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PubMed2006

Multiple-criterion evaluation of reported mutations: a proposed scoring system for the intragenic somatic mutation literature.

In an accompanying paper, we review the theoretical principles of tumor mutations and the observed patterns of mutations in the cancer literature. These patterns are discussed in the context of a perceived dichotomy in quality that exists among mutation reports. Due to the frequency of mis-reporting, a systematic approach to the somatic mutation literature in human cancer is needed. We propose a multiple-criterion numerical tool, referred to as the scoring SISTM (System for Intragenic Somatic Tumor Mutations), which effectively discriminates promising and unpromising somatic mutation reports in human cancer. Reports are assessed on 12 criteria, and are given a final score of 15 or less. Scores in the range of 10 to 15 are suggestive of well-presented reports of disease-inducing somatic mutations. Reports with scores less than 10 should be viewed with skepticism.

Biomarkers, Tumor↗

PubMed2001

[Proto-oncogene RET somatic mutations in medullary thyroid carcinoma].

UNLABELLED: Somatic mutations of the RET protooncogene are present in 23-68% cases of sporadic medullary thyroid carcinoma (MTC). The aim of the study was to introduce the RET somatic mutations analysis in tumor tissue as well as to evaluate their types and frequencies in postoperative specimens of MTC patients treated in the Center of Oncology in Gliwice. MATERIAL: 14 tumor tissues obtained from sporadic MTC patients and two control groups--six and four specimens from patients with MEN 2A and MEN 2B syndrome respectively. METHODS: Tumor tissue DNA isolation followed by PCR amplification of RET exons 10, 11, 13, 14, 16 and automated, fluorescent sequencing of PCR products. We identified somatic mutation ATG > ACG in codon 918, exon 16 in 7 of 14 (50%) of analyzed sporadic MTC cases. We also found one deletion/insertion mutation in RET exon 11 that encompasses cysteine codon 634 and has not been published so far. The types and frequencies of found RET gene mutations were similar to previously reported. The analysis of RET somatic mutations supports the differentiation between the sporadic and inherited MTC. The presence of somatic mutation and its simultaneous absence in the germline proves sporadic type of cancer.

Carcinoma, Medullary↗

PubMed1994

Kinetics of somatic mutation in lymph node germinal centres.

Somatic mutation activity in immunoglobulin V kappa genes during the response to the hapten 2-phenyl-5-oxazolone was measured in lymph node B-cell populations at various timepoints after footpad immunization. When the V kappa Ox1 genes rearranged to the J kappa 5 segment were amplified from genomic DNA using the polymerase chain reaction and sequenced, somatic mutations could be detected as early as day 4 after immunization. Somatic mutations were also detected after sequencing RNA from oxazolone-specific hybridomas derived from lymph node cells at day 4 after immunization. These early mutations were found mostly in cells with a germinal centre phenotype. No indication of selection at the population level by apoptosis was detected until day 7 after immunization. These results suggest somatic mutations can be induced very early during the immune response in lymph node cells, prior to the peak of clonal expansion and selection with regard to antigen binding.

Animals↗

PubMed1987

Patterns of somatic mutations in immunoglobulin variable genes.

The mechanism responsible for somatic mutation in the variable genes of antibodies is unknown and may differ from previously described mechanisms that produce mutation in DNA. We have analyzed 421 somatic mutations from the rearranged immunoglobulin variable genes of mice to determine if the nucleotide substitutions differ from those generated during meiosis and if the presence of nearby direct and inverted repeated sequences could template mutations around the variable gene. The results reveal a difference in the pattern of substitutions obtained from somatic mutations vs. meiotic mutations. An increased frequency of T:A to C:G transitions and a decreased frequency of mutations involving a G in the somatic mutants compared to the meiotic mutants is indicated. This suggests that the mutational processes responsible for somatic mutations in antibody genes differs from that responsible for mutation during meiosis. An analysis of the local DNA sequences revealed many direct repeats and palindromic sequences that were capable of templating some of the known mutations. Although additional factors may be involved in targeting mutations to the variable gene, mistemplating by nearby repeats may provide a mechanism for the enhancement of somatic mutation.

Animals↗

PubMed2001

Somatic mutation rate of the APC gene.

BACKGROUND: Somatic inactivation of the wild-type APC gene is involved in the development of adenoma of familial adenomatous polyposis. This situation is also true in sporadic adenomas. It is of biological interest to know the somatic mutation rate of the APC gene. METHODS: The number of stem cells of the colon (N) and somatic mutation rate of the APC gene in a stem cell in a year (m) can induce age-specific incidence of adenomas. The number of stem cells was estimated as 10(8) according to previous reports. In the general population, expected adenomas at the end of age n years will be approximately Nm2n2/4. In patients with polyposis, the expected number of adenomas will be Nmn/2. By setting several figures for m, the expected incidence of adenomas was compared with the actual occurrences. RESULTS: If the mutation rate was set between 2/10(6) and 3/10(6) mutations/stem cell/year, the calculated numbers were well fitted to the actual data. Expected adenomas in polyposis patients at the age of 20 and 40 years were 2000 and 4000 and these were within actual experiences. CONCLUSIONS: This is the first study to estimate the somatic mutation rate of the APC gene. The estimated somatic mutation rate of the APC gene was between 2/10(6) and 3/10(6) mutations/stem cell/year.

Adenoma↗

PubMed2005

Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes.

Somatic mutations have a role in the pathogenesis of a number of diseases, particularly cancers. Here we present data supporting a role of mitochondrial somatic mutations in an autoimmune disease, rheumatoid arthritis (RA). RA is a complex, multifactorial disease with a number of predisposition traits, including major histocompatibility complex (MHC) type and early bacterial infection in the joint. Somatic mutations in mitochondrial peptides displayed by MHCs may be recognized as non-self, furthering the destructive immune infiltration of the RA joint. Because many bacterial proteins have mitochondrial homologues, the immune system may be primed against these altered peptides if they mimic bacterial homologues. In addition, somatic mutations may be influencing cellular function, aiding in the acquirement of transformed properties of RA synoviocytes. To test the hypothesis that mutations in mitochondrial DNA (mtDNA) are associated with RA, we focused on the MT-ND1 gene for mitochondrially encoded NADH dehydrogenase 1 (subunit one of complex I - NADH dehydrogenase) of synoviocyte mitochondria from RA patients, using tissue from osteoarthritis (OA) patients for controls. We identified the mutational burden and amino acid changes in potential epitope regions in the two patient groups. RA synoviocyte mtDNA had about twice the number of mutations as the OA group. Furthermore, some of these changes had resulted in potential non-self MHC peptide epitopes. These results provide evidence for a new role for somatic mutations in mtDNA in RA and predict a role in other diseases.

Arthritis, Rheumatoid↗

PubMed1977

Validation of the in vivo somatic mutation method in the mouse as a prescreen for germinal point mutations.

The in-vivo somatic mutation method developed by us in an earlier X-ray experiment was tested for its usefulness in chemical mutagenesis work, specifically in the prescreening for germinal point mutations. In order to explore possible parallelisms, the 7 compounds chosen for study, as well as the genetic markers used, were those with which large-scale specific-locus mutation-rate experiments in germcells had been conducted in the past or were in progress. From 1--3 dose levels were tested for each compound. On day 10 1/4 after copulation of C57BL females with T males, a single injection of the test compound was administered, and about 2000 offspring altogether were subsequently scored for survival, morphology, and presence of spots of various types. In accordance with our earlier results we found 3 types of spots: white near midline ventral spots (WMVS) which probably result from killing of melanocyte precursor cells; spots resulting from misdifferentiation; and the remainder, which probably result from expression of the recessive by one of several mechanisms (RS). Induction of teratogenic effects, which were stage-specific rather than agent-specific, generally paralleled induction of WMVS's. Both are interpreted as resulting from cell killing. Induction of RS's did not always parallel induction of WMVS's, but roughly paralleled relative frequencies of specific-locus mutations induced in spermatogonia by the same compounds. Even though the in vivo somatic-mutation method probably detects genetic changes additional to point mutations, the results indicate that it may be a useful prescreen for germinal specific-locus mutations, provided care is taken to distinguish between the 3 types of spots, only one of which (RS) is indicative of expression of the recessive.

Animals↗

PubMed2002

The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage.

Few data exist on somatic mutation in the epithelial cell lineages that play a central role in human biology and disease. To delineate the "landscape" of somatic mutation in a human epithelial cell lineage, we determined the frequency and molecular nature of somatic mutations occurring in vivo in the X-linked HPRT gene of kidney tubular epithelial cells. Kidney epithelial mutants were frequent (range 0.5 to 4.2 x 10(-4)) and contained a high proportion of unreported HPRT base substitutions, -1-bp deletions and multiple mutations. This spectrum of somatic mutation differed from HPRT mutations identified in human peripheral blood T lymphocytes and from germ-line HPRT mutations identified in Lesch-Nyhan syndrome or hyperuricemia patients. Our results indicate that DNA damage and mutagenesis may have unusual or mechanistically interesting features in kidney tubular epithelium, and that somatic mutation may play a more important role in human kidney disease than has been previously appreciated.

Cells, Cultured↗

PubMed1992

Somatic mutations at CA-repeat loci.

We found somatic mutations, detected as novel PCR bands, at three separate polymorphic CA-repeat loci. At one of these loci, analyzed in a three-generation pedigree, a new band generated from the same paternal allele was observed in four of six offspring. The other two children inherited the alternative paternal allele unchanged. Somatic mutations at two additional loci were identified upon subsequent comparison of banding patterns among 25 cancers and their corresponding normal tissues at 15 CA-repeat loci. Since somatic mutations of CA-repeats seem to be quite frequent, individuals who are mosaic for CA-repeat alleles at a particular locus probably are not unusual. Hence, the possibility of somatic mutation generating new length alleles at CA-repeat loci should be considered when one compares DNA samples, whether in forensic and paternity testing, loss of heterozygosity studies, or linkage analyses.

Alleles↗

PubMed2003

A highly sensitive detection method for somatic mutations in p53 gene.

A simple and highly sensitive detection method for somatic mutations, which is applicable to diagnostic samples is developed. This method detects somatic mutations that are lower than several percent in abundance. The unique feature with this method is that single-nucleotide primer extension is carried out in the absence of dye terminators that carry respective bases in the wild type gene. Data of mutation sites and bases in the target genes are obtained from databases. Primers of different nucleotide length are designed so that electrophoreses of the single-nucleotide primer extension products allow identification of respective mutations. Based on somatic mutation data in IARC TP53 mutation database, this method was applied to p53 somatic mutations. Results showed that extension reactions in 5 separate tubes allowed detection of mutations in human p53 gene for the most frequent 12 mutations in a nucleotide sequence of 14,049-14,522, which cover hot spot regions in exons 7 and 8. Confirming these results, reported mutations of p53 in human culture cells, MiaPaCa2, TE-6, RPMI8226, DLD1, and PC-3 are detected at 5% relative abundance in the sample DNA.

DNA Mutational Analysis↗

PubMed1997

Somatic mutation of the glucose-6-phosphate dehydrogenase (g6pd) gene in colonic stem cells and crypt restricted loss of G6PD activity.

The study of somatic mutation frequency, particularly stem cell somatic mutation, is important to the understanding of mechanisms of carcinogenesis. The models currently in use for studies in stem cell tissues such as the colon infer the presence of stem cell somatic mutation from alteration in enzyme function, when this has shown to be mutagen dose dependent, restricted to the unit of clonal architecture, and persistent. The present study identifies and characterises somatic mutations in the g6pd gene in individual mouse colonic crypts showing histochemically demonstrable loss of G6PD activity. Microdissection of single crypts, showing either normal or low G6PD activity by histochemistry was performed in mice treated with ethylnitrosourea (ENU), and the presence of point mutations sought by PCR and direct sequencing. Because of the limitation of the small amount of partially degraded (due to fixation) DNA available from each crypt, only about 20% of the coding region of the g6pd gene could be sequenced. Despite this, somatic mutations were identified in 3 of the 9 crypts analysed which showed loss of G6PD activity, but in none of the crypts with normal activity. Each of the mutations identified would be predicted to lead to a decrease in enzyme activity. We conclude that we have confirmed that the crypt restricted loss of G6PD activity is indeed due to stem cell somatic mutation in the g6pd gene, and suggest that the G6PD model can be used as a paradigm for other models where somatic mutation is inferred from a change in histochemically identifiable gene expression.

Animals↗

PubMed1992

Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene.

We examined somatic mutations of the adenomatous polyposis coli (APC) gene in 63 colorectal tumors (16 adenomas and 47 carcinomas) developed in familial adenomatous polyposis (FAP) and non-FAP patients. In addition to loss of heterozygosity (LOH) at the APC locus in 30 tumors, 43 other somatic mutations were detected. Twenty-one of them were point mutations; 16 nonsense and two missense mutations, and three occurred in introns at the splicing site. Twenty-two tumors had frameshift mutations due to deletion or insertion; nineteen of them were deletions of one to 31 bp and three were a 1-bp insertion. One tumor had a 1-bp deletion in an intron near the splicing site. Hence, 41 (95%) of 43 mutations resulted in truncation of the APC protein. Over 60% of the somatic mutations in the APC gene were clustered within a small region of exon 15, designated as MCR (mutation cluster region), which accounted for less than 10% of the coding region. Combining these data and the results of LOH, more than 80% of tumors (14 adenomas and 39 carcinomas) had at least one mutation in the APC gene, of which more than 60% (9 adenomas and 23 carcinomas) had two mutations. These results strongly suggest that somatic mutations of the APC gene are associated with development of a great majority of colorectal tumors.

Adenoma↗

PubMed1998

Harmful somatic mutations: lessons from the dark side.

The ability of somatic mutation to modify the course of an immune response is well documented. However, emphasis has been placed almost exclusively on the ability of somatic mutation to improve the functional characteristics of representative antibodies. The harmful effects of somatic mutation, its dark side, have been far less well characterized. Yet evidence suggests that the number of B cells directed to wastage pathways as a result of harmful somatic mutation probably far exceeds the number of cells whose antibodies have been improved. Here we review our recent findings in understanding the structural and functional consequences of V-region mutation.

Animals↗

PubMed2005

Somatic mutations of epidermal growth factor receptor in colorectal carcinoma.

PURPOSE: Somatic mutations of the epidermal growth factor receptor (EGFR) gene may predict the sensitivity of non-small cell lung carcinoma to gefitinib. However, no mutations have been reported for colorectal carcinoma. We therefore analyzed EGFR mutations in colorectal adenocarcinomas by the combined use of laser microdissection and sequencing of genomic DNA. EXPERIMENTAL DESIGN: We examined 11 representative colorectal adenocarcinoma cell lines and 33 clinical samples of colorectal carcinoma. In the clinical cases, we carefully dissected only carcinoma cells from frozen sections by laser microdissection. After DNA extraction and PCR, we examined EGFR mutations by sequencing genomic DNA. RESULTS: None of 11 colorectal carcinoma cell lines exhibited somatic mutations, but 4 of 33 clinical tumors (12%) exhibited mutations in the EGFR kinase domain. This may be the first report of somatic mutations in colorectal adenocarcinoma. CONCLUSIONS: Our findings suggest that a distinct minority of colorectal adenocarcinomas exhibit somatic mutations of EGFR, and these tumors may be susceptible to gefitinib treatment.

Base Sequence↗

PubMed2004

Somatic mutations of KIT in familial testicular germ cell tumours.

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

DNA Mutational Analysis↗

PubMed2002

Systemic lupus erythematosus patients under immunosuppressive treatment express high levels of the immunoglobulin lambda variable IGLV8S1 gene with silent somatic mutations.

Systemic lupus erythematosus (SLE) patients express high titers of somatically mutated serum autoantibodies against nuclear structures including double-stranded DNA. These somatic mutations accumulate codons for basic amino acids in the immunoglobulin variable regions of both, heavy and light chains, facilitating binding to nucleic acids. The variable (V) immunoglobulin lambda 8 (IGLV8S1) gene contributes to autoreactive B-cell repertoire of auto-immune patients. Accumulation of immune complexes of these anti-DNA autoantibodies causes severe systemic inflammation in SLE. The current treatment of lupus disease is based on immunosuppressive drugs, but the precise role for this therapy remains to be defined. To evaluate the in vivo effect of combined immunosuppressive treatment on B-lymphocytes repertoire of SLE patients, we have developed an approach using the IGLV8S1 gene as a marker. The transcription of this gene in treated SLE patients was increased. However, we observed a trend, in these patients, to conserve complementarity determining regions (CDRs) and framework regions (FRs) of Vlambda8 polypeptide light chain deduced sequence, from its germline counterpart. Sequencing IGLV8S1 cDNA of untreated SLE patients, taken as a control for treatment effect, displayed a decreased frequency of silent somatic mutations (consequently high frequency of replacement mutations) in the Vlambda8 polypeptide chain deduced sequence. These data suggest that the immunosuppressive drug treatment modulates the positive selection of somatically mutated Vlambda8 light chain.

Adult↗

PubMed1994

Comparison of somatic mutation frequency among immunoglobulin genes.

We analyzed the frequency of somatic mutation in immunoglobulin genes from hybridomas that secrete anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) monoclonal antibodies. A high frequency of mutation (3.3-4.4%) was observed in both the rearranged VH186.2 and V lambda 1 genes, indicating that somatic mutation occurs with similar frequency in these genes in spite of the absence of an intron enhancer in lambda 1 chain genes. In contrast to the high frequency in J-C introns, only two nucleotide substitutions occurred at positions -462 and -555 in the 5' noncoding region in one of the lambda 1-chain genes and in none of the other three so far studied. Since a similar low frequency of somatic mutation was observed in the 5' noncoding region of inactive lambda 2-chain genes rendered inactive because of incorrect rearrangement, this region may not be a target or alternatively, may be protected from the mutator system. We observed a low frequency of nucleotide substitution in unrearranged V lambda 1 genes (approximately 1/15 that of rearranged genes). Together with previous results (Azuma T., N. Motoyama, L. Fields, and D. Loh, 1993. Int. Immunol. 5:121), these findings suggest that the 5' noncoding region, which contains the promoter element, provides a signal for the somatic mutator system and that rearrangement, which brings the promoter into close proximity to the enhancer element, should increase mutation efficiency.

Animals↗

PubMed1998

Somatic mutation and aging.

A key prediction of the somatic mutation theory of aging is that there is an invariant relationship between life span and the number of random mutations. A number of studies at a number of gene loci have shown that somatic mutations of a variety of types accumulate with age. Dietary restriction, which prolongs life span, results in slowed accumulation of HPRT mutants in mice. Conversely, senescence-accelerated mice, which have been bred to have a shortened life span, show accelerated accumulation of somatic mutations.

Aging↗