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At least 19 recordsLinked to original sources
PubMed1991

Somatic hypermutagenesis in immunoglobulin genes. I. Correlation between somatic mutations and repeats. Somatic mutation properties and clonal selection.

Based on the analysis of some immunoglobulin V-gene sequences, somatic mutations are assumed to occur by correction of complementary violations in heteroduplexes formed by direct or inverted repeats. Correlation between somatic mutations and repeats is investigated by a statistical weights method in 323 somatic substitutions in 14 V-genes. Assuming absence of correlation, the probability of observing data in the sample would be very low (0.00004). This result supports the idea that somatic mutations may arise from heteroduplex repair. The high frequency of these mutations in complementarity-determining regions (CDRs) of V-genes may be due to a high concentration of repeats in these regions. Analysis of somatic substitutions has revealed that stabilizing selection seems to provide conservation of framework regions (FRs) (which leads to preservation of the protein's three-dimensional structure). Positive selection may be provided by B-lymphocyte proliferation with large changes in CDRs.

Animals↗
PubMed2001

Testing the reverse transcriptase model of somatic mutation.

Somatic hypermutation of the variable (V) regions of rearranged immunoglobulin genes leads to antibody affinity maturation. Although this process has been extensively studied, the mechanisms responsible for these multiple point mutations are still elusive. One mechanism that was proposed over 10 years ago by Steele and Pollard was that an intrinsic reverse transcriptase (RT) copies the nascent mRNA creating the large number of observed point mutations due to its high error rate. A cDNA copy of the mutated V region would then replace the endogenous DNA through a gene conversion-like event, thus integrating these point mutations into the genome. This model of hypermutation would account for the very high mutation rate, the presence of hotspots, strand bias, the requirement for transcription and localization of mutation within the immunoglobulin V region. Using AZT and ddC to inhibit endogenous RTs, we have assayed for somatic mutation using a murine in vivo model. Somatic mutation occurred at similar frequencies and with the same characteristics with or without treatment of RT inhibitors, suggesting that standard reverse transcription is not required for antibody V region hypermutation in the mouse.

Animals↗
PubMed2001

Common polymorphisms and somatic mutations in human base excision repair genes in ovarian and endometrial cancers.

The purpose of this study was to determine whether the human APEX and OGG1 genes, encoding proteins important in base excision repair (BER) of DNA, contain nucleotide sequence polymorphisms or are mutated somatically in tumors from women diagnosed with ovarian or endometrial cancer. Based upon the analysis of germline DNA from 83 individuals, 63 with ovarian cancer and 20 with endometrial cancer, we found two missense polymorphisms in APEX (Q51H and D 148E) and two missense (A3P and S326C) and one intronic (Exon 5-15 bp) polymorphism in OGG1. The frequencies of the various alleles (in the ovarian and endometrial cancer patients combined) were 4.8% for 51-His and 56.2% for 148-Glu in APEX, and 1.0% for 3-Pro and 20.0% for 326-Cys in OGG1. Somatic mutations in APEX (P112L, W188X and R237C) were identified in three of 20 endometrial tumors, but no mutations were identified in APEX in 43 ovarian tumors, or in OGG1 at either tumor site. Given the crucial role of the APEX and OGG1 proteins in BER of oxidative DNA damage, the identified polymorphisms are good candidates for genetic epidemiologic studies of cancer susceptibility, while the finding that three of 20 (15%) endometrial tumors have somatic mutations in APEX suggests that inactivation of the BER pathway is important for the development of endometrial cancer in at least a subset of cases.

Alleles↗
PubMed2025

Inherited rare epidermal growth factor receptor mutation and somatic mutations in patients with non-small cell lung cancer: a case report.

BACKGROUND: Recent advances in molecular oncology have increasingly illuminated the role of germline EGFR mutations in non-small cell lung cancer (NSCLC). This case report presents the presence of a unique familial occurrence of EGFR mutations in patients with NSCLC. CASE DESCRIPTION: A mother and son, both never-smokers of Caucasian ethnicity, were diagnosed with advanced metastatic lung adenocarcinoma. In one patient, tumor molecular analysis by next generation sequencing (NGS) identified two EGFR mutations: the activating mutation c.2573T > G; p.Leu858Arg (p.L858R) in exon 21 of the EGFR gene, and the somatic non-pathogenic mutation c.2612 C > A; p.Ala871Glu (p.A871E) in exon 21 of the EGFR gene. The second patient also harbored the same two EGFR mutations. The patient underwent genetic testing which revealed the germline origin of the A871E mutation. Whether the presence of this mutations was associated with increased predisposition to cancer has yet to be determined. Our case report highlights the need for further exploration of the role of germline mutations, including the A871E mutation, in tumorigenesis and its implications for treatment response and inheritance patterns. CONCLUSIONS: The investigation and comprehension of the significance of each individual EGFR mutation hold the promise for potential in cancer prevention or early diagnosis within family cohorts and understanding the mechanisms of tumorigenesis in sporadic cases.

Humans↗
PubMed1998

Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells.

Immunoglobulin (Ig)M+IgD+ B cells are generally assumed to represent antigen-inexperienced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM+IgD+ peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM+IgD+ B cells. IgM+IgD+CD27(+) B cells resemble class-switched and IgM-only memory cells in terms of cell phenotype, and comprise approximately 15% of PB B lymphocytes in healthy adults. Moreover, a very small population (<1% of PB B cells) of highly mutated IgD-only B cells was detected, which likely represent the PB counterpart of IgD-only tonsillar germinal center and plasma cells. Overall, the B cell pool in the PB of adults consists of approximately 40% mutated memory B cells and 60% unmutated, naive IgD+CD27(-) B cells (including CD5(+) B cells). In the somatically mutated B cells, VH region genes carry a two- to threefold higher load of somatic mutation than rearranged Vkappa genes. This might be due to an intrinsically lower mutation rate in kappa light chain genes compared with heavy chain genes and/or result from kappa light chain gene rearrangements in GC B cells. A common feature of the somatically mutated B cell subsets is the expression of the CD27 cell surface antigen which therefore may represent a general marker for memory B cells in humans.

Adult↗
PubMed1992

B-cell proliferation initiated by Ia cross-linking and sustained by interleukins leads to class switching but not somatic mutation in vitro.

Somatic mutations that are acquired by antibody V genes of antigen-stimulated B cells ultimately provide the clonal diversity from which memory B cells are selected during immune responses to T-cell-dependent antigens. Somatic mutations apparently are not acquired when B cells are stimulated by mitogens nor when they participate in immune responses to T-cell-independent antigens. Since the basis of T-cell-dependent humoral immunity is T-cell recognition of processed antigen in the context of class II major histocompatibility glycoproteins (Ia) on the B-cell surface, we sought to determine whether the ligation of Ia on B cells induces somatic mutation. B cells were stimulated in vitro by a procedure in which their proliferation was dependent upon ligation of surface Ia with antibody. Sequences of hybridoma V genes derived from these B cells revealed no somatic mutations despite prolonged stimulation in vitro and the induction of immunoglobulin secretion and switching to isotypes characteristic of T cell-dependent humoral immunity. We infer that Ia-mediated signalling and isotype switching are not causally related to somatic mutation. The avenue of differentiation that leads to somatic mutation in memory B cells is apparently separable from that leading to proliferation, immunoglobulin secretion and switching.

Animals↗
PubMed2004

Cellular and molecular studies of B cells exhibiting reverse somatic mutation throughout life.

Somatic mutation of immunoglobulin (Ig) genes plays an important role in generating antibody diversity. The frequency of somatic mutation appears to vary throughout life. However, this process has been difficult to study in vivo because the DNA in and around rearranged V genes undergoes random mutation, causing silent or replacement mutations. Therefore, we have developed a transgenic mouse model for studying the frequency of B cells exhibiting mutation in young and old mice. The system is based on a reporter transgene (HuG-X) that encodes a chimeric Ig heavy chain composed of a murine VDJ segment and a human IgG1 constant region. The VDJ has been mutated to contain a TAG stop codon in the D segment. Therefore, the transgene is transcribed but not translated. Point mutation of the stop codon results in expression of the chimeric H chain, which is readily detected as human IgG1 expression. In vivo, we found that the transgene undergoes spontaneous reverse somatic mutation at a low frequency. Treatment of HuG-X mice with anti-IgD greatly increases the frequency of somatic mutation. The observed mutation frequency in anti-IgD-treated mice increases with age until adulthood, then plateaux and finally declines in aged mice. The mutations in the stop codon were associated with increased double-stranded DNA breaks (DSB) within and around the TAG site. Our results demonstrate that the rate of frequency of spontaneous reverse mutation is very low in vivo, yet it is significantly increased after stimulation with anti-IgD antibodies. The frequency of point mutation is age dependent and correlates with increased DSB.

Animals↗
PubMed2001

Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers.

DNA mismatch repair is of considerable scientific and medical importance because of its essential role in maintaining genomic integrity, and its association with hereditary non-polyposis colon cancer (HNPCC). Germline mutations in five mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) have been associated with HNPCC susceptibility. Our laboratory recently identified MLH3, a novel DNA mismatch repair gene. We screened the MLH3 coding sequence in 60 probands with increased genetic risk factors for colorectal cancer susceptibility and no mutations in the other candidate genes. No definite MLH3 germline mutations were found. We subsequently screened 36 colon tumors, and discovered an appreciable frequency of somatic MLH3 coding mutations in MSI-H tumors (25%). In four of six tumors, evidence of biallelic inactivation was noted. Furthermore, MLH3 nonsense mutations were identified in two of 12 microsatellite stable (MSS) tumors with 14q24 loss of heterozygosity. While our analyses do not exclude the existence of germline MLH3 mutations in patients with increased genetic risk factors for colorectal cancer susceptibility, they suggest such mutations are uncommon in this patient population. The finding of an appreciable frequency of somatic MLH3 mutations is consistent with a possible role for this gene in the progression of colorectal cancer tumorigenesis. Hum Mutat 17:389-396, 2001. Published 2001 Wiley-Liss, Inc.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Problems of somatic mutation and cancer.

Somatic mutation plays a key role in transforming normal cells into cancerous cells. The analysis of cancer progression therefore requires the study of how point mutations and chromosomal mutations accumulate in cellular lineages. The spread of somatic mutations depends on the mutation rate, the number of cell divisions in the history of a cellular lineage, and the nature of competition between different cellular lineages. We consider how various aspects of tissue architecture and cellular competition affect the pace of mutation accumulation. We also discuss the rise and fall of somatic mutation rates during cancer progression.

Cell Lineage↗
PubMed2026

Caloric restriction modulates genome-wide somatic mutation in mice.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.

DNA↗
PubMed1978

Relationship between somatic mutation and neoplastic transformation.

Somatic mutation and neoplastic transformation of diploid Syrian hamster embryo cells were examined concomitantly. Mutations induced by benzo[a]pyrene and N-methyl-N'-nitro-N-nitrosoguanidine were quantitated at the hypoxanthine phosphoribosyltransferase and Na(+)/K(+) ATPase loci and compared to phenotypic transformations measured by changes in cellular morphology and colony formation in agar. Both cellular transformations had characteristics distinct from the somatic mutations observed at the two loci. Morphological transformation was observed after a time comparable to that of somatic mutation but at a frequency that was 25- to 540-fold higher. Transformants capable of colony formation in agar were detected at a frequency of 10(-5)-10(-6), but not until 32-75 population doublings after carcinogen treatment. Although this frequency of transformation is comparable to that of somatic mutation, the detection time required is much longer than the optimal expression time of conventionally studied somatic mutations. Neoplastic transformation of hamster embryo cells has been described as a multistep, progressive process. Various phenotypic transformations of cells after carcinogen treatment may represent different stages in this progressive transformation. The results are discussed in this context and the role of mutagenesis in the transition between various stages is considered. Neoplastic transformation may be initiated by a mutational change, but it cannot be described completely by a single gene mutational event involving a dominant, codominant, or X-linked recessive locus. Neoplastic transformation induced by chemical carcinogens is more complex than a single gene mutational process. Thus, this comparative study does not give experimental support to predictions of the carcinogenic potential of chemicals based on a simple extrapolation of the results obtained from conventional somatic mutation assays.

Adenosine Triphosphatases↗
PubMed2002

V(H) gene analysis of splenic marginal zone lymphomas reveals diversity in mutational status and initiation of somatic mutation in vivo.

Tumors of the splenic marginal zone can present in spleen or blood. The maturational status of the neoplastic B cells from each site appears heterogeneous, with either unmutated or mutated variable-region heavy chain (V(H)) genes. To determine an influence of tissue location, we assessed matched blood and splenic tumor cells from 4 patients and found them identical. However, one patient with unmutated V(H) genes in blood and spleen developed a clonally related diffuse large B-cell lymphoma in the chest wall. Strikingly, this subclone had undergone significant somatic mutation, with clear intraclonal heterogeneity. To our knowledge, this is the first case of a B-cell tumor showing initiation of somatic mutation in vivo. The finding emphasizes that the tissue microenvironment can influence tumor cell behavior and possibly affect disease progression. Importantly, because several replacement mutations were located within or close to the complementarity-determining regions (CDRs), it raises the question of a role for antigen in driving tumor growth.

Amino Acid Sequence↗
PubMed1994

Somatic mutations at T-cell antigen receptor and glycophorin A loci in pediatric leukemia patients following chemotherapy: comparison with HPRT locus mutation.

Frequencies of somatic mutations in pediatric patients with leukemia were evaluated following intensive treatment at three different loci: the hypoxanthine-guanine phosphoribosyl transferase (HPRT), T-cell antigen receptor (TCR), and glycophorin A (GPA) gene. Thirty-two children with acute lymphoblastic leukemia (ALL), nine children with acute myelogenous leukemia (AML), and 20 age-matched healthy controls were included in the study of mutant frequencies (Mfs) at the HPRT and TCR loci. Among these patients and controls, individuals with heterozygous MN blood type, i.e., 14 children with ALL, three children with AML, and nine healthy controls, served for the further assessment of variant frequency (Vf) at the GPA locus. In ALL patients, geometric mean Mfs and Vfs at these loci were significantly higher than in healthy controls. The high Mf value at the HPRT locus persisted for up to 8 years after the end of chemotherapy. On the other hand, the Mf values at the TCR locus and Vf values at the GPA locus declined gradually with time. In AML patients, on the other hand, the geometric mean Mf only at the TCR locus was significantly higher than in the controls, albeit to a lesser degree than in ALL patients. These data suggest that anti-cancer therapy induces somatic mutations at various loci and that ALL patients are more susceptible to mutagenic intervention than are AML patients.

Adolescent↗
PubMed2000

Somatic mutation of bcl-6 genes can occur in the absence of V(H) mutations in chronic lymphocytic leukemia.

Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated V(H) genes consistent with a naive B cell, and the other with mutated V(H) genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5' noncoding region of the bcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in V(H) and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated V(H) genes, with 4 of 10 cases clearly showing mutations in bcl-6. In those CLLs defined by somatically mutated V(H) genes, 4 of 9 cases predictively showed bcl-6 mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of V(H) genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the V(H) and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.

Chromosome Deletion↗
PubMed1979

In vivo somatic mutation systems in the mouse.

In an effort to meet the need for a fast and cheap in vivo prescreen for inherited mammalian point mutations, a somatic forward-mutation method, originally developed in an X-ray experiment, has more recently been tested in work with chemical mutagens. The method makes use of coat-color mutations because (a) the gene product is usually locally expressed, (b) mosaics can be detected with minimal effort, and (c) opportunities for making comparison with induction of germinal point mutations are greatest.--Following treatment of embryos that are heterozygous at specific coat-color loci, various induced genetic changes can result in expression of the recessive (RS) in clones derived from "mutant" melanocyte precursor cells. However, other events, such as decrease in the number of precursor cells, or disturbed differentiation, can also result in spots, which with careful classification can usually be distinguished from RS's on the basis of their location and color. When this is done, the relative RS frequencies for a series of compounds at least roughly parallel the relative spermatogonial mutation rates. The fact that easily measurable (though low) RS rates are obtained with compounds that have yielded negative results in spermatogonial tests is not surprising in view of the fact that RS's can be caused by several mechanisms besides point mutation.--In spite of the parallelism observed in one laboratory, the usefulness of the in vivo somatic mutation method as a prescreen could come to be doubted because of major discrepancies between results of similar experiments at different laboratories. However, it appears probable that at least some of these discrepancies are due to failure to discriminate between spots that probably resulted from melanocyte insufficiency and spots that resulted from expression of the recessive.--Reverse somatic mutation systems can potentially avoid some of the pitfalls of forward mutation systems. Such system are still in developmental stages.

Animals↗
PubMed1995

Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation.

To investigate the putative role of BRCA1, a gene involved in hereditary breast and ovarian cancer, in sporadic ovarian tumors among Japanese women, we examined 76 unselected primary ovarian cancers for mutations in the coding region of BRCA1 using the single-strand conformation polymorphism technique. Although no somatic mutations were detected in any of the tumors, constitutional mutations were identified in four cases: two frameshifts, one nonsense mutation and one intronic base substitution 32 bp downstream of exon 22; RT-PCR experiments revealed that the single-base substitution in the intron seemed to increase the transcript lacking exon 22. All four cases were judged to involve truncation of the gene product. The evidence reported here supports a rather limited role of BRCA1 in ovarian carcinogenesis in the Japanese population.

BRCA1 Protein↗
PubMed2024

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n&#xa0;= 343) and mutant (n&#xa0;= 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Humans↗
PubMed2002

Mutation cluster region, association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal familial adenomatous polyposis.

Studies of adenomatous polyposis coli (APC) mutations in familial adenomatous polyposis (FAP) have focused on large bowel disease. It has been found that: 1) germline APC mutations around codon 1300 are associated with severe colorectal polyposis; 2) somatic APC mutations in colorectal tumors tend to cluster approximately between codons 1250 and 1450; and 3) patients with germline mutations close to codon 1300 tend to acquire somatic mutations (second hits) in their colorectal polyps by allelic loss, whereas the tumors of other FAP patients have truncating second hits. Using new and published data, we have investigated how germline and somatic APC mutations influence the pathogenesis of upper gastrointestinal polyps in FAP. We have compared the results with those from colorectal disease. We found that somatic mutations in upper gastrointestinal polyps cluster approximately between codons 1400 and 1580. Patients with germline APC mutations after codon 1400 tend to show allelic loss in their upper gastrointestinal polyps; the tumors of other patients have truncating somatic mutations after codon 1400. Finally, patients with germline mutations after codon 1400 tend to have more severe duodenal polyposis (odds ratio, 5.72; 95% confidence interval, 1.13 to 28.89; P = 0.035). Thus, in both upper gastrointestinal and colorectal tumors, a specific region of the APC gene is associated with severe disease, clustering of somatic mutations, and loss of the wild-type allele. However, the region concerned is different in upper gastrointestinal and colorectal disease. The data suggest that loss of all APC SAMP repeats is probably necessary for duodenal and gastric tumorigenesis in FAP, as it is in colonic tumors. Compared with colonic tumors, however, retention of a greater number of beta-catenin binding/degradation repeats is optimal for tumorigenesis in upper gastrointestinal FAP.

Adenomatous Polyposis Coli↗