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Results for “somatic instability”

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At least 379 records · Page 21Linked to original sources
PubMed2000

Evaluation of the role of mitotic instability in karyotypically normal men with oligozoospermia.

OBJECTIVE: To estimate the incidence of sex chromosome aneuploidies in the somatic cells of karyotypically normal infertile men and fertile donors. DESIGN: A prospective, two-phase, controlled study. SETTING: Reproductive medicine and medical genetics units of a teaching hospital. PATIENT(S): Ten patients with oligozoospermia and 10 sperm donors with proved fertility, all with a normal karyotype 46 XY. INTERVENTION(S): Multicolor fluorescence in situ hybridization (FISH) of peripheral blood lymphocytes using a probe cocktail containing the alpha satellites DXZ1 for the X centromere and DYZ1 for the heterochromatic region of the long arm of the Y and the radiolabeled alpha satellite D18Z1 for chromosome 18. MAIN OUTCOME MEASURE(S): The incidence of sex chromosome aneuploidies in both groups. RESULT(S): A 13-fold increase in sex chromosome aneuploidies was observed in the somatic cells of infertile men with "unexplained" oligozoospermia compared to donors (P=.008). CONCLUSION(S): These findings provide suggestive evidence for the existence of an inherent mitotic instability in men with unexplained oligozoospermia.

Adult↗
PubMed2005

Molecular theory of cancer.

The mutation theory of cancer was always confronted by alternative (vitalistic) theories, which insist that cancer (like life itself) cannot be reduced to molecular interactions. In fact, the most fundamental feature of the somatic mutation theory of cancer is that it is a molecular theory, meaning that all the complexity of cancer on any level (e.g., tissue) can be explained on the molecular level. To emphasize the essence of mutation theory, cancer-causing mutation can be defined as any (a) molecular event that is (b) somatically inheritable and (c) selectable (e.g., provides selective advantage in restrictive/carcinogenic conditions). Here I review molecular (somatic mutation) theory and its alternatives and discuss that molecular interactions can completely explain complex tissue phenomena such as benign tumors and stroma initiated tumorigenesis. In addition, molecular theory predicts extragenetic somatic hereditary in cancer (e.g., posttranslational protein modifications that initiate and are supported by positive feedback loops) and also explains the relationship between selection for resistance, hallmarks of cancer and genetic instability. From molecules to cells to the organism, this review discusses how somatically heritable molecular alterations (genetic, epigenetic and extragenetic) alter translation of cellular signals, resulting in resistance to growth inhibition and apoptosis, that is manifested as secondary hallmarks of cancer (metastasis, angiogenesis and immortality) and, finally, as the amazing ability of some cancer cells such as canine transmissible sarcoma to 'live in a wild' like unicellular mammalian species.

Genes, Tumor Suppressor↗
PubMed2004

Destructive cycles: the role of genomic instability and adaptation in carcinogenesis.

Classical theories of carcinogenesis postulate that the accumulation of several somatic mutations is responsible for oncogenesis. However, these models do not explain how non-mutagenic carcinogens cause cancer. In addition, known mutation rates appear to be insufficient to account for observed cancer rates. Moreover, the current theory doesn't easily account for the long latencies observed in human cancers. Proponents of an aneuploidy-driven theory of carcinogenesis suggest that genomic instability has a causative role in carcinogenesis. In support of this theory, pre-neoplastic cells frequently display genomic instability while normal cells do not. Data obtained from a variety of model organisms have revealed that disruption of the cell cycle controls required for homeostasis results in the acquisition of genomic instability. Subsequently, this genomic instability becomes self-propagating via 'destructive cycles' and provides a medium for cellular selection and adaptation. Genomic instability allows numerous genetic and epigenetic alterations to accumulate during carcinogenesis without markedly changing phenotype until they are qualitatively or quantitatively sufficient to be selectively advantageous in the tumor microenvironment. Observations of adaptation in tumor cell populations and application of chaos theory may help elucidate the mechanism that drives the enormous genetic heterogeneity observed in tumors and provide insights into the development of new therapeutic cancer interventions and treatments.

Animals↗
PubMed2003

Molecular characterization of an inherited ring (19) demonstrating ring opening.

Ring chromosomes arise following breakage in both chromosome arms and rejoining of the centric segment at the broken ends or by end-to-end fusion of the telomeres. The phenotype of ring carriers is unpredictable, and developmental abnormalities may occur even when the ring appears to be structurally balanced. This is believed to be due to mitotic instability from abnormal segregation and sister chromatid exchange in somatic cells. Although ring chromosomes usually arise as de novo events, transmittal from mosaic carriers to offspring sometimes occurs. In such cases, offspring with ring mosaicism in combination with a normal cell line remain unexplained. In this report, we used detailed molecular and cytogenetic analyses of a prenatally detected, inherited ring (19) to observe the behavior of the ring chromosome in culture, and to investigate the mechanism of inherited ring chromosome mosaicism.

Amniocentesis↗
PubMed2001

The retinoblastoma gene: a prototypic and multifunctional tumor suppressor.

Genome instability has been implicated in the generation of multiple somatic mutations that underlie cancer. Germline mutation in the retinoblastoma (RB) gene leads to tumor formation in both human and experimental animal models, and reintroduction of wild-type RB is able to suppress neoplastic phenotypes. Rb governs the passage of cells through the G1 phase-restriction point and this control is lost in most cancer cells. Rb has also been shown to promote terminal differentiation and prevent cell cycle reentry. Recent studies implicate Rb in mitotic progression, faithful chromosome segregation, checkpoint control, and chromatin remodeling, suggesting that Rb may function in the maintenance of genome integrity. It is likely that Rb suppresses tumor formation by virtue of its multiple biological activities. A single protein capable of performing multiple antioncogenic functions may be a common characteristic of other tumor suppressors including p53 and BRCA1/2.

Animals↗
PubMed2006

Genomic profiles of colorectal cancers differ based on patient smoking status.

Human sporadic colorectal cancer is the result of a lengthy somatic evolutionary process facilitated by various forms of genomic instability. Such instability arises endogenously from mutations in genes whose role is to preserve genomic integrity, and exogenously from environmental agents that generate genomic damage. We have found that cigarette smoking shifts the genomic profiles and genomic instability patterns of colorectal carcinomas. The genomic profiles of 57 consecutive cancers were examined; 31 cases were current or former smokers and 26 were nonsmokers. Genome-wide allelotypes of 348 markers were examined, along with comparative genomic hybridization (CGH) on ordered BAC microarrays, microsatellite instability, and inter-(simple sequence repeat) polymerase chain reaction instability. Tumors from nonsmokers exhibited losses of heterozygosity, particularly on chromosomes 14 and 18, whereas tumors from smokers exhibited a more diffuse pattern of allelic losses. Tumors from smokers exhibited higher overall rates of loss of heterozygosity, but showed lower rates of background microsatellite instability (MSI-L). On BAC array CGH, higher levels of generalized amplifications and deletions were observed in tumors from smokers, differentially affecting male smokers. In the transforming growth factor-beta signaling pathway, MADH4 mutations were more common in tumors from smokers, whereas transforming growth factor-beta RII mutations were more common among nonsmokers.

Adult↗
PubMed1998

Subjective symptoms and breathing pattern at rest and following hyperventilation in anxiety and somatoform disorders.

The purpose of the present study was to investigate the diagnostic specificity of bodily symptoms and respiratory behavior at rest and after a hyperventilation provocation test (HVPT) in patients that were either grouped according to the DSM classification or diagnosed as suffering from hyperventilation syndrome. Nine hundred three anxiety and somatoform patients, showing symptoms supposedly caused by psychogenic hyperventilation, and 170 healthy subjects, were studied. Breathing pattern and end-tidal CO2 concentration were recorded during breathing at rest and following a HVPT. Subjective symptoms in daily life and after HVPT were measured. A principal-components analysis was performed on both the symptoms and breathing variables and their specificity levels were compared in the two classifications of patients. Some symptoms in daily life were grouped together with the same symptoms after the HVPT, other symptoms were not. This suggests that the HVPT elicited partly specific symptoms, and partly reproduced the symptoms experienced in daily life. Similar findings were observed with respect to the breathing variables. Patients with panic differed from other patients with anxiety disorders by an increased level of symptoms and a FETCO2 decline at rest. The HVPT may be informative for diagnosis because it provokes some of the typical somatic and psychological symptoms, and it identifies the breathing instability that is characteristic of both patients with HVS and with anxiety. The same symptoms and breathing variables characterized the patients, whatever their classification. Overall, the specificity of breathing variables is rather low.

Adult↗
PubMed1996

DNA alterations in sporadic colorectal tumors do not correlate with tumor staging diagnosed by the TNM system.

Blood normal and tumor tissue samples of 23 patients with sporadic colorectal tumors were screened for DNA alterations in the tumor relevant genes APC, K-ras, DCC and p53. Six different microsatellite regions were analyzed for instability by a new developed non-radioactive method. Somatic DNA alterations were found in 17 tumor samples: 13 carried single or multiple changes in single genes; six carried alterations in microsatellites; two tumors showed tumor suppressor gene mutations in addition to microsatellite changes. We found no indications of correlations between current genetic models of colorectal tumor progression and the established TNM system for histopathological tumor classification.

Aged↗
PubMed1999

Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL, Saccharomyces cerevisiae SGS1 and Schizosaccharomyces pombe rqh1. We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.

Adenosine Triphosphatases↗
PubMed2001

Unraveling human cancer in the mouse: recent refinements to modeling and analysis.

The ability to manipulate the mouse genome has made the mouse the primary mammalian genetic model organism. It has been possible to model human cancer in the mouse by overexpressing oncogenes or inactivating tumor suppressor genes, and these experiments have provided much of our in vivo understanding of cancer. However, these transgenic approaches do not always completely and accurately model human carcinogenesis. Recent developments in transgenic and knockout approaches have improved the accuracy of modeling somatic cancer in the mouse and analyzing the genomic instability that occurs in murine tumors. It is possible to use retroviral gene delivery, chromosome engineering and inducible transgenes to selectively manipulate the genome in a more precise spatial and temporal pattern. In addition, the development of powerful cytogenetic tools such as spectral karyotyping, fluorescence in situ hybridization and comparative genome hybridization have improved our ability to detect chromosomal rearrangements. Finally, global patterns of gene expression can be determined by microarray analysis to decipher complex gene patterns which occur in cancers. Several of these advances in mouse modeling of human cancer are discussed in this review.

Animals↗
PubMed2004

Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.

Microsatellite instability (MSI) characterizes tumors arising in patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome. HNPCC is a hereditary autosomal dominant disease caused by germline mutations in genes from the DNA (MMR) mismatch repair system. In these tumors, the loss of MMR compromises the genome integrity, allowing the progressive accumulation of mutations and the establishment of a mutator phenotype in a recessive manner. It is not clear, however, whether MSI can be detected in HNPCC carriers before tumor diagnosis. The aim of this study was to evaluate the presence of genetic instability in MMR gene carriers in peripheral blood lymphocytes of carriers and non-carriers members of two HNPCC families harboring a germline MLH1 and MSH2 mutation, respectively. An extensive analysis of the allelic distribution of single molecules of the polyA tract bat26 was performed using a highly sensitive PCR-cloning approach. In non-carriers, the allelic distribution of single bat26 molecules followed a gaussian distribution with no bat26 alleles shorter than (A)21. All mutation carriers showed unstable alleles [(A)20 or shorter] with an overall frequency of 5.6% (102/1814). We therefore suggest that low levels of genomic instability characterize MMR mutation carriers. These observations suggest that somatic mutations accumulate well before tumor diagnosis. Even though it is not clear whether this is due to the presence of a small percentage of cells with lost MMR or due to MMR haploinsufficiency, detection of these short unstable alleles might help in the identification of asymptomatic carriers belonging to families with no detectable MMR gene mutations.

Adaptor Proteins, Signal Transducing↗
PubMed2004

MSH2-dependent germinal CTG repeat expansions are produced continuously in spermatogonia from DM1 transgenic mice.

Myotonic dystrophy type 1 is a neuromuscular affection associated with the expansion of an unstable CTG repeat in the DM protein kinase gene. The disease is characterized by somatic tissue-specific mosaicism and very high intergenerational instability with a strong bias towards expansions. We used transgenic mice carrying more than 300 unstable CTG repeats within their large human genomic environment to investigate the dynamics of CTG repeat germinal mosaicism in males. Germinal mosaicism towards expansions was already present in spermatozoa at 7 weeks of age and continued to increase with age, suggesting that expansions are continuously produced throughout life. To determine the precise stage at which germinal expansions occur during spermatogenesis, we sorted and collected the different germ cell types produced during spermatogenesis from males of different ages and analyzed the CTG repeat mosaicism in each fraction. Strong mosaicisms towards expansions were already observed in spermatogonia before meiosis. In transgenic Msh2-deficient mice, germinal instability of the CTG repeats (only contractions) also occurs premeiotically. No significant difference in mosaicism was detected between spermatogonia and spermatozoa, arguing against continued expansions during postmeiotic stages. This indicates that germinal expansions are produced at the beginning of spermatogenesis, in spermatogonia, by a meiosis-independent mechanism involving MSH2.

Age Factors↗
PubMed2000

Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma.

The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL. In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly. In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues. In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel "proto-oncogenes" involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcgammaRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.

Journal Article↗
PubMedDate not supplied

[Professional chronic radiation exposure: prospects for studying mutagenic effects in generations using the Southern Ural DNA bank of irradiated people and their offspring].

Data on the established DNA Bank were summarized. The DNA Bank included workers of the Mayak nuclear facility in the Southern Ural, who were exposed to chronic radiation predominantly from external gamma-rays in different doses, and their families for the future study on radiation mutations in somatic cells of parents and possible transmission of genome instability through the germline. At present the DNA Bank contains genetic material from 1500 individuals, among whom there are 223 families.

Databases, Nucleic Acid↗
PubMed2005

[Interphase cytogenetics in estimation of genomic mutations in somatic cells].

The review considers the current state, possibilities, and perspectives of using interphase cytogenetics in the estimation of genomic mutations in human and animal somatic cells for aims of genetic toxicology and genetic instability analysis. Possible mechanisms underlying action of mutagens causing numeric chromosome aberrations are discussed.

Animals↗
PubMed1990

Establishment and characterization of continuous cell line MTC-SK derived from a human medullary thyroid carcinoma.

Tumor cells of a human medullary thyroid carcinoma were isolated and propagated in tissue culture. Several cell lines with different morphology developed from the primary culture, among others a fibroblast-like growing cell line (MTC-F) and a cell line growing as a suspension of single cells and spherical cell clusters (MTC-SK). The MTC-SK cell line was serially propagated for 90 passages, over 3 years. When examined at different times throughout the in vitro period, MTC-SK exhibited properties characteristic of medullary thyroid carcinomas: the cells maintained their epithelioid morphology; endocrine granules were demonstrated in the cytoplasm by electron microscopy; in situ hybridization confirmed the production of calcitonin- and bombesin-mRNA (gastrin releasing peptide); the cells revealed positive immunoreactivity with antibodies to calcitonin, calcitonin gene-related peptide, and bombesin. The in vitro properties of the MTC-SK cells corresponded to the results obtained from the tissue of origin. Cytogenetic studies of the MTC-F cell line revealed a supernumerary metacentric chromosome (20?). In the MTC-SK cell line the predominant findings were terminal chromosomal rearrangements most frequently concerning chromosome 11p, i.e., the locus of the calcitonin and calcitonin gene-related peptide genes and the H-ras oncogene, and a characteristic instability of the centromeric region of chromosome 16 and somatic pairing of the homologous chromosomes 16.

Calcitonin↗
PubMed1995

Relationship between balance system function and agoraphobic avoidance.

There is a striking similarity between the situations avoided by people with agoraphobia and the environments which provoke disorientation in people with organic balance disorders. This study investigated the possibility that agoraphobia might be linked to balance system dysfunction by comparing the results of balance system tests in 36 people with symptoms of panic and agoraphobia and 20 normal controls. A traditional battery of audiovestibular tests was supplemented with moving platform posturography, which assesses the postural instability induced by disorienting perceptual conditions. Subjects also completed questionnaire measures of somatic symptoms of dizziness and anxiety, agoraphobic cognitions, avoidance behaviour and state anxiety. Over 60% of the Ss with symptoms of panic and agoraphobia were destabilised by the disorienting perceptual conditions, compared with just 10% of the normal controls. Postural instability was strongly related to reported agoraphobic avoidance (r = 0.63, P < 0.01), even after controlling for symptoms, anxiety and agoraphobic cognitions. In our discussion we consider alternative interpretations of these findings, future directions for research, and implications for therapy.

Adult↗
PubMed1998

The mutation properties of spinal and bulbar muscular atrophy disease alleles.

We studied the gene for the trinucleotide repeat disorder X-linked spinal and bulbar muscular atrophy (SBMA) to quantify the spectrum of mutations and gain insight into genetic anticipation. This analysis was performed using single sperm typing from an affected individual. This method allows the quantification of large numbers of meioses and therefore provides accurate information about genetic instability of the CAG repeat expansions which cause SBMA. Among 198 X chromosome-containing sperm cells, 20% had a CAG repeat number equal to the donor's somatic DNA of 49 CAG repeats, 56% were expansions, and 24% contractions. Most of the expansions (84%) and contractions (94%) were between 1 and 3 CAG repeats. These results are consistent with those obtained from one previously studied SBMA patient and reveal greater CAG repeat instability in sperm than in somatic tissue. Our results indicate that in SBMA, in contrast to sperm typing analysis of Huntington's disease, there is relative stability of the CAG repeat number during paternal transmissions and that the spectrum of mutations is narrow. These results are in agreement with the limited available clinical data and suggest that anticipation may not be a significant feature of this disease.

Adult↗