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PubMed1982

Somatic mutation in a cultured mouse myeloma cell affects antigen binding.

The S107 mouse myeloma cell line synthesizes an IgA antibody that binds the hapten phosphocholine and is similar if not identical in its heavy and light chain variable region sequence to the predominant antibody produced by BALB/c mice in response to immunization with phosphocholine. This cell line frequently and spontaneously generates somatic variants producing immunoglobulins with decreased ability to bind antigen. One such variant, S 107.U1, is described here. This variant has a decreased ability to bind phosphocholine when it is attached to a carrier, although its affinity for free hapten is the same as that of the parent. This decrease in antigen binding is associated with a single amino acid substitution at the fifth residue in the JH segment.

Amino Acid Sequence↗
PubMed1992

Conserved patterns of somatic mutation and secondary VH gene rearrangement create aberrant Ig-encoding genes in Epstein-Barr virus-transformed and normal human B lymphocytes.

Expression of N-terminal-truncated Ig heavy chains without normal light chain expression has been shown to occur in human B cell tumor lines, and to be due to diverse types of structural alteration within the expressed Ig heavy and light chain genes. Due to the tumor cell origin of these lines, generation of aberrant Ig-encoding genes may only occur after malignant transformation, reflecting the release of the tumor B cell from the need to express functional Ig for continued clonal proliferation. The genetic basis for expression of VH-truncated mu chains without light chains in several Epstein-Barr virus (EBV)-transformed human B cell lines was investigated with the aim that this information would lead to detection of similarly aberrant Ig genes in normal human B lymphocytes. Analysis of the productive mu genes in three truncated mu-only human B cell lines showed a consistent structural change where a secondary VH-VHDJH gene rearrangement had occurred. The site of VH-VH joining was suggestive of a V(D)J recombinase-mediated event. A consistent pattern of mutation was also observed in the normal-sized, but non-functional kappa light chain transcripts, making them incapable of coding for a functional kappa chain. Using genomic DNA from peripheral blood lymphocytes of a donor whose B cells were originally used to make one of the truncated mu-only EBV B cell lines, a similarly mutated V kappa gene was detected and a similar composite VH-VH gene was cloned. The lack of such aberrant VH and V kappa genes in non-lymphoid cells of this individual showed that the structural abnormalities in the expressed Ig genes arose somatically during development of that B cell clone. The presence of these altered Ig heavy and light chain genes in the genomic DNA of untransformed lymphocytes also shows that generation of such variant B cell clones can be a pre-neoplastic event and occurs by genetic mechanisms active during normal B cell development.

Amino Acid Sequence↗
PubMed2003

Dietary fruit and vegetables protect against somatic mutation in vivo, but low or high intake of carotenoids does not.

Epidemiological studies have demonstrated protective effects of vegetables and fruit on risk of cancer, but underlying mechanisms remain unclear. Intervention studies have in some cases contradicted previous epidemiological evidence, e.g. for beta-carotene supplementation and lung cancer, emphasizing the need for mechanistic data. We assessed in vivo mutagenic effects of several dietary items using the HPRT (hypoxanthine-guanine phosphoribosyl transferase) gene assay with T-lymphocytes from 312 individuals (158 lung cancer cases, 154 population controls), who provided information on diet and smoking habits. HPRT mutant frequency (MF) was significantly decreased in relation to intake of vegetables, citrus fruits and berries, respectively, as well as calculated vitamin C intake from diet. There was a significant U-shaped association with dietary carotenoid intake, with lowest MF near population average carotenoid intakes and higher mutation frequencies both at low and high intakes, and a similar borderline significant association was observed for beta-carotene. Our study is consistent with known diet-cancer associations and provides novel human in vivo mechanistic support for a cancer-protective effect of vegetables and fruit by modulation of somatic mutagenesis. Our results also provide support for the increase in lung cancer risk observed particularly in smokers in studies of beta-carotene supplementation.

Adult↗
PubMed1997

Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.

Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient's genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.

Adult↗
PubMed1990

The importance of glutathione and glutathione transferase for somatic mutations in Drosophila melanogaster induced in vivo by 1,2-dichloroethane.

Two principal pathways of metabolism of the carcinogenic compound 1,2-dichloroethane (DCE) have been proposed. One is a mixed function oxidase dependent pathway requiring oxygen and NADPH. The other pathway depends on the presence of glutathione (GSH) and glutathione transferase (GST). The aim of this study was to investigate the role of the latter pathway for the in vivo mutagenicity of DCE in the somatic wing spot test in Drosophila melanogaster. DCE caused a dose-dependent increase of wing spots. In order to investigate the role of cellular GSH for the mutagenicity, the level of GSH was decreased by 24 h pretreatment with buthionine sulfoximine (BSO), an efficient inhibitor of GSH synthesis. This pretreatment decreased the GSH level to approximately 6% as compared to the control. The pretreatment also resulted in a significant decrease of the mutagenicity of DCE. Treatment of the larvae with phenobarbiturate (PB) resulted in approximately 200% induction of cytosolic GST, and a corresponding increase in the DCE mutagenicity. These results indicate that the important pathway in vivo for the mutagenicity of DCE is dependent on GSH and GST. A similar experimental protocol was used to study interactions between aflatoxin B1 (AFB) and GSH and GST. No effect of the treatment with BSO on the mutagenicity of AFB was observed, while pretreatment with PB caused a decrease of the mutagenicity of AFB.

Aflatoxins↗
PubMed1993

Effects of 5-azacytidine on somatic mutation in a soybean test system.

The mutagenic activity of 5-azacytidine (azaC) was assayed in heterozygous soybean plants (Y11y11), according to the appearance of mutational spots (yellow, dark green and twin) on the leaves. When soybean seeds were treated with azaC at 10-100 micrograms/ml, azaC was found to be significantly mutagenic and to exert heritable effects in the soybean test system. Treatment with azaC increased the frequency of twin spots on the leaves. AzaC would thus appear to cause somatic crossing over as its major effect.

Azacitidine↗
PubMed1988

Somatic mutation induced by heliotrine in Drosophila.

The pyrrolizidine alkaloid heliotrine has been shown to be a powerful mutagen in Drosophila. This report has evaluated the teratogenicity of heliotrine in this organism. The alkaloid was fed to larvae and its teratogenic effects measured in various developmental stages of the insect. The pupal stage is predominantly affected. The main consequences of treatment were failed eclosions at higher alkaloid concentrations (10(-4) M), while lower concentrations (10(-5) M) permitted the eclosion of adults, but these showed abdominal abnormalities ranging from severe distortions to reduced numbers of tergite bristles. mei-9 strains of Drosophila were more sensitive to the production of somatic chromosomal changes as well as the teratogenic effects of the alkaloid. These strains also showed reduced numbers of cells in histoblast nests of 6-hour-old prepupae. It is suggested that reduced numbers of histoblast cells in prepupae may be a consequence of genetic damage and this in turn leads to the abdominal distortions and reduced bristle numbers observed.

Animals↗
PubMed1989

A natural autoantibody is encoded by germline heavy and lambda light chain variable region genes without somatic mutation.

While nonmutated germline variable region (V) genes have been found to encode heavy or light chains of various human autoantibodies, the use of germline V genes by both chains of a given autoantibody has not been documented. Recently, we reported that the heavy chain V gene (designated Humha346) of the Kim4.6 anti-DNA antibody is identical to a germline VH gene, 1.9III. To investigate whether this autoantibody was entirely germline encoded, we searched for the germline counterpart to the Kim4.6 V lambda segment (designated Humla146) and isolated a V lambda I gene designated Humlv117, which was identical to Humla146. Together with the sequence identity of the Kim4.6/Humha346 and 1.9III VH genes, the current data provide the first direct proof that an autoantibody can be encoded entirely by germline V genes without any somatic change. In addition, Humlv117 is the first V lambda I germline gene that has been isolated, and is highly homologous to the V lambda genes expressed in two lymphomas. Thus, this V lambda I gene should provide a useful tool for investigating the expression of the human V lambda gene repertoire, particularly with regard to autoimmune and/or lymphoproliferative diseases.

Amino Acid Sequence↗
PubMed2006

Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease.

Individuals with X-linked lymphoproliferative disease (XLP) display defects in B cell differentiation in vivo. Specifically, XLP patients do not generate a normal number of CD27 memory B cells, and those few that are present are IgM. Recent studies have suggested that IgMCD27 B cells are not true memory cells, but rather B cells that guard against T cell-independent pathogens. Here we show that human XLP IgMCD27 B cells resemble normal memory B cells both morphologically and phenotypically. Additionally, IgMCD27 B cells exhibited functional characteristics of normal memory B cells, including the ability to secrete more Ig than naive B cells in response to both T cell-dependent and -independent stimuli. Analysis of spleens from XLP patients revealed a paucity of germinal centers (GCs), and the rare GCs detected were poorly formed. Despite this, Ig variable region genes expressed by XLP IgMCD27 B cells had undergone somatic hypermutation to an extent comparable to that of normal memory B cells. These findings reveal a differential requirement for the generation of IgM and Ig isotype-switched memory B cells, with the latter only being generated by fully formed GCs. Production of affinity-matured IgM by IgMCD27 B cells may protect against pathogens to which a normal immune response is elicited in XLP patients.

Adolescent↗
PubMed1994

An isotype switched and somatically mutated rheumatoid factor clone isolated from a MRL-lpr/lpr mouse exhibits limited intraclonal affinity maturation.

Employing site-directed mutagenesis we have reconstructed and expressed the germ-line precursor of an expanded rheumatoid factor (RF) clone. This RF clone, designated clone F, was isolated from an autoimmune MRL/MpJ-lpr/lpr mouse. Most of the clone members were extensively mutated and isotyped-switched. The predominant isotype of clone F was gamma 3. The RF bound specifically to the MRL gamma 2 a allotype (Igh-1j) but not to the B6 gamma 2a allotype (Igh-1b). The germ-line antibody was also found to bind gamma 2a in an RF assay. The affinities of the germ-line RF and representative members of the clone were measured in an ELISA-based equilibrium binding assay. The dissociation constant (Kd) of the germ-line RF was 2.5 x 10(-6) M. All of the expressed clone members had affinities within a two- to sixfold range of the germ line, indicating that the mechanisms of somatic hypermutation and selection resulted in only limited affinity maturation of this autoantibody clone.

Amino Acid Sequence↗
PubMed1994

Two acquired immunodeficiency syndrome-associated Burkitt's lymphomas produce specific anti-i IgM cold agglutinins using somatically mutated VH4-21 segments.

We analyzed the reactivity and the structure of the VH and VL segments of two IgM monoclonal antibodies (MoAbs) produced by spontaneously in vitro outgrowing cell lines, HBL-2 and HBL-3, established from two acquired immunodeficiency syndrome (AIDS) patients with Epstein-Barr virus (EBV)-negative Burkitt's lymphoma (BL). These B-cell clones were representative of the respective neoplastic parental clones, as determined by immunophenotypic and molecular genetic analysis. The IgM MoAbs were highly specific for the i determinant on red blood cells (cold agglutinins), but bound none of the other eight self and nine foreign antigens (Ags) tested, including those most commonly recognized by natural antibodies or autoantibodies. Structural analysis showed that the IgM MoAb VH segment sequences were 93.5% and 84.2% identical with that of the germline VH4-21 gene, which encodes the vast majority of cold agglutinins that are specific for the i/l carbohydrate Ag and are produced under chronic lymphoproliferative conditions. The HBL-2 MoAb VH4-21 gene segment was juxtaposed with 20P3 and JH6 genes and paired with a V lambda 1 segment, the sequence of which was 95.5% identical to that of the germline Humlv117 gene; the HBL-3 MoAb VH4-21 gene segment was juxtaposed with DXP'1 and JH5 genes and paired with a V lambda 1 segment, the sequence of which was 86.7% identical to that of the germline Humlv1L1 gene. The high degree of conservation of the VH4-21 gene in the human population, the nature of the nucleotide differences in the expressed VH4-21 segments, and the presence of nucleotide substitutions in the HBL-2 and HBL-3 IgM MoAb JH and/or J lambda segments suggested that the MoAb V segments underwent a process of somatic hypermutation. This was formally shown in the HBL-3 MoAb VH segment, by differentially targeted polymerase chain reaction amplification of the HBL-3 MoAb-producing cell genomic DNA. In addition, cloning and sequencing of the genomic DNA from fibroblasts of the same patient whose neoplastic B cells gave rise to the HBL-3 cell line yielded a germline copy of the VH4-21 gene. Thus, the expression of VH4-21 gene products may be involved in a self Ag-driven process of clonal B-cell expansion and selection associated with BL in these AIDS patients.

Agglutinins↗
PubMed1996

Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions.

The CDKN2 gene, encoding the cyclin-dependent kinase inhibitor p16, is a tumour suppressor gene that maps to chromosome band 9p21-p22. The most common mechanism of inactivation of this gene in human cancers is through homozygous deletion; however, in a smaller proportion of tumours and tumour cell lines intragenic mutations occur. In this study we have compiled a database of over 120 published point mutations in the CDKN2 gene from a wide variety of tumour types. A further 50 deletions, insertions, and splice mutations in CDKN2 have also been compiled. Furthermore, we have standardised the numbering of all mutations according to the full-length 156 amino acid form of p16. From this study we are able to define several hot spots, some of which occur at conserved residues within the ankyrin domains of p16. While many of the hotspots are shared by a number of cancers, the relative importance of each position varies, possibly reflecting the role of different carcinogens in the development of certain tumours. As reported previously, the mutational spectrum of CDKN2 in melanomas differs from that of internal malignancies and supports the involvement of UV in melanoma tumorigenesis. Notably, 52% of all substitutions in melanoma-derived samples occurred at just six nucleotide positions. Nonsense mutations comprise a comparatively high proportion of mutations present in the CDKN2 gene, and possible explanations for this are discussed.

Amino Acid Sequence↗
PubMed1998

Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors.

The PTEN (MMAC1/TEP1) tumor suppressor gene was recently isolated and mapped to human chromosome band 10q23. Homozygous deletions and mutations of PTEN were observed in cell lines and sporadic cancers of the breast, kidney, and central nervous system. Germline mutations in PTEN were recently found in Cowden disease, an autosomal dominant inherited syndrome, previously mapped to chromosome bands 10q22-23. This disease is associated with a wide variety of malignancies and hamartomas of ectodermal, mesodermal, and endodermal origin. The most common neoplasms in Cowden disease patients arise in the breast, skin, and thyroid (follicular subtype). To determine the involvement of PTEN in sporadic follicular thyroid tumors, we first analyzed sporadic follicular adenomas and carcinomas for deletions of the PTEN gene. Loss of heterozygosity was found in 7/26 (27%) follicular carcinomas and 2/27 (7%) follicular adenomas, one of which was a small hemizygous deletion (approximately 3 cm). Sequence analysis of the entire PTEN coding region revealed two mutations in carcinomas with 10q loss. Our findings suggest that the PTEN tumor suppressor gene is occasionally inactivated in sporadic follicular thyroid tumors.

Adenocarcinoma, Follicular↗