quantity was observed. The evaluation of MN number in buccal mucosa cells shows genomic instability caused by malignant tumor in somatic cells of humans.

Breast Neoplasms↗
PubMed1998

Nutrition, cancer, and aging.

The parallel increase in cancer risk with advancing age is well recognized, and several pathophysiological mechanisms common to both conditions have been proposed to explain this interrelationship. The importance of nutrition, both in delaying the aging process and in protecting against cancer is also well recognized, and it is therefore of interest to compare the relative impact several of the more widely studied dietary manipulations may have on each of these conditions. For example, caloric restriction, which putatively reduce oxidative stress and effectively increases life span in animals also seems to reduce the incidence of many cancers, possibly due to diminished mitogenesis. Likewise, oxidative damage to DNA appears to be common to both processes but may be more important in the mitochondria with respect to aging and in the nucleus in relation to cancer. Inadequate dietary folate and impaired DNA methylation status are closely associated with increased cancer risk, and recently defective somatic cell methylation and accumulated genetic instability have been proposed as key mechanisms contributing to senescence. Several other well-established anticancer dietary strategies, which include increased fiber intake and the consumption of more fruits and vegetables, have not been studied extensively in relation to aging, although many of the phytochemicals considered important as chemopreventive agents for cancer may well contribute to delaying the aging process. Although not directly related to nutrition, but nevertheless highly relevant, is the question of physical activity, which has been strongly linked to a reduction in risk of some cancers. Although less is known with respect to exercise and biological markers of aging, physical activity does appear to retard the age-related decline in the muscle strength and in the bone density.

Aging↗
PubMed2004

Three classes of genes mutated in colorectal cancers with chromosomal instability.

Although most colorectal cancers are chromosomally unstable, the basis for this instability has not been defined. To determine whether genes shown to cause chromosomal instability in model systems were mutated in colorectal cancers, we identified their human homologues and determined their sequence in a panel of colorectal cancers. We found 19 somatic mutations in five genes representing three distinct instability pathways. Seven mutations were found in MRE11, whose product is involved in double-strand break repair. Four mutations were found among hZw10, hZwilch/FLJ10036, and hRod/KNTC, whose products bind to one another in a complex that localizes to kinetochores and controls chromosome segregation. Eight mutations were found in Ding, a previously uncharacterized gene with sequence similarity to the Saccharomyces cerevisiae Pds1, whose product is essential for proper chromosome disjunction. This analysis buttresses the evidence that chromosomal instability has a genetic basis and provides clues to the mechanistic basis of instability in cancers.

Animals↗
PubMed2005

Can chromosomal instability initiate tumorigenesis?

Cancers result from the accumulation of inherited and somatic mutations in oncogenes and tumor suppressor genes. These genes encode proteins that function in growth regulatory and differentiation pathways. Mutations in those genes increase the net reproductive rate of cells. Chromosomal instability (CIN) is a feature of most human cancers. Mutations in CIN genes increase the rate at which whole chromosomes or large parts of chromosomes are lost or gained during cell division. CIN causes an imbalance in chromosome number (aneuploidy) and an enhanced rate of loss of heterozygosity, which is an important mechanism of inactivating tumor suppressor genes. A crucial question of cancer biology is whether CIN is an early event and thus a driving force of tumorigenesis. Here we discuss mathematical models of situations where inactivation of one or two tumor suppressor genes is required for tumorigenesis. If two tumor suppressor genes have to be inactivated in rate-limiting steps, then CIN is likely to emerge before the inactivation of the first tumor suppressor gene.

Animals↗
PubMed2004

Estimating mutant microsatellite allele frequencies in somatic cells by small-pool PCR.

Identifying microsatellite instability (MSI) by partitioning DNA into multiple small pools containing only single genome amounts of DNA results in trapping both progenitor and low-frequency mutant alleles into pools where they can be identified and counted following PCR. Statistical approaches determining both the frequencies and the significant differences between frequencies of these Poisson-distributed alleles are presented. Results indicate a level of sensitivity and quantification not possible by standard PCR methods. Using material from colon cancer patients with high levels of MSI in their tumors, we also present the molecular and robotic methods for carrying out such studies. Validation experiments indicated mutants detectable at frequencies >0.03 above background. Frequencies obtained in tumor tissue (>0.25) met the expectations of the approach. Significant levels of MSI were detected in the constitutive tissue of the patient carrying a germ-line mutation for mismatch repair, suggesting both mechanistic and clinical applications of the procedure.

Adult↗