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PubMed1992

Generation and analysis of random point mutations in an antibody CDR2 sequence: many mutated antibodies lose their ability to bind antigen.

We have investigated the impact of mutations on the binding functions of the phosphocholine (PC)-specific T15 antibody in the absence of antigen selection pressure. The H chain complementarity determining region 2 (CDR2) sequence of T15 antibody was saturated with point mutations by in vitro random mutagenesis. From the mutant library, 289 clones were screened by direct DNA sequencing. The point mutations generated by this method were randomly distributed throughout the CDR2 region and included all kinds of substitutions. 46 unique mutant antibodies, containing one to four point mutations each, were expressed in SP2/0 myeloma cells. Functional analysis on these antibodies has provided insights into several aspects of somatic mutation. (a) The majority (26/46) of mutant antibodies either lost (20/46) or had reduced (6/46) ability to bind PC-protein conjugates or R36a, a PC-expressing strain of Streptococcus pneumoniae. In contrast, none of the mutant antibodies displayed increased binding for these PC antigens. Taken together with calculations of destructive mutations elsewhere in the V region, the data suggest that somatic mutation may cause extensive wastage among B cells during clonal expansion after antigen stimulation. (b) The frequency of binding-loss mutants increased sharply when a second mutation was introduced into the CDR2 sequence; it appears that, in some cases, two or more mutations are needed to destroy binding. (c) The mutant antibodies were tested for their reactivity to 11 non-PC antigens as well as to three PC analogues. None of the mutants gained new reactivity or changed their ability to discriminate structural analogues, supporting the notion that the major role of somatic mutation is to increase or decrease affinity rather than to create new specificities. (d) Mutations in at least five different positions in CDR2 were deleterious, suggesting that these residues may be essential for antigen binding. Three of these positions are novel in that they had not been identified to be important for binding PC by previous crystallographic analysis. (e) Introduction of mutations into two highly conserved residues in CDR2 did not alter the overall conformation of the V region as judged by antiidiotypic analysis, and, in some cases, did not affect the antigen binding function. The results thus indicate that even nonconservative substitutions of invariant residues need not be deleterious, suggesting that their conservation may be due to reasons other than maintaining antibody structure or specificity.

Amino Acid Sequence↗
PubMed1981

Somatic eye mutation in Drosophila melanogaster as a short-term test for mutagens and carcinogens.

Six mutagenic and/or carcinogenic agents were tested for their ability to cause somatic eye mutation (red sectors on a yellow eye) in Drosophila melanogaster. Results were analysed by the chi-squared method and by the Kolmogorov-Smirnov two-sample (non-parametric) test. Methyl methanesulphonate, cyclophosphamide, acriflavine and procarbazine were active, whereas acetamide and tetracycline failed to elicit a significant response. Thus, relative to other mutagenicity assays, this somatic system seemed to possess no special ability to correctly identify carcinogens because both acriflavine and acetamide were misidentified on a carcinogenicity basis. However, it could be a suitable alternative to the recessive lethal test for mutation, because of its technical simplicity and rapidity, subject to an increase in the size of the data base.

Acetamides↗
PubMed2002

Expression and mutation analyses of MKK4, a candidate tumour suppressor gene encoded by chromosome 17p, in human gastric adenocarcinoma.

Homozygous deletion or somatic mutations of mitogen-activated protein kinase kinase 4 (MKK4), a candidate tumour suppressor gene located at 17p11, have been observed in many types of human tumours. To explore the likelihood that MKK4 acts as a suppressor in gastric tumorigenesis, we examined the expression and mutation status of MKK4 in 144 gastric tissues and cell line specimens. Expression of the MKK4 transcript was easily detectable in all normal and benign tumour tissues and none of 102 primary carcinomas and cell lines showed an abnormal reduction in MKK4 expression. Expression levels of MKK4 transcript showed no cancer-specific reduction in 43 matched sets and did not correlate with stage, grade and histopathological types of the tumours. Western blot analysis also revealed that MKK4 protein expression in carcinoma tissues and cell lines is comparable to non-cancerous tissues. A significant loss of heterozygosity (LOH) was detected at telomeric markers of the MKK4, locus. However, no allelic deletion of the MKK4 gene or at the centromeric loci was identified. Moreover, no evidences for somatic mutations leading to amino acid substitutions or frameshifts of MKK4 were identified in the carcinoma tissues and cell lines, whereas a substantial fraction of the same set showed allelic loss or mutations of the TP53 gene located at 17p13, suggesting that LOH at telomeric loci or the TP53 locus might not extend into the MKK4 gene in gastric cancers. In this study, we also report the identification of a highly conserved MKK4 processed pseudogene, which shares 95% homology with the coding region of the functional MKK4 transcript. Collectively, our data demonstrate that genomic deletion or somatic mutation of MKK4 is infrequent in gastric cancers, suggesting that MKK4 might not be a critical target of genetic inactivation in gastric tumorigenesis.

Adenocarcinoma↗
PubMed1998

Antigen receptor engagement turns off the V(D)J recombination machinery in human tonsil B cells.

The germinal center (GC) is an anatomic compartment found in peripheral lymphoid organs, wherein B cells undergo clonal expansion, somatic mutation, switch recombination, and reactivate immunoglobulin gene V(D)J recombination. As a result of somatic mutation, some GC B cells develop higher affinity antibodies, whereas others suffer mutations that decrease affinity, and still others may become self-reactive. It has been proposed that secondary V(D)J rearrangements in GCs might rescue B cells whose receptors are damaged by somatic mutations. Here we present evidence that mature human tonsil B cells coexpress conventional light chains and recombination associated genes, and that they extinguish recombination activating gene and terminal deoxynucleotidyl transferase expression when their receptors are cross-linked. Thus, the response of the recombinase to receptor engagement in peripheral B cells is the opposite of the response in developing B cells to the same stimulus. These observations suggest that receptor revision is a mechanism for receptor diversification that is turned off when antigen receptors are cross-linked by the cognate antigen.

Animals↗
PubMed2003

A study of mitochondrial DNA mutations in peripheral lymphocytes in an aging cohort.

Somatic mutation in the mitochondrial genome occurs much more rapidly than in the nuclear genome and is a feature, possibly contributory, of the aging of cells and tissues. Identifying mitochondrial sequence changes in blood DNA of elderly subjects may provide a maker for the epigenetic changes of mitochondrial DNA known to occur in tissues with lower cellular turnover, and would also have implications for immunosenescence. No large-scale epidemiological studies have been reported previously. In this study we have established long-PCR banks of the mitochondrial genome from peripheral lymphocytes for an elderly cohort of 716 individuals with a range of measured aging phenotypes, and we have established assays for three widely reported mutations: the 4977 bp and 8048 bp deletions and point mutation A3243G. No individuals were identified with detectable heteroplasmy for these changes. Implications for tissue and population prevalence are discussed. The mitochondrial long-PCR DNA banks established will be useful for a wide range of studies of somatic mutation and of germline haplotypes in relation to aging.

Aged↗
PubMed1993

Analysis of somatic cell mutations at the glycophorin A locus in atomic bomb survivors: a comparative study of assay methods.

The glycophorin A (GPA) assay for in vivo somatic cell mutations was performed on blood samples from 39 survivors of the atomic bomb at Hiroshima. Parallel analyses were performed at two laboratories using three different GPA assay methods to enumerate cells lacking expression of either the M- or N-allele of GPA. All assay methods yielded significant dose-dependent increases in hemizygous GPA variant cell frequencies (VFs) and smaller increases in homozygous VFs. The slopes of the fitted linear dose-response functions did not differ significantly among assay methods used in the present study, or from slopes obtained in a study reported previously. The version of the assay described most recently (BR6) appears best suited for future studies because the assay has a higher precision than earlier methods. Variant frequencies from different assay methods measuring the same variant cell type agreed with each other better than with the estimated dose, suggesting that the imprecision in the assay is not primarily responsible for VFs that differ from the fitted dose response. Consistent deviations from the dose response were seen for some individuals, suggesting either errors in dose estimates for these individuals or interindividual differences in susceptibility or other exposures. For the study population as a whole, however, discrepancies between assays for M-loss and N-loss variants suggest stochastic factors may have an important effect on individual VFs for A-bomb survivors.

Chromosome Mapping↗
PubMed2005

Mutational analysis of TP53 and p21 in familial and sporadic ovarian cancer in Japan.

OBJECTIVE: To investigate whether somatic mutations in cell cycle checkpoint genes, TP53 and p21, are involved in the development of ovarian cancer with or without BRCA1 germline mutation. METHODS: We analyzed somatic genetic alterations of TP53 and p21 in 46 ovarian cancer patients with BRCA1 germline mutations and 93 sporadic patients, using direct sequencing for the entire coding sequences in TP53 and p21. RESULTS: TP53 somatic mutations were detected in 25 of the 46 BRCA1 cases and 40 of the 93 sporadic cases (54.3% vs. 43.0%). In contrast, p21 somatic mutations were detected in 1 of the 46 BRCA1 cases and 2 of the 93 sporadic cases (2.2% vs. 2.2%). TP53 mutations in sporadic cases more frequently occurred in exons 6-11 than those in cases with germline BRCA1 mutations (84.4% vs. 56.3%: P = 0.013). The proportion of sporadic cases with TP53 mutations in non-serous tumors (e.g. endometrioid, clear cell, or mucinous) was significantly lower than that in serous tumors (18.5% vs. 53.0%: P = 0.0038). However, there was no significant difference between the proportion of BRCA1 cases with TP53 mutation in non-serous and in serous tumors (37.5% vs. 57.9%). CONCLUSIONS: Our results suggest that somatic mutation of TP53 plays less of a role in the carcinogenesis of sporadic non-serous tumors than in that of sporadic serous tumors or BRCA1-related tumors. Furthermore, p21 somatic mutation appears to be less involved in the development of ovarian cancer than TP53 somatic mutation.

Adult↗
PubMed1984

Transplacental genetic and cytogenetic effects of alkylating agents in the mouse. I: Induction of somatic coat color mutations.

Induction of somatic coat color mutations by the alkylating agents ENU, MNU, EMS, MMS, DES, DMS, and trenimon and by the tuberculostatic drug INH was investigated in the mammalian spot test. Positive results were obtained with EMS (100 mg/kg), ENU (20-60 mg/kg), and INH (100 mg/kg), while trenimon (100 micrograms/kg), DES (225 mg/kg), and MNU (2 mg/kg) yielded inconclusive data. No mutagenic activity was found for MMS (125 mg/kg) and DMS (50 mg/kg). The mutagenic potency of monofunctional alkylating agents at subtoxic doses decreases as follows ENU greater than EMS greater than DES greater than MMS = DMS. The hypothesis that somatic coat color mutations in the mouse are predominantly due to intragenic changes is discussed. Differences in the RS frequency between offspring of the crosses NMRI X DBA and C57 X T are due to differences in loci available for mutation induction. Mutations that uncover the recessive allele p contribute to a significant extent to the total RS frequency observed in the mammalian spot test.

Alkylating Agents↗
PubMed1997

Molecular characterization of IgA- and/or IgG-switched chronic lymphocytic leukemia B cells.

The immunoglobulin (Ig) variable region (V) genes expressed by IgM chronic lymphocytic leukemia (CLL) B cells display little or no somatic mutations. However, preliminary findings have shown that Ig V genes of IgA and IgG CLLs may be somatically mutated, suggesting that isotype-switched CLLs may represent a "subtype" of the disease. To investigate the degree and nature of somatic mutations and the role of antigen (Ag) in the clonal selection and expansion of isotype-switched CLLs, and to determine whether specific oncogene or tumor suppressor gene mutations are associated with isotype-switched CLLs, we analyzed the expressed Ig VH gene, bcl-1 and bcl-2 proto-oncogene, and p53 tumor suppressor gene configurations of 3 IgA-, 1 IgG-, and 1 IgA/ IgG-expressing CLLs. These isotype-switched CLL B cells expressed surface HLA-DR, CD19, CD23, and CD5, and displayed no alterations of the bcl-1 and bcl-2 oncogenes and the p53 tumor-suppressor gene. The cDNA VH-D-JH gene sequence was joined with that of the C alpha gene in the B cells of the three IgA CLLs, and with that of the C gamma gene in the IgG CLL B cells. In the IgA/IgG-coexpressing CLL B cells, identical VH-D-JH cDNA sequences were spliced to either C alpha or C gamma genes. In all five CLLs, the pattern of C mu DNA probe hybridization to the digested genomic DNAs was consistent with deletion of the C mu exon from the rearranged Ig gene locus, suggesting that these CLL B cells had undergone DNA switch recombination. In one IgA CLL, the expressed VH gene was unmutated. In all other class-switched CLLs, the Ig VH segment gene was mutated, but the point mutations were not associated with intraclonal diversification. In one IgA and in the IgA/IgG-coexpressing CLL, the nature and distribution of the mutations were consistent with Ag selection. These findings suggest that IgA- and/or IgG-expressing CLLs represent, in their VH gene structure, transformants of B cells at different stages of ontogeny. They also suggest that Ag may play a role in the clonal selection of some of these isotype-switched leukemic cells, but bcl-1 and bcl-2 oncogene rearrangements and p53 tumor suppressor gene mutation are not associated with the pathogenesis of isotype-switched CLLs.

Amino Acid Sequence↗
PubMed2026

Genetic control of local mutation rates.

Mutations are the source of evolutionary novelty but also the cause of genetic diseases and cancer. Mutation rates are known to be heterogeneous along the genome, however the extent to which local mutation rates vary among individuals in a population and are genetically determined is unknown. To test this, we analyzed the chromosomal distribution of somatic mutations in cell lines from 1,662 individuals, controlling for the confounding effects of DNA replication timing on local mutation rates and of trans-acting modulators on global mutation rates. We describe substantial interindividual variation in mutation rates across the human genome. By comparing mutation-rate variation to individuals' genotypes, we identified 35 instances in which polymorphic alleles in the population associate with somatic mutation rates in their vicinity. We call these mutation quantitative trait loci (mutQTLs). mutQTLs associated with somatic mutations in lymphoblastoid cell lines and in chronic lymphocytic leukemia, and with germline genetic variants. Two of the four mutQTLs inferred to be associated with germline mutation-rate variation were located within large clusters of zinc-finger genes and transposable elements, where they functioned as cis-mutators conferring an increased rate of mutation in their vicinity. mutQTLs provide a portal into the evolution of mutation rate heterogeneity across the genome and across individuals.

Humans↗
PubMed2003

Mutational analysis of Noxa gene in human cancers.

There has been mounting evidence that dysregulation of apoptosis is involved in the mechanisms of cancer development and somatic mutations of apoptosis-related genes have been reported in human cancers. Noxa, a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family, is known to interact with anti-apoptotic Bcl-2 family members and induces apoptosis. The aim of this study was to explore the possibility that the Noxa gene is mutated in human cancers. We have analyzed the entire coding region and all splice sites of the Noxa gene for the detection of somatic mutations in a series of human cancers, including carcinomas from stomach, colon, liver, urinary bladder and lung by polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP), and DNA sequencing. We found one somatic mutation of the Noxa gene in a transitional cell carcinoma (TCC) of the urinary bladder. To evaluate the functional alterations of the mutant in apoptosis, we overexpressed the mutant and wild-type Noxa in 293T and HeLa cells, but could not find any significant difference in cell death between the wild-type and mutant Noxa. These data suggest that Noxa is rarely mutated in human carcinomas and that the contribution of Noxa gene mutation in the pathogenesis of human cancer might not be related to cell death mechanisms.

Adenocarcinoma↗
PubMed2006

Pharmacogenetics of alkylator-associated acute myeloid leukemia.

Therapy-related acute myeloid leukemia (t-AML) is a lethal late complication of alkylator chemotherapy. The genetic basis of susceptibility to t-AML is poorly understood. Both t-AML and de novo AML are complex genetic diseases, requiring cooperating mutations in interacting pathways for disease initiation and progression. Germline variants of these 'leukemia pathway' genes may cooperate with somatic mutations to induce both de novo and therapy-related AML. Several cancer susceptibility syndromes have been identified that cause an inherited predisposition to de novo and t-AML. The genes responsible for these syndromes are also somatically mutated in sporadic AML. We reason that germline polymorphism in any gene somatically mutated in AML could contribute to t-AML risk in the general population. Identification of these susceptibility alleles should help clinicians develop tailored therapies that reduce the relative risk of t-AML.

Alkylating Agents↗
PubMed2004

Effect of vanillin on toxicant-induced mutation and mitotic recombination in proliferating somatic cells of Drosophila melanogaster.

Vanillin (VA; C8H8O3) is a flavoring agent that in previous studies has both increased and decreased the genotoxicity of chemical agents, depending on the nature of both the agent and the genetic event measured. The ability of VA to modulate the mutagenicity and recombinogenicity of three different monoalkylating agents, N-ethyl-N-nitrosourea (ENU), N-methyl-N-nitrosourea (MNU), and ethyl methanesulfonate (EMS), and the intercalating agent bleomycin (BLEO) was examined using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. While neither the mutagenicity nor the recombinagenicity of ENU or MNU was modified by posttreatment with VA, EMS-induced genetic toxicity was enhanced by as much as 30%. This overall enhancement included a synergistic increase in mitotic recombination and a lesser decrease in mutation. Posttreatment with VA also produced an increase in the genotoxicity of BLEO, which was characterized by increases of 120% and 180% for 0.5% and 1% VA, respectively. This enhancement was restricted to an increase in recombinational events, since no alteration in BLEO-induced mutation was observed. The data suggest that the major VA-modulatory action on genotoxicity in D. melanogaster is related to its synergistic effects on somatic recombination, which has a greater consequence on overall genotoxicity than its antimutagenic effects. Since the SMART assay is specifically sensitive to mitotic crossing-over, our data suggest that VA promotes toxicant-induced homologous recombination, at least in the proliferative cells of Drosophila.

Alkylating Agents↗
PubMed2001

HPRT mutations in humans: biomarkers for mechanistic studies.

The X-chromosomal gene for hypoxanthine-guanine phosphoribosyltransferase (HPRT), first recognized through its human germinal mutations, quickly became a useful target for studies of somatic mutations in vitro and in vivo in humans and animals. In this role, HPRT serves as a simple reporter gene. The in vivo mutational studies have concentrated on peripheral blood lymphocytes, for obvious reasons. In vivo mutations in T cells are now used to monitor humans exposed to environmental mutagens with analyses of molecular mutational spectra serving as adjuncts for determining causation. Studies of the distributions of HPRT mutants among T cell receptor (TCR) gene-defined T cell clones in vivo have revealed an unexpected clonality, suggesting that HPRT mutations may be probes for fundamental cellular and biological processes. Use of HPRT in this way has allowed the analyses of V(D)J recombinase mediated mutations as markers of a mutational process with carcinogenic potential, the use of somatic mutations as surrogate markers for the in vivo T cell proliferation that underlies immunological processes, and the discovery and study of mutator phenotypes in non-malignant T cells. In this last application, the role of HPRT is related to its function, as well as to its utility as a reporter of mutation. Most recently, HPRT is finding use in studies of in vivo selection for in vivo mutations arising in either somatic or germinal cells.

Biomarkers↗
PubMed1975

Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma.

The incidences of some childhood cancers have been shown to fit a two-mutation hypothesis for cancer initiation. According to this hypothesis, the first mutation can be either germinal or somatic while the second is always somatic. A probabilistic model involving the mean number of tumors per genetically susceptible individual is developed as a function of age and is compared with age incidence data for retinoblastoma. The change in the mean number of tumors with time is interpreted in terms of the growth of retinal cells. In patients who are not genetically susceptible, the times of occurrence of the first and second somatic mutations can be inferred from a comparison of familial and non-familial unilateral case incidences. The total incidences of hereditary and nonhereditary forms of retinoblastoma are related to germinal and somatic mutation rates. The even distribution of certain childhood cancers throughout the world suggests that their incidences are determined by spontaneous mutation rates rather than by local environmental mutagenic carcinogens.

Child↗
PubMed1997

Analysis of rearranged immunoglobulin heavy chain variable region genes obtained from a bone marrow transplant (BMT) recipient.

Haematopoietic stem cell transplantation has been used for the treatment of many different malignant and non-malignant diseases. The immune system of transplant recipients must be regenerated from the transplant inoculum, and it is not surprising that many transplant recipients are deficient in generating specific antibody responses to exogenous stimuli. This B cell immunodeficiency in these patients is associated with clinically significant infections, although the underlying mechanism remains unknown. We have previously shown that the pattern of usage of V(H) genes was similar between healthy subjects and BMT recipients, indicating that the immunodeficiency was not due to a dramatic imbalance in V(H) utilization. However, motif-specific hybridization analysis indicated that the accumulation of somatic mutations was much greater among rearrangements in controls than in BMT recipients. The failure of BMT recipients to accumulate somatic mutations in rearranged V(H) genes correlates with an absence of IgD- B cells, and is consistent with a defect in antigen-driven B cell responses. In the current study, which extends those findings, we have determined the nucleotide sequences of 68 heavy chain rearrangements from one patient as well as 39 rearrangements from a healthy control. Analysis of these sequences made possible a more precise definition of variable region configuration and of the status of somatic mutation in this BMT recipient. The results validate the hybridization data and support the conclusion that, although somatic hypermutation and, by inference, antigen-driven responses are detected in BMT recipients, they are deficient compared with healthy subjects as late as 1 year after transplant.

Base Composition↗
PubMed2001

BRCA1 and BRCA2 and the genetics of breast and ovarian cancer.

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.

BRCA2 Protein↗
PubMed2006

PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma.

Phosphatidylinositol 3-kinases (PI3K) are a group of heterodimeric lipid kinases that regulate many cellular processes. Gene amplification and somatic mutations mainly within the helical (exon 9) and kinase (exon 20) domains of PIK3CA, which encode the 110-kDa catalytic subunit of PI3K and are mapped to 3q26, have been reported in various human cancers. Herein, 14 human oral squamous cell carcinoma (OSCC) cell lines and 108 primary OSCC tumors were investigated for activating mutations at exons 9 and 20 as well as amplifications in PIK3CA. PIK3CA missense mutations in exons 9 and 20 were identified in 21.4% (3/14) of OSCC cell lines and 7.4% (8/108) of OSCC tumors by genomic DNA sequencing. An increase in the copy number of PIK3CA, although small, was detected in 57.1% (8/14) of OSCC lines and 16.7% (18/108) of OSCC tumors using quantitative real-time PCR. A significant correlation between somatic mutations of PIK3CA and disease stage was observed: the frequency of mutations was higher in stage IV (16.1%, 5/31) than in a subset of early stages (stages I-III) (3.9%, 3/77; P = 0.042, Fisher's extract test). In contrast, the amplification of PIK3CA was observed at a similar frequency among all stages. AKT was highly phosphorylated in OSCC cell lines with PIK3CA mutations compared to those without mutations, despite the amplification. The results suggest that somatic mutations of the PIK3CA gene are likely to occur late in the development of OSCC, and play a crucial role through the PI3K-AKT signaling pathway in cancer progression.

Adult↗