Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Somatic variant”

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 757 records · Page 42Linked to original sources
PubMed1994

The Reed-Sternberg cells of Hodgkin disease are clonal.

Relatively little progress has been made in understanding the nature of the Reed-Sternberg (RS) cell and its morphologic variants in Hodgkin disease (HD). This is primarily due to the fact that RS cells represent a minute subpopulation within HD lesions. To investigate the clonal origin of RS cells and variants, we studied 27 HD lesions obtained from 11 patients. Using an image analyzer (CAS 200) we were able to demonstrate that CD30-positive RS cells are clonal elements with unique and individualized DNA profiles and that the DNA content of any given patient RS cell population is constant over time and in different pathologic sites. Using 1, 9, 11, and X alpha satellite chromosome probes and interphase cytogenetics, we also demonstrated that RS cells obtained from different tissue samples of the same patient have a unique and often abnormal chromosomal pattern. To definitively prove the hypothesis that CD30-positive RS cells are clonal elements, we investigated the presence of point mutations within p53 gene exons 5 through 9 and found that only a single patient possessed a nonsense p53 somatic point mutation (Arg to His). This same mutation could be identified in all of his available biopsies. Altogether, these findings demonstrate that RS cells and variants in HD are clonal and represent the neoplastic elements of this entity.

Base Sequence↗
PubMed1997

Screening for ESR mutations in breast and ovarian cancer patients.

In the present study, leukocyte DNA from 143 patients with familial clustering of breast and/or ovarian cancer and tumour DNA from 96 breast carcinomas were screened for base mutations in the estrogen receptor gene (ESR). Three patients with a family history of cancer were carrying a Gly160Cys germline substitution. This alteration was also detected in eight (four females and four males) of 729 controls (366 female, 363 males), indicating that the substitution probably represents a polymorphism. However, in the 229 female controls in whom family history of cancer was known, one of two who had a sister with breast cancer was carrying the variant allele. Hence, a possible clinical significance of the glycine into cysteine cannot be completely ruled out and should be further investigated. Somatic mutations were not detected in any of the tumours studied, and the present data do not provide support for somatic ESR base mutations as an important mechanism for hormonal therapy resistance in estrogen receptor-positive breast carcinomas.

Adult↗
PubMed1997

Histone H1 variants as sperm-specific nuclear proteins of Rana catesbeiana, and their role in maintaining a unique condensed state of sperm chromatin.

Amino acid analyses of nuclear basic proteins of an anuran amphibian, Rana catesbeiana, revealed that they are comprised of a full set of core histones and three types of lysine-rich, sperm-specific proteins. On the basis of their amino-acid compositions and partial amino-acid sequences of their trypsin-resistant cores, the sperm-specific proteins could be defined as members of the histone H1 family. Both micrococcal nuclease digestion and electron microscopy indicated that sperm chromatin consists of nucleosomal and fibrillar DNA structures which are irregularly interspersed with each other. When sperm nuclei were incubated with nucleoplasmin, nuclei decondensed to some extent, and the sperm-specific H1s were removed, but not completely. The residual sperm-specific histone H1 variants were also found in reconstituted male pronuclear chromatin, comprising regularly spaced nucleosomes. We conclude that sperm-specific histone H1 variants are essential for chromatin condensation in the sperm nuclei, but that their complete removal is not necessary for the remodeling into somatic chromatin that takes place after fertilization.

Amino Acid Sequence↗
PubMed1986

Measurements of the frequency of human erythrocytes with gene expression loss phenotypes at the glycophorin A locus.

An assay method is described for determining the frequency of human erythrocytes having a gene expression loss phenotype at the glycophorin A locus presumably due to in vivo somatic mutational events in erythroid precursor cells. Monoclonal antibodies specific for the M and N glycophorin A alleles are used to identify variant cells that lack the expression of one allele in blood samples from MN heterozygotes. Flow cytometry and sorting are used to enumerate and purify variant cells. Using three different antibody combinations which are sensitive to the loss of either the M or the N allele, we find that variant cells occur at a frequency of 1 X 10(-5) in normal donors. We also detect variant cells with an apparent homozygous phenotype suggesting that events leading to homozygosity may occur at similar frequencies to gene loss events. Significant increases in variant cell frequency are observed in cancer patients after exposure to mutagenic chemotherapy drugs.

Adult↗
PubMed1997

Molecular carcinogenesis of prostate cancer: potential clinical relevance and nursing implications.

OBJECTIVES: Describe the current state of knowledge on the molecular basis of prostate carcinogenesis, potential clinical relevance of findings, and nursing implications. DATA SOURCES: Published research articles, clinical summaries, proceedings of conferences, and personal communication with investigators. CONCLUSION: The understanding of the molecular basis of prostate cancer lags behind that of other common solid tumors. Until recently, much research was reliant on cell line and animal data. Epidemiologic studies, a recently recognized hereditary variant, and cytogenetic analysis of human prostate tissue have provided insight into prostate carcinogenesis. Like other cancers, prostate cancer results from combined somatic and genetic mutations, gene activations, and interplay of genetic and environmental factors. To date, the most consistent changes are those of allelic loss events with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. No specific genes have yet been identified. Clinical applications of these findings are still in developmental stages or early stages of clinical trials. IMPLICATIONS FOR NURSING PRACTICE: An understanding of the molecular basis of cancer is requisite to the provision of up-to-date patient education and to understanding newly developing diagnostic, treatment, and preventive strategies.

Cocarcinogenesis↗
PubMed2003

Hypermutable minisatellites, a human affair?

Minisatellites are a class of highly polymorphic GC-rich tandem repeats. They include some of the most variable loci in the human genome, with mutation rates ranging from 0.5% to >20% per generation. Structurally, they consist of 10- to 100-bp intermingled variant repeats, making them ideal tools for dissecting mechanisms of instability at tandem repeats. Distinct mutation processes generate rare intra-allelic somatic events and frequent complex conversion-like germline mutations in these repeats. Furthermore, turnover of repeats at human minisatellites is controlled by intense recombinational activity in DNA flanking the repeat array. Surprisingly, whereas other mammalian genomes possess minisatellite-like sequences, hypermutable loci have not been identified that suggest human-specific turnover processes at minisatellite arrays. Attempts to transfer minisatellite germline instability to the mouse have failed. However, yeast models are now revealing valuable information regarding the mechanisms regulating instability at these tandem repeats. Finally, minisatellites and tandem repeats provide exquisitely sensitive molecular tools to detect genomic insults such as ionizing radiation exposure. Surprisingly, by a mechanism that remains elusive, there are transgenerational increases in minisatellite instability.

Humans↗
PubMed1973

Immunoglobulin and glucose-6-phosphate dehydrogenase as markers of cellular origin in Burkitt lymphoma.

Two independent marker systems, G-6-PD isoenzymes and cell membrane-associated IgM, were used to trace the cellular origin of Burkitt lymphoma. Application of the G-6-PD system is dependent upon the fact that, in accordance with inactivity of one X chromosome in each somatic cell, females heterozygous for the usual B gene (Gd(B)) at the X-linked G-6-PD locus and the variant allele Gd(A) (or Gd(A-)) have two types of cells. Gd(B) is active in one cell population, which consequently produces B type enzyme; in the other population Gd(A) is active, producing the variant A enzyme. Therefore, tumors with a clonal origin in a Gd(B)/Gd(A) heterozygote should exhibit only one enzyme type (B or A) whereas those with multicellular origin may show both A and B enzymes. Utilization of the immunoglobulin system is based upon the supposition that in lymphoid neoplasms with clonal origin either all or none of the tumor cells should have surface-associated IgM and kappa-reactivities. 33 of 34 relatively homogeneous (with respect to content of neoplastic cells) individual Burkitt tumors from 19 G-6-PD heterozygotes had single enzyme phenotypes. Similarly, of 95 tumors tested, 92 consisted essentially of IgM(+) or (-) cells. Two neoplasms could not be definitely classified and one tumor had two cell populations. These data suggest a clonal origin for most Burkitt tumors, but the one neoplasm with a double G-6-PD phenotype (A/B) and the one tumor that had two populations of cells with respect to surface IgM, could have originated from multiple cells. G-6-PD was determined in each of two tumors from seven heterozygotes and in all cases both tumors had the same single enzyme phenotype. Surface-associated IgM was tested in four tumors from one patient, three from another, and in two neoplasms from 11 patients. With one exception, all tumors from the same patient were concordant with respect to IgM. These findings suggest that the entire disease has a clonal origin, i.e., it emerges at one focus and then spreads to other parts of the body. Cells from 36 recurrent neoplasms were typed for G-6-PD (in heterozygotes) and/or IgM. In one previously reported patient, initial and recurrent tumors were discordant for G-6-PD. Two other patients had IgM phenotypes in recurrences that were discordant with those found in their initial tumors. Phenotypes from three of nine relapses which occurred after 5 mo were discordant for G-6-PD or IgM but no discordance was detected among 27 earlier recurrences. Thus, some "late" recurrences may be due to emergence of "new" maligant cell lines whereas most early relapses are due to reemergence of the original malignant clones. The probable unicellular origin of Burkitt lymphoma and the findings in tumor recurrences are discussed in terms of the disease's putative viral etiology.

Animals↗
PubMed1999

Extremely complex repeat shuffling during germline mutation at human minisatellite B6.7.

Human minisatellite B6.7 is a highly variable locus showing extensive heterozygosity with alleles ranging from six to >500 repeat units. Paternal and maternal mutation rates to new length alleles were estimated from pedigrees at 7.0 and 3.9% per gamete, respectively, indicating that B6.7 is one of the most unstable minisatellites isolated to date. Mutation at this locus was also analysed by small pool PCR of sperm and blood DNA. Male germline instability varied from <0.8 to 14% per allele and increased with tandem array size. In contrast, the frequency of mutants in somatic (blood) DNA was far lower (<0.5%), consistent with a meiotic origin of germline mutants. Sperm mutants were further characterized by minisatellite variant repeat mapping using four major polymorphic sites within the B6.7 repeats. This highly informative system revealed a wide variety of changes in allele structure, including simple intra-allelic duplications and deletions and more complicated inter- and intra-allelic transfers of repeat blocks, as seen at other human minisatellites. The main mode of sperm mutation, however, resulted in extremely complex allele reorganization with evidence of inter-allelic transfer plus the generation of novel repeats by rearrangement at the sub-repeat level, suggesting that recombinational instability at B6.7 is a complex multistep process.

Alleles↗
PubMed1995

Stage-specific distribution of the spermatid-specific histone 2B in the rat testis.

Male germ cells contain a number of histone variants, most of which are synthesized during either the mitotic or the meiotic stages of spermatogenesis. A spermatid-specific H2B (ssH2B) variant has been identified in mouse round spermatids that has an additional 12 amino acids at its carboxyl terminus as compared to somatic H2Bs. Until now, the presence of this protein in other mammals has not been known. Northern blot analysis using an oligonucleotide probe complementary to a unique coding region of the C-terminus of mouse ssH2B showed that mRNA encoding this protein was present in isolated rat round spermatids. Furthermore, immunoblot analysis of basic nuclear proteins from round spermatids probed with an anti-ssH2B antiserum that recognizes the novel peptide sequence indicated that the protein was present in round spermatids but not in pachytene spermatocytes. The ssH2B comigrated with H2A.X by acid-urea (2.5 M) PAGE and migrated slightly more slowly than TH2B by acid-urea-Triton PAGE. When seminiferous tubules were microdissected stage-specifically and basic nuclear proteins were immunoblotted, ssH2B was detected in tubule sections of stages II-VI. It reached a maximum level in stages VII-VIII and then decreased to minimal levels in stages XIII-I. Since ssH2B was not detected in pachytene spermatocytes, the stage-specific levels of ssH2B corresponded to the respective steps of spermatids present in the tubules. While ssH2B constituted a relatively small amount (approximately 2%) of total H2B protein in round spermatids, its presence in both the mouse and the rat suggests that its function may be conserved in mammalian spermatogenic cells.

Animals↗
PubMed2002

Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer.

The activating transcription factor 2 (ATF-2) gene, which encodes a transcription factor involved in multiple intracellular signal transduction pathways, is located on human chromosome 2q32, which is a common region of LOH in human lung cancer. In neuroblastoma and breast cancer, a high incidence of LOH was detected on chromosome 2q. Recently we found that breast cancer is frequently developed in heterozygous mutant mice for the ATF-2 gene. Therefore, the ATF-2 gene was considered as a candidate tumor suppressor gene on 2q. To assess the role of the ATF-2 gene as a tumor suppressor in human carcinogenesis, we examined genetic alterations of the ATF-2 gene in 9 breast cancer cell lines, 10 neuroblastoma cell lines and 46 lung cancer cell lines. For this purpose, we first determined the exon-intron structure of the ATF-2 gene in the human genome. The ATF-2 gene was composed of 14 exons and 13 introns, and the ATG start codon and the TGA stop codon were present in exons 3 and 14, respectively. Genetic variants of the ATF-2 gene were detected in 5 of the 46 (10.6%) lung cancers, but not in neuroblastomas and breast cancers. Three of the five variants detected in lung cancers were genetic polymorphisms, while the remaining two, consisting of non-synonymous and synonymous substitutions, were possibly somatic mutations. The present result indicates that the ATF-2 gene is not a major tumor suppressor gene on chromosome 2q, however, it is possible that ATF-2 alterations may be involved in the development of a small subset of lung cancers.

Activating Transcription Factor 2↗
PubMed1984

Density-dependent regulation of growth in somatic hybrids between normal Chinese hamster fibroblasts and V79-8 (G1-) cells.

The purpose of this work was to determine the relationship between the presence of a G1 period in the mitotic cycle and a cell's ability to respond to density-dependent regulation of growth (DDR). Somatic hybrids were obtained between normal fibroblasts from newborn Chinese hamsters, which show a strong response to DDR, and V79-8 Chinese hamster cells, which are insensitive to DDR. Two variant V79-8 sublines were used, one reported to lack a G1 period (G1-) and the other with a G1 period (G1+). Fourteen hybrid clones were isolated in selective medium and analysed for growth properties and cell cycle parameters; their hybrid nature was supported by chromosome counts. All hybrid clones, irrespective of whether a V79-8 G1- or G1+ cell was one of the parents, showed pronounced DDR and had G1 periods of various lengths. Previous experiments had shown the absence of G1 to be dominant in somatic hybrids between V79-8 G1- and G1+ cell lines. Our results may mean that the G1- property provided by V79-8 is unable to overcome the very long G1 of normal fibroblasts, or in cells that can be arrested in G1 in response to DDR, some function prevents the dominant effect of the G1- cell on at least part of the G1 period.

Animals↗
PubMed2006

Somatic mitochondrial DNA mutations in primary and metastatic ovarian cancer.

OBJECTIVE: To date, most mtDNA mutations in cancer have been identified in the control region (D-loop) containing the major promoters. However, almost all studies used one sample per tumor and there is no clear evidence whether metastatic deposits harbor different mtDNA variants. To establish whether different mtDNA variants can be found in the same cancer but at different sites, we analyzed a series of unilateral and bilateral primary epithelial ovarian cancers as well as paired metastatic tumor deposits. METHODS: We sequenced the D-loop region in 52 different tumor samples of 35 ovarian cancer cases, as well as matched normal tissues. Seventeen of those 35 cases had bilateral ovarian cancer, with a sample from each tumor analyzed. RESULTS: Eighty-six polymorphisms (4 new in ovarian cancer) were detected, and 9 different somatic mtDNA mutations were found in 26% (9 of 35) of ovarian cancer cases; all were homoplasmic in nature. Six of the mutations were novel in ovarian cancer. In 24% (4 of 17) of cases with bilateral ovarian tumors, different mtDNA variants were found between paired tumors, suggesting the presence of different clonal populations of cancer cells. Metastatic tumor deposits showed identical mtDNA variants to those found in at least one of the ovarian tumors in cases with bilateral ovarian cancer. CONCLUSION: Our data demonstrate that multiple tumor samples from the same patient may harbor different mtDNA variants.

Base Sequence↗
PubMedDate not supplied

Stage-dependent enzymatic activities in spermatogenesis of mice with the standard karyotype and of chromosomal variants with impaired fertility.

The enzymatic activities of thiamine pyrophosphatase (TPPase), acid phosphatases (ACPases), alkaline phosphatases (APases) and steroid-3 beta-ol dehydrogenase (beta-HSDH) in different germ cells and somatic cells in the testis of three cytogenetically determined states of fertility (i.e. normal, impaired fertility and sterility) were studied histochemically in the mouse. The TPPase, ACPases and APases activities showed a characteristic stage dependent pattern when the activities were related to the typical twelve stages of the seminiferous epithelium in the mouse, according to Oakberg (1956). Comparing the enzymatic patterns of the activities in the normal spermatogenic process versus the impaired and sterile conditions, the following conclusions can be drawn: even in impaired and sterile conditions the enzymatic activity patterns retain their characteristic stage dependence; the pattern of beta-HSDH and ACPases is not altered in the impaired and sterile conditions; TPPase and APases patterns are modified in impaired and sterile mice. It is concluded that the kinetics of the enzyme activities can serve as a useful marker for characterizing pathological spermatogenic processes.

3-Hydroxysteroid Dehydrogenases↗
PubMed1979

[Genetic study of the resistance of mouse somatic cells to colchicine (high resistance level)].

The studies of the high level of colchicine resistance of mouse L cells have shown that two mutagens (EMS and NMM) do not induce cell variants resistant to 8 microgram/ml of colchicine in the population of mouse heteroploid L-53 cells (subline of L cells, the level of colchicine resistance 140) and that colchicine resistance of L-53 cells gradually diminishes when cells are propagated in non-selective conditions: after 1 month it diminishes 2-fold, after 3 month--9-fold. The extent of the decrease of the drug resistance was the same in 6 independent cultures obtained from the inoculum of 200 cells and in control cultures propagated by large quantities of cells. These data coincide with the results of the previous studies of lower level of colchicine resistance. In both studies the frequency of the occurrence of colchicine resistant variants in selective medium was about 2.10(-4). These data are consistent with the hypothesis that colchicine resistance of mouse L cells is not due to a gene mutation.

Animals↗
PubMed1999

Mosaicism for a serotonin transporter gene promoter-associated deletion: decreased recombination in depression.

Transcriptional activity of the human serotonin transporter gene (5HTT) is modulated by complex interaction of multiple genomic and cellular factors. Variability of a polymorphic repetitive element (5HTTLPR) is associated with anxiety, depression, and aggression-related traits and may influence the risk to develop affective spectrum disorders. 5HTTLPR variants display a unique DNA secondary structure that has the potential to regulate the transcriptional activity of the associated 5HTT promoter. The structure of the 5HTTLPR is also likely to precipitate a 381-bp somatic deletion in the 5HTT's promoter region [del(17)(q11.2)] that is observed in 20-60% of genomic DNA isolated from mononuclear blood cells and postmortem brain. The localization of the deletion breakpoints adjacent to identical putative signal sequences (CAGCC) suggests a V(D)J recombinase-like rearrangement event. In comparison with healthy controls, del(17)(q11.2)/wildtype sequence ratios showed a decrease of the deleted variant in recurrent unipolar depression. Our results also suggest that mosaicism of del(17)(q11.2) is likely to be regulated by tissue-specific as well as 5HTTLPR-dependent mechanisms. The findings confirm that the pericentric region of human chromosome 17 is highly unstable and furnishs additional evidence for intricate complexity of 5HTT regulation under physiological condition and in disease.

Adult↗
PubMed1992

Saudi variant of multiple sulfatase deficiency.

We describe eight patients with multiple sulfatase deficiency (MSD, or Austin's disease) who differ phenotypically from classic neonatal-, childhood-, or juvenile-onset MSD. The age of onset was in childhood. The patients presented with somatic and facial features of mucopolysaccharidosis reminiscent of Maroteaux-Lamy and Morquio syndromes. They differed from classic MSD by the presence of corneal cloudiness, macrocephaly, severe dysostosis multiplex, and gibbus and the absence of ichthyosis, retinal degeneration, severe deafness, severe mental retardation, and dementia. The main neurologic presentation was cervical cord compression due to axis abnormalities. Despite neuroradiologic evidence of white-matter changes, neurologic presentation was not like metachromatic leukodystrophy. The sulfatase deficiencies were more marked than in the classic juvenile form of MSD, but less marked than in the classic childhood-onset form of MSD. Steroid sulfatase activity was spared except in one patient. This Saudi variant of MSD accounts for 5% of all lysosomal storage diseases in the Cell Repository Registry of our Inborn Errors of Metabolism Laboratory.

Child↗
PubMed1994

CD44 expression in colorectal adenomas is an early event occurring prior to K-ras and p53 gene mutation.

Neoplastic progression of colorectal epithelial cells from benign adenomas to malignant carcinomas appears to result from a series of genetic alterations involving both oncogenes and tumor suppressor genes. This progression was recently found to be associated with expression of splice variant isoforms of CD44, a cell surface hyaluronate receptor implicated in carcinogenesis. In this study we examined the relationship of CD44 expression to somatic genetic events in the adenoma-carcinoma sequence: point mutation of K-ras in codons 12 and 13 and overexpression of p53 protein as a marker of gene mutation. Among 22 small adenomas, CD44 was present in 9 (41%), of which only 1 contained a K-ras mutation. CD44 was absent in the other 2 small adenomas positive for K-ras mutation or p53 overexpression. In contrast to the early expression of CD44 in small adenomas, mutations of K-ras and p53 were detected preferentially in large adenomas and late-stage adenomas containing carcinoma. The frequent expression of CD44 prior to K-ras and p53 gene alterations in colorectal neoplasia suggests that activation of CD44 gene expression is related to earlier events in the adenoma-carcinoma sequence, possibly cell activation and proliferation following APC gene mutation or alteration of DNA methylation.

Adenoma↗
PubMed2000

Dynamics of one-pass germinal center models: implications for affinity maturation.

During an immune response, the affinity of antibodies that react with the antigen that triggered the response increases with time, a phenomenon known as affinity maturation. The molecular basis of affinity maturation has been partially elucidated. It involves the somatic mutation of immunoglobulin V-region genes within antigen-stimulated germinal center B cells and the subsequent selection of high affinity variants. This mutation and selection process is extremely efficient and produces large numbers of high affinity variants. Studies of the architecture of germinal centers suggested that B cells divide in the dark zone of the germinal center, then migrate to the light zone, where they undergo selection based on their interaction with antigen-loaded follicular dendritic cells, after which they exit the germinal center through the mantle zone. Kepler and Perelson questioned this architecturally driven view of the germinal center reaction. They, as well as others, argued that the large number of point mutations observed in germinal center B cell V-region genes, frequently 5 to 10 and sometimes higher, would most likely render cells incapable of binding the antigen, if no selection step was interposed between rounds of mutations. To clarify this issue, we address the question of whether a mechanism in which mutants are generated and then selected in one pass, with no post-selection amplification, can account for the observed efficiency of affinity maturation. We analyse a set of one-pass models of the germinal center reaction, with decaying antigen, and mutation occurring at transcription or at replication. We show that under all the scenarios, the proportion of high affinity cells in the output of a germinal center varies logarithmically with their selection probability. For biologically realistic parameters, the efficiency of this process is in clear disagreement with the experimental data. Furthermore, we discuss a set of, possibly counterintuitive, more general features of one-pass selection models that follow from our analysis. We believe that these results may also provide useful intuitions in other cases where a population is subjected to selection mediated by a selective force that decays over time.

Animals↗