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At least 253 records · Page 14Linked to original sources
PubMed1983

The organization of c-rel in chicken and turkey DNAS.

The process of transduction of a proto-oncogene involves the loss of intervening sequences, the loss of 3' mRNA terminal sequences, and possible base changes. It is not possible to know how similar the c-rel sequences we studied are to sequences from which v-rel arose. If one of the alleles we studied is identical to progenitor sequences of v-rel, then base changes must have occurred during the process of transduction. Alternatively, there may exist an allele of c-rel which did not need to undergo base changes to give rise to v-rel. The polymorphism of c-rel within a turkey population and between chicken and turkey shows clear evidence in c-rel coding sequences have not been detected within a turkey population. There is an EcoRI site in c-rel from turkey which is not in v-rel. There are unequal length substitutions in c-rel within the turkey population and between chicken and turkey. Unequal length substitutions can be explained if there has been a combination of two events, for example, insertion or deletion with extensive base changes, or two insertions or deletions. Two events occurring in a short evolutionary time span might occur if c-rel is diverging at a relatively fast rate. c-rel is much less conserved across species lines, in nucleic acid hybridization to v-rel (Chen et al. 1981; Wong and Lai 1981) than other proto-oncogenes, consistent with it diverging at a relatively fast rate. Since the evolutionary changes that have been seen for c-rel are in noncoding sequences, it is most likely that v-rel arose by transduction of a somatic mutation generated variant of c-rel or by transduction which involves sequence changes or later mutations.

Animals↗
PubMed1998

[What is the value of recent molecular biology knowledge for surgical oncologic therapy of soft tissue sarcoma?].

While clinical progress in the treatment of soft-tissue sarcoma is rather slow, some major contributions to the understanding of oncogenesis of these rare tumors have been achieved in the last decade. The central role of cell cycle regulation has been demonstrated in hereditary (p53, RB) and somatic mutations or variant expression of genes associated with cell cycle regulation (p53, BCL2, MDM2). For a subset of soft tissue sarcomas harboring chromosomal translocations, fusion genes resulting from these specific translocations were cloned and characterized. The clinical use of these fusion genes may not be restricted to diagnosis and prognosis, since these may serve as specific targets for molecular and immunologic therapy approaches.

DNA Mutational Analysis↗
PubMed1987

Studies on the polyoma tumor-specific transplantation antigen (TSTA): selection and characterization of TSTA-negative segregants from somatic hybrids.

Two polyoma-TSTA-negative variants were selected independently from a polyoma fibrosarcoma/Moloney lymphoma somatic hybrid, by repeated passages in polyoma-virus-preimmunized mice. One of the variants had lost all its polyoma DNA, while the other only retained a deleted piece of its integrated polyoma DNA. In contrast to the parental hybrid clone, none of the variants produced detectable amounts of T-antigens. This finding indicates that a detectable expression of the products of the polyoma virus early genome, the T-antigens, is important either directly or indirectly for the expression of TSTA.

Animals↗
PubMed2002

The role of polymerase eta in somatic hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant.

To determine the possible role of polymerase eta (pol eta) in somatic hypermutation of B cells, a mutational analysis of 24 nonproductive rearrangements from a patient with xeroderma pigmentosum variant with a defect in pol eta was conducted. Although the mutational frequency of A and T bases decreased in WA (A/T, A) motifs, regardless of their RGYW (purine, G; pyrimidine, A/T) context, the overall mutational frequency of A or T bases was not affected. Moreover, the overall mutational frequency of the sequences examined was not decreased. There was an apparent increase in the number of insertions and deletions. The results are consistent with the conclusion that pol eta specifically targets WA motifs. However, its overall contribution to the somatic hypermutational process does not appear to be indispensable and in its absence other mechanisms maintain mutational activity.

Base Pair Mismatch↗
PubMed2004

Restricted specificity of Xenopus TFIIIA for transcription of somatic 5S rRNA genes.

Xenopus transcription factor IIIA (TFIIIA) is phosphorylated on serine-16 by CK2. Replacements with alanine or glutamic acid were made at this position in order to address the question of whether phosphorylation possibly influences the function of this factor. Neither substitution has an effect on the DNA or RNA binding activity of TFIIIA. The wild-type factor and the alanine variant activate transcription of somatic- and oocyte-type 5S rRNA genes in nuclear extract immunodepleted of endogenous TFIIIA. The glutamic acid variant (S16E) supports the transcription of somatic-type genes at levels comparable to those of wild-type TFIIIA; however, there is no transcription of the oocyte-type genes. This differential behavior of the phosphomimetic mutant protein is also observed in vivo when using early-stage embryos, where this mutant failed to activate transcription of the endogenous oocyte-type genes. Template exclusion assays establish that the S16E mutant binds to the oocyte-type 5S rRNA genes and recruits at least one other polymerase III transcription factor into an inactive complex. Phosphorylation of TFIIIA by CK2 may allow the factor to continue to act as a positive activator of the somatic-type genes and simultaneously as a repressor of the oocyte-type 5S rRNA genes, indicating that there is a mechanism that actively promotes repression of the oocyte-type genes at the end of oogenesis.

Amino Acid Substitution↗
PubMed1993

[The characteristics of homologous DNA recombination in somatic cells. I. The construction of a DNA plasmid containing deletion variants of the aminoglycoside phosphoribosyltransferase gene].

A plasmid DNA family containing deletion variants of Neo-gene has been constructed for investigation of somatic cell homologous recombination. Experimental data are presented provided by studies of extrachromosomal recombination, recombination following plasmid transfection into somatic cells, and recombination in the nuclear extracts. The opportunities of application of the plasmid constructions in the different pattern homologous recombination experiments performed on mammalian cells have been discussed.

Animals↗
PubMed2002

Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients.

Allelic loss of the long arm of chromosome 11 is frequent in neuroendocrine tumors (NET) of different organs. However, the MEN1 gene on 11q13 is mutated only in a subset of NET and allelic losses on 11q frequently extend to the telomere. In this genetic region lies the tumor suppressor gene SDHD which is associated with hereditary paragangliomas (PGL1). We sought to determine whether SDHD plays a role in the development of sporadic NET. By mutation and deletion analysis of SDHD we were unable to detect any SDHD mutation in 45 NET of the lung, gastrointestinal tract, pancreas or parathyroid. However, we found allelic deletions in 20 to 50% of all tumors but parathyroid adenomas. Furthermore, we found heterozygous germline variants in 2/8 paragangliomas. A first case of variant c.149 A>G (H50R) was found in a patient with an extra-adrenal pheochromocytoma, the other variant c.34 G>A (G12S) in a patient with a paratracheal paraganglioma, C-cell hyperplasia of the thyroid and hyperplasia of ACTH-producing cells of the pituitary gland. Both variants were absent in 93 controls. Our results demonstrate that somatic SDHD mutations are rare in sporadic NET. However, LOH alone could lead to a complete loss of function since SDHD is an imprinted gene. Furthermore, we describe two germline variants possibly causing hereditary paragangliomas.

Genes, Tumor Suppressor↗
PubMed2007

Single nucleotide polymorphism array analysis of cancer.

PURPOSE OF REVIEW: Classifying tumors and identifying therapeutic targets requires a description of the genetic changes underlying cancer. Single nucleotide polymorphism (SNP) arrays provide a high-resolution platform for describing several types of genetic changes simultaneously. With the resolution of these arrays increasing exponentially, they are becoming increasingly powerful tools for describing the genetic events underlying cancer. RECENT FINDINGS: The ability to map loss of heterozygosity (LOH) and overall copy number variations using SNP arrays is known. Techniques have recently been developed to map LOH at high resolution in the absence of paired normal data. Copy number variations described by SNP array studies are now reaching resolutions enabling the identification of novel oncogenes and tumor suppressor genes. The ability to determine allele-specific copy number changes has only recently been described. Moreover, SNP arrays offer a high-throughput platform for large-scale association studies that are likely to lead to the identification of multiple germline variants that predispose to cancer. SUMMARY: SNP arrays are an ideal platform for identifying both somatic and germline genetic variants that lead to cancer. They provide a basis for DNA-based cancer classification and help to define the genes being modulated, improving understanding of cancer genesis and potential therapeutic targets.

Chromosome Aberrations↗
PubMed1989

The gene encoding the human preproacrosin (ACR) maps to the q13-qter region on chromosome 22.

Human proproacrosin is specified by a single gene (ACR). Using a series of human-rodent somatic cell hybrids containing variant complements of human chromosomes, the preproacrosin gene was found to cosegregate with human chromosome 22. Somatic cell hybrids containing translocation chromosomes carrying parts of chromosome 22 were used to locate the preproacrosin gene to the region 22q13-22qter. By probing the DNA of 82 individuals, a restriction fragment length polymorphism was found with SstI in 14 cases.

Acrosin↗
PubMed2026

SeqQC-former: A sequence-quality fusion framework for QC-aware review prioritization of candidate somatic SNVs in cancer genomics.

The accurate prioritization of candidate somatic single-nucleotide variants (SNVs) remains a challenge due to the substantial variability in sequencing quality across genomic loci. SeqQC-Former is a sequence-quality fusion framework that integrates the local nucleotide context with read-level quality-control (QC) covariates derived from matched tumor-normal sequencing data. This integration generates QC-aware prioritization scores for the downstream review of candidate variants. Unlike conventional variant callers, SeqQC-Former is designed not to infer biological truth but to support post-calling review and prioritization under heterogeneous sequencing conditions. The framework was trained and evaluated on a SEQC2-derived dataset comprising 89,447 candidate loci, including 1378 positive and 88,069 negative loci. In chromosome-held-out validation, which aims to reduce potential genomic-position leakage, SeqQC-Former demonstrated strong discrimination (AUROC = 0.9479; AUPRC = 0.9448), indicating good generalization to previously unseen chromosomes. Given that the SEQC2-derived labels contain QC-associated information; these results should be interpreted as an evaluation of QC-aware prioritization capability rather than an independent validation of biological variant correctness. Ablation analyses revealed that structured QC covariates provided the dominant predictive signal under the current SEQC2-derived labeling regime. SeqQC-Former achieved a significantly higher AUROC than classical machine-learning baselines, as determined by DeLong's test (p&#x202f;<&#x202f;0.01). Application to 53,164 glioblastoma variants demonstrated that external predictions were sensitive to QC scaling and threshold selection, underscoring that model outputs should be interpreted as QC-dependent prioritization scores rather than calibrated probabilities or definitive biological classifications. Overall, SeqQC-Former offers a reproducible post-calling QC-aware prioritization framework for large-scale somatic SNV review and underscores the importance of explicitly modeling sequencing-quality information when interpreting structured cancer genomics datasets.

Humans↗
PubMed1985

Immunohistochemical distribution of the histone H1(0)/H5 variant in various tissues of adult Xenopus laevis.

The cellular distribution of the histone H1(0)/H5 variant has been examined immunohistochemically in various tissues of adult Xenopus laevis, using monoclonal antibodies against this variant that was isolated from erythrocyte nuclei. The H1(0)/H5 variant appears not to be erythrocyte-specific and appears to be present in all cell types of liver, stomach, and skin. In contrast, in oocyte nuclei the H1(0)/H5 variant cannot be detected, whereas they do contain H1; the nuclei of spermatogenic cells contain the H1(0)/H5 variant, but probably less than the somatic cells. In Xenopus no H1(0) variant distinct from H5 seems to occur and the H1(0)/H5 variant apparently may perform a functional role related to mammalian H1(0).

Animals↗
PubMed1985

Primary structure of the two variants of a sperm-specific histone H1 from the annelid Platynereis dumerilii.

The amino acid sequences of the two variants (H1a 121 residues and H1b 119 residues) of the sperm-specific histone H1 from the polychaete annelid Platynereis dumerilii have been completely established. Comparison of the sequences of these two variants shows one deletion of two residues in histone H1b and 22 substitents, of which most occur in the globular domain. The two variants differ highly in a sequence of nine residues adjacent to the conservative phenylalanine residue of histone H1 (64-72 in H1a, 62-70 in H1b) which makes H1a less hydrophobic than H1b. The small molecular size of Platynereis H1a and H1b is a unique feature among the histones H1 of which the size ranges between 189 residues (chicken erythrocyte H5) and 248 residues (sea urchin sperm H1). H1a and H1b have short N- and C-terminal basic domains but the size of the globular domain (approximately equal to 80 residues) is similar to that of other H1s. In the globular region the variant H1a exhibits a close relationship with somatic or sperm H1s whereas the variant H1b is more related to H5 histones.

Amino Acid Sequence↗
PubMed1983

Complementation analysis of dexamethasone resistance in L cells.

Glucocorticoid-resistant variants of L cells were characterized by somatic cell hybridization. Neither of the variants had a clearly dominant phenotype in hybrids with a glucocorticoid-sensitive fibroblast line. Hybrids of one of the resistant variants and a resistant fibroblast line showed complementation--the hybrid clones were sensitive to dexamethasone. Complementation, however, disappeared after continued culture of the hybrid cells.

Animals↗
PubMed1998

Blastic variant of mantle cell lymphoma shows a heterogenous pattern of somatic mutations of the rearranged immunoglobulin heavy chain variable genes.

Mantle cell lymphoma is a distinct clinicopathological entity associated with t(11;14) and cyclin D1 overexpression. The majority of cases show uniform morphological and phenotypic features characterized by a monotonous proliferation of small-to-medium-sized irregular B cells that express CD5 and bright surface immunoglobulin IgM and IgD. By sequence analysis of the rearranged immunoglobulin heavy chain variable genes (VH), it has been shown that these lymphoma cells carry little if no somatic mutations, as described for the fetal CD5+ cells or B1 cells. Besides mantle cell lymphoma with classic histological features, a morphological variant of mantle cell lymphoma with blastic features and a more aggressive clinical course has been described. To investigate whether this variant is closely related, by the cell of origin, to typical cases, we analysed the presence and the pattern of somatic mutations of the VH genes in a series of nine cases diagnosed as such. Our cases of blastic mantle cell lymphomas rearrange most frequently VH4 and VH3 family genes. In three cases there was a complete homology to published germline genes, and a near complete homology was documented in another three. In contrast, the remaining three cases showed somatic mutations in their rearranged VH genes. Mutation analysis revealed evidence for antigen selection in one of these three cases. Taken together, these data are similar to those of normal adult-type B1 cells and those described for chronic lymphocytic leukaemia (CLL) but slightly different to those reported for classic mantle cell lymphoma. It is likely that blastic mantle cell lymphoma as well as CLL originates from adult-type B1 cells. More cases will need to be studied to determine whether classic mantle cell lymphoma is different from the blastic subtype and if it arises from fetal-type B1 cells.

Amino Acid Sequence↗
PubMed2006

Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice.

Somatic hypermutation of Ig genes enables B cells of the germinal center to generate high-affinity immunoglobulin variants. Key intermediates in somatic hypermutation are deoxyuridine lesions, introduced by activation-induced cytidine deaminase. These lesions can be processed further to abasic sites by uracil DNA glycosylase. Mutagenic replication of deoxyuridine, or of its abasic derivative, by translesion synthesis polymerases is hypothesized to underlie somatic hypermutation. Rev1 is a translesion synthesis polymerase that in vitro incorporates uniquely deoxycytidine opposite deoxyuridine and abasic residues. To investigate a role of Rev1 in mammalian somatic hypermutation we have generated mice deficient for Rev1. Although Rev1-/- mice display transient growth retardation, proliferation of Rev1-/- LPS-stimulated B cells is indistinguishable from wild-type cells. In mutated Ig genes from Rev1-/- mice, C to G transversions were virtually absent in the nontranscribed (coding) strand and reduced in the transcribed strand. This defect is associated with an increase of A to T, C to A, and T to C substitutions. These results indicate that Rev1 incorporates deoxycytidine residues, most likely opposite abasic nucleotides, during somatic hypermutation. In addition, loss of Rev1 causes compensatory increase in mutagenesis by other translesion synthesis polymerases.

Animals↗
PubMedDate not supplied

Molecular patterns of nuclear and mitochondrial microsatellite alterations in breast tumors.

The widespread distribution of microsatellite sequences within the human genome has allowed researchers to identify alternative patterns of microsatellite alterations in cancer cells. Among them, aneuploid patterns of nuclear microsatellites, pseudo-diploid microsatellite instability patterns, and also patterns of microsatellite instability within the mitochondrial genome. In this context, while aneuploid patterns of multiple genomic gains and losses had already been described in breast tumors, data on nuclear microsatellite instability still remain controversial and limited data on mitochondrial instability are available. In order to clarify this, we undertook an extensive analysis of nuclear and mitochondrial microsatellite alterations in breast ductal adenocarcinomas, stratified by grades. No instability was detected in any of the 40 dinucleotide microsatellites analysed nor in bat26 and APDelta3 mononucleotide repeats, clearly concluding that microsatellite instability is not a feature of ductal breast tumorigenesis. Instead, microsatellites defined a clear pattern of aneuploid genomic gains and losses among which, losses of BRCA1 at D17S855 and gains of plakoglobin at D17S846 significantly associated to grade III tumors and poor prognosis. On the other hand, mitochondrial instability at the transcription control region was also detected in 10.8% of cases. None of the new mitochondrial variants was found in the normal tissue counterparts, confirming that these new variants arise as sporadic somatic mutations in the tumor cells. Also, no association was found between heteroplasmy in the normal tissue and mitochondrial instability in the tumors. We therefore suggest that these new variants arise in tumors as a consequence of the progressive accumulation of slippage somatic mutations and the intrinsic instability of these microsatellite sequences. Finally, our results also confirm that mitochondrial instability does not associate with nuclear MSI.

Adult↗
PubMed1992

Antigen binding and idiotype analysis of antibodies obtained after electroporation of heavy and light chain genes encoding phosphocholine-specific antibodies: a model for T15-idiotype dominance.

Antibodies bearing the T15 idiotype dominate the murine primary immune response to phosphocholine (PC). Analysis of antigen binding of antibodies derived from V1:DFL16.1:JH1 (VH1) germline and N region-derived variant heavy (H) chains and kappa 22, kappa 24, and kappa 8 light (L) chains demonstrates that the T15H:kappa 22L (T15) antibody binds PC at least 20-40 times better than other antibodies derived from alternate germline forms of the VH1 H chain and kappa 22, kappa 24, or kappa 8 L chains. To achieve affinities in the same range as the T15 antibody, kappa 24 and kappa 8 L chain-containing antibodies must have H chains derived from variant N region or somatically mutated VH1 genes. Single amino acid differences at the VD junction of the various germline and N region variant VH1 H chains dictate the L chain that can associate with the H chain to produce a PC-specific antibody. Several H:L combinations give rise to T15 or M167 idiotype-positive antibodies that lack specificity for PC, and single amino acid substitutions or insertions at the VH1:D junction result in the loss of T15 or M167 idiotopes. Based on these observations, our data support a molecular model involving both preferential gene rearrangement and antigen-driven B cell selection to explain T15 idiotype dominance in the immune response to PC. In the absence of N region diversification, large numbers of neonatal B cells bearing the T15H:kappa 22L surface immunoglobulin M (sIgM) receptors would be selected and expanded by autologous or environmental PC antigen into the long-lived peripheral B cell pool.

Amino Acid Sequence↗