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PubMed1977

Hemoglobin and the genetic code. Evolution of protection against somatic mutation.

One-half of the twenty amino acids of the genetic code are just one mutational step away from the chain-terminator codons UAA, UAG, and UGA. It is postulated that somatic mutation to terminator is a hazard to which the organism has and to respond by adjusting certain proteins in the direction of fewer mutable residues. This view is supported by calculations based on the primary structure of five of the human hemoglobin chains. Each chain is scored for mutability to terminator in accord with the numbers and kinds of amino acids present. Among the adult chains, the most essential one, the alpha, has lowest mutability. The beta and delta follow, and in order of the presumed harm to the organism of a shortage of chain copies. Ante-natal chains tend to have higher mutabilities, supporting the view that cumulative mutational change in DNA can do little if the gene ceases to transcribe early in life. Two other predicitons based on the supposition of effective selection against mutability to terminator are also met: chain length of polypeptides is negatively correlated with their scores for mutability to terminator, and examination of the recently determined sequence of beta messenger RNA shows preferential use of codons that are not readily mutable to terminator.

Amino Acid Sequence↗
PubMed1995

Analysis of the relationship between age of larvae at mutagen treatment and frequency and size of spots in the wing somatic mutation and recombination test in Drosophila melanogaster.

The relationship between the induction of mutant clones and the time of mutagen treatment was studied in the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. Larvae trans-heterozygous for the recessive marker mutations multiple wing hairs (mwh) and flare (flr) were produced. Batches of these larvae were then treated with mutagen at different ages spanning all three larval instars. Methyl methanesulfonate was fed acutely for 2 h by immersing the larvae in a solution of the mutagen mixed with powdered cellulose. Wings of the surviving adult flies were mounted and scored for the presence of spots. The frequency and size of single and twin spots were recorded separately. Twin spots are produced exclusively by mitotic recombination, whereas single spots can result from various types of mutational and exchange events. There exists a clear correlation between time of induction and frequency as well as size of the single spots. In young larvae only few but very large spots are induced, whereas in older larvae the frequencies are considerably increased but the sizes are smaller. The twin spots show a different relationship. Practically no twin spots are found in very young and in very old larvae. The results demonstrate that in the wing spot test the optimal age of the larvae for mutagen treatment is 72 h.

Animals↗
PubMed1998

Analysis of the in vivo nitrosation capacity of the larvae used in the wing somatic mutation and recombination test of Drosophila melanogaster.

The in vivo nitrosation capacity of third-instar larvae of Drosophila melanogaster was assessed using the wing somatic mutation and recombination test (SMART). Larvate derived from two different crosses, the standard cross (ST) and the high bioactivation cross (HB) both involving the recessive wing cell markers multiple wing hairs (mwh) and flare (flr3), were used. The HB cross is characterised by an increased cytochrome P450-dependent bioactivation capacity for promutagens and procarcinogens. The larvae were treated either with methyl urea, sodium nitrite or its combination. N-Nitrosomethylurea was used as a positive control. The wings of the resulting flies were analysed for the occurrence of mutant spots produced by various types of mutational events or by mitotic recombination. Methyl urea is negative in the ST and the HB cross, whereas sodium nitrite is weakly genotoxic in both crosses. However, the combination of both compounds produces highly increased frequencies of mutations and recombinations predominantly in the HB cross. The genotoxic effects produced by the combined treatments were considerably increased when mashed potatoes or an agar-yeast medium were used for the treatment instead of the standard instant medium. Treatment of larvae with the mixture resulting from the in vitro reaction of nitrosation precursors also resulted in high frequencies of induced spots comparable to those recorded with the potent genotoxin N-nitrosomethylurea. Further experiments showed that the genotoxic effect resulting from the in vivo exposure to nitrosation precursors can be reduced by co-treatment with catechin, a known nitrosation inhibitor. The present study demonstrates that the wing spot test is well suited for the determination of genotoxicity produced by in vivo nitrosation processes and for the study of their modulation by individual compounds or dietary complex mixtures.

Animals↗
PubMed1999

Somatic mutations of the first 14 exons of APC in hamartomatous polyps of the colon.

Although hamartomatous or hyperplastic polyps are rarely accompanied by adenomatous or carcinomatous foci, the role of APC (MIM# 175100) mutations in these polyps is not clear. The neoplastic potential of these polyps was assessed with regard to somatic mutation of the first 14 exons of APC. DNA from 14 hamartomatous polyps (12 patients with juvenile polyp, JP; two patients with Peutz-Jeghers syndrome, PJS) and 27 hyperplastic polyps was used. Exons 1-14 of APC were amplified using verified oligonucleotide primers, and PCR-SSCP analysis was performed. Translation-terminating mutation in exon 15 was also screened using the protein truncation test. All mutations found were transitions or transversions with heterozygous alleles of both wild-type and mutant APC in exons 2, 9, 10, and 11. Four hamartomatous polyps (three from JP and one from PJS) showed seven, new mutations and one common APC variant (codon 486), whereas no hyperplastic polyps demonstrated mutation. APC mutation was not correlated with previous history of colorectal carcinoma or number of polyps. Since all mutations were missense or silent mutations occurred in exons not previously known to have functionally relevant area, their phenotypic implication appeared to be limited.

Colonic Polyps↗
PubMed2005

Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck.

PURPOSE: Recently, the kinase domain mutations of epidermal growth factor receptor (EGFR) gene have been identified in non-small-cell lung cancer, and these mutations have been related to the clinical response to the tyrosine kinase inhibitor gefitinib. Gefitinib treatment has also shown clinical benefits in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to explore the possibility that SCCHN harbored the EGFR mutations. EXPERIMENTAL DESIGN: In this study, we analyzed EGFR gene in 41 SCCHN for the detection of the somatic mutations by PCR-single-strand conformational polymorphism analysis. RESULTS: Overall, we detected three EGFR mutations (7.3%), and all of the mutations were the same in-frame deletion mutation in exon 19 (E746_A750del). CONCLUSION: These data indicated that in addition to non-small-cell lung cancer, SCCHN harbors the EGFR gene mutations, and suggested the rationale for the clinical applicability of gefinitib to SCCHN patients.

Adult↗
PubMed1999

Frequent somatic mutations of the beta-catenin gene in intestinal-type gastric cancer.

The increased level of cytoplasmic beta-catenin through the mutations to either beta-catenin or adenomatous polyposis coli (APC) has been proposed as an important oncogenic step in various tumors. Gastric cancer showed frequent genetic alterations of the APC gene, and the risk for gastric cancer in familial adenomatosus polyposis patients is 10 times higher than that in the general population. These findings raise the possibility that mutations of beta-catenin may also be associated with the development of gastric cancer. We detected seven somatic mutations in a portion of exon 3 encoding for the glycogen synthase kinase 3beta phosphorylation consensus region of the beta-catenin gene in 43 gastric cancers. All of these mutations were missense mutations, of which five are in the highly conserved aspartic acid 32 and two are in serine 29; all of these seven mutations were detected exclusively in intestinal-type gastric cancers (7 of 26; 26.9%), but not in the diffuse-type (0 of 17). We concluded that disruption of the APC/beta-catenin/T cell factor-lymphoid enhancer binding factor pathway might play an important role especially in the development of intestinal-type gastric cancer.

Base Sequence↗
PubMed2005

Somatic mutational analysis of DAX1 in testes from men with idiopathic azoospermia.

Mutations in the orphan nuclear receptor DAX1 (NR0B1) cause X-linked adrenal hypoplasia congenital (AHC), a disorder characterized by primary adrenal failure, hypogonadotropic hypogonadism. and azoospermia. We tested the hypothesis that DAX1 somatic mutations in human testis may cause azoospermia. DAX1 sequencing analysis in 15 testicular biopsy samples from men with idiopathic nonobstructive azoospermia did not reveal mutations in the coding region of the gene. We conclude that somatic abnormalities in DAX1 are absent or uncommon in these patients.

Adult↗
PubMed1991

Effects of tannic acid on spontaneous and induced somatic mutations in Drosophila melanogaster.

The effects of tannic acid (TA) alone and in combination with direct acting chemical genotoxins and gamma-radiation were investigated in Somatic Mutation and Recombination Tests (SMARTs) using Drosophila melanogaster. Treatment with TA alone (2.5-15 mmol/l) resulted in a moderate but dose dependent induction of mosaic spots in males and females, indicating that the compound possesses mutagenic and recombinogenic activity. When TA (10 mmol/l) was given simultaneously with MMS, 4-NQO and cis-DDP, a potentiating effect on their mutagenicity was observed in males whereas in females no such increase was measured. The frequency of 4-NQO induced mosaic spots in males was raised more than threefold in presence of TA, for MMS and cis-DDP the enhancement was approximately 2-fold; with gamma-radiation no synergistic effect occurred. The different response in the two sexes indicates that TA preferentially induces gene mutations and deletions but has no enhancing effect on the number of mosaic spots which are formed as a consequence of recombinogenic events.

Animals↗
PubMed2004

Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors.

We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperparathyroidism (FIHP). Seven patients with sporadic parathyroid cancers and 35 with parathyroid adenomas with no family history of primary hyperparathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with parathyroid cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic parathyroid cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic parathyroid cancer. The finding that two of the seven patients with sporadic parathyroid cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.

Adenoma↗
PubMedDate not supplied

The canine p53 gene is subject to somatic mutations in thypoid carcinoma.

In many different types of tumors in man and mouse, p53 is the tumor suppressor gene most frequently affected by a combination of somatic mutation and loss of the wildtype allele. In order to develop a molecular tool to study the genetic evolution of tumors in the dog, we have cloned an evolutionary conserved part of the canine homologue of p53. The isolated genomic segment, 534 bp in length, contains the 3' half of exon 5, the complete exon 6 and the 5' half of exon 7, as well as the intronic intervening sequences. The gene organization of this segment shows strong homology to that published earlier for a number of other species, including man, mouse, and Xenopus laevis. This conservation is apparent at the DNA sequence level, as well as at the deduced aminoacid sequence level. mRNA expression can be detected at low levels in normal tissues with increased mitotic activity, and in the Madin-Darby canine kidney cell line. A-->G T transversion was found in 1 out of 23 investigated primary thyroid carcinomas at a position corresponding to codon 174 in the human p53, and was predicted to give rise to an aminoacid substitution in the protein. These results suggest that p53 plays a role in the development of malignancy in the dog, in a way comparable to that in man.

Amino Acid Sequence↗
PubMed1996

Evidence for somatic mutation and affinity maturation of diabetes associated human autoantibodies to glutamate decarboxylase.

The processes that lead to the production of islet cell autoantibodies in insulin-dependent (type 1) diabetes mellitus (IDDM) are largely unknown. Humoral autoimmunity may be the result of an antigen-independent polyclonal B cell activation, or a consequence of an antigen driven B cell activation and selection for the antigen. We have analysed the gene elements encoding the immunoglobulin variable regions of seven human monoclonal islet cell antibodies (MICA) 1-7 directed to the major islet autoantigen glutamate decarboxylase (GAD65). These autoantibodies were derived from two patients with newly diagnosed IDDM. The variable gene regions of the MICA revealed different sequences, and no relation between V gene usage and shared epitope recognition of the MICA was evident. An elevated usage of VH 1, VH 4 and Vlambda 2 gene segments was observed. The underrepresentation of VH 3 family members in the MICA discriminated them from most autoantibodies. The high relative avidities for GAD65 of MICA 1, 3, 4 and 6 and their high, nonrandom ratio of replacement versus silent mutations in the antigen binding regions indicated that the humoral response to GAD65 is driven by the antigen. MICA 2, 5 and 7 showed as well an excess of replacement mutations in the antigen binding regions, but revealed lower relative avidities for their antigen. Since these clones accumulated many somatic mutations in their variable gene regions, they may be characteristic for later stages of the autoimmune disease. The results suggest that, in humans, an antigen driven B cell activation and affinity maturation process may contribute to the production of GAD65-autoantibodies found in patients with IDDM.

Antibodies, Monoclonal↗
PubMed1980

[Caffeine modification of the frequency of ethyleneimine- and ethylmethane sulfonate-induced somatic mutations and mitotic crossing over in Drosophila melanogaster].

Frequencies of somatic mosaics in heterozygous females (w+/w; sn+/sn; y sn/++; t+/+sn) and in hemizygous wild type males was estimated after supplementary action of caffeine on early larvae treated with ethylene imine (EI) or ethylmethanesulfonate (EMS). Frequencies of somatic point mutations induced by both EI and EMS, which have been revealed as single spots (w or sn) in hemizygous males, decrease after supplementary effect of caffeine. Frequencies of somatic mosaics decrease also under the caffeine effect on heterozygous females (w+/w) treated by comparatively low doses of EMS which can induce more probably point mutations than chromosome breaks. Caffeine increases the frequency of somatic mosaics at high doses of EMS, which can produce not only point mutations, but also chromosome breaks. Supplementary effect of caffeine on all genotypes of heterozygous females significantly increases the frequencies of EI induced somatic mosaics (mitotic recombinations and chromosome aberrations).

Animals↗
PubMed1992

Somatic mutations in the neurofibromatosis 1 gene in human tumors.

The neurofibromatosis 1 (NF1) gene product, neurofibromin, contains a GTPase-activating protein (GAP)-related domain, or NF1 GRD, that is able to down-regulate p21ras by stimulating its intrinsic GTPase. Since p21ras.GTP is a major regulator of growth and differentiation, mutant neurofibromins resulting from somatic mutations in the NF1 gene might interfere with ras signaling pathways and contribute to the development of tumors. We describe an amino acid substitution in the NF1 GRD, altering Lys-1423, that has occurred in three tumor types: colon adenocarcinoma, myelodysplastic syndrome, and anaplastic astrocytoma, and in one family with neurofibromatosis 1. The GAP activity of the mutant NF1 GRD is 200- to 400-fold lower than that of wild type, whereas binding affinity is unaffected. Thus, germline mutations in NF1 that cause neurofibromatosis 1 can also occur in somatic cells and contribute to the development of sporadic tumors, including tumors not associated with neurofibromatosis 1.

Adenocarcinoma↗
PubMedDate not supplied

Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma.

Our previous studies of a translocated c-myc gene in the Raji Burkitt's lymphoma cell showed somatic mutations in exons 1 and 2. We have extended these observations to two other translocated c-myc genes and find a common occurrence of mutation in the noncoding exon 1. We also found that in Raji cells, unlike other Burkitt's lymphoma cell lines, the normal allele of the c-myc gene is transcribed as well as the translocated gene. These results support a model in which c-myc oncogene activation in Burkitt's lymphoma occurs by disruption of a normal transcriptional control mechanism in which the c-myc protein is itself involved.

Base Sequence↗
PubMed1994

Persistence of a rheumatoid factor (RF)-producing B cell clone with a somatically mutated Ig kappa chain in a patient with rheumatoid arthritis.

The V kappa IV gene encoding the light chain of an IgA has been shown to have undergone 31 somatic mutations compared with the single existing V kappa IV germ-line gene. We now show the persistence of the rearranged and mutated DNA coding for this RF over a period of 5 years in the peripheral blood lymphocytes (PBL) of the patient with rheumatoid arthritis (RA). The sequence of the RF has been conserved to identity over this period. These results raise the possibility that the particular antigenic stimulus leading to RF production in this RA patient is active over a long period of time.

Arthritis, Rheumatoid↗
PubMed1988

Somatic mutation in peripheral lymphocytes of former workers at the Okunojima poison gas factory.

The former workers at the Okunojima poison gas factory comprise a high risk group for malignant tumors such as respiratory tract cancer. Demonstration of injury to somatic cell genes in this group may provide important data for evaluating the association between mustard gas and malignant tumors. So we measured the frequency of T lymphocytes lacking the hypoxanthine guanine phosphoribosyl transferase (HGPRT) activity, by cloning with interleukin 2 (IL2). In this study, we performed cloning of T lymphocytes lacking the HGPRT activity using recombinant IL2 (rIL2) and observed an increased frequency of somatic mutation in poison gas workers who had had more chances to be exposed to mustard gas and those who had worked for a longer period. This result suggested that inhalation of small amounts of mustard gas damaged somatic cell genes, resulting in carcinogenesis.

Aged↗
PubMed1995

Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenström's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL.

V(D)J recombination and somatic hypermutations are developmentally regulated during B-cell differentiation; therefore, DNA analysis of the Ig gene delineates the cellular origin of B-cell neoplasms. We analyzed the third complementarity-determining region and adjacent regions of the Ig heavy-chain gene of tumor cells from 7 patients with Waldenström's macroglobulinemia (WM) and from 10 patients with B-cell chronic lymphocytic leukemia (CLL), 2 of whom progressed to high-grade non-Hodgkin's lymphoma (NHL), ie, Richter's syndrome (RS). There were no intraclonal variations resulting from VH replacements or ongoing somatic mutations in both WM and CLL. We found replacement mutations in the D and/or JH segments in all patients with WM and in 4 of the 10 patients with CLL, including the 2 RS patients. Replacement mutations were clustered in codon 102 of the JH segment. Preferential utilization of the JH4 gene was found in WM (5 of 7 [71.4%]) and in CLL (7 of 10 [70.0%]), and DXP family genes in CLL (5 of 10 [50.0%]). In conclusion, WM and CLL with RS are generated under the influence of antigenic stimulation and selection. However, the majority of CLL may arise from a distinct subpopulation that has the restricted repertoire of nonmutated Ig genes.

Adult↗