Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Somatic mutation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources
PubMed2005

Somatic mutations of the protein kinase gene family in human lung cancer.

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.

Adenocarcinoma↗
PubMed1993

Somatic mutations in c-myc intron I cluster in discrete domains that define protein binding sequences.

The activated c-myc allele in Burkitt's lymphoma tumor cells is associated with a clustering of somatic mutations within intron I near the exon I boundary. We have identified several discrete protein binding sites within this region of c-myc intron I designated as myc intron factor-1 (MIF-1), MIF-2, and MIF-3. In addition to our previous characterization of a 20-nucleotide binding site for MIF-1, we now have identified adjacent 20-nucleotide and 34-nucleotide binding sites for MIF-2 and MIF-3, respectively. All three elements are protected from exonuclease digestion by nuclear protein extracts, and each gives rise to a distinct migration pattern on mobility shift assays. In addition, MIF-1, 2, and 3 share a 5-nucleotide (TTATG) internal sequence, which may account for cross-competition of these binding sites in the exonuclease protection experiment. Deletion mutant analyses showed that selective removal of the MIF-3 binding site alone was sufficient to enhance chloramphenicol acetyltransferase reporter activity similar to that observed with larger deletions of myc intron I. We have demonstrated that somatic mutations in activated c-myc alleles are frequently clustered in discrete domains that define protein recognition sequences.

Base Composition↗
PubMedDate not supplied

[Heterozygosity loss and somatic mutations in type I and II dominant autosomal renal polycystic kidney disease: evidence of a recessive mechanism at a cell level in cystogenesis].

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder mainly characterized by renal cyst formation. Cysts in ADPKD are focal in nature, since only a small fraction of nephrons become cystic. The hypothesis that a second hit may be required for cyst formation has been proposed. This hypothesis suggests that inactivation of the inherited wild-type allele by a somatic mutation triggers cyst formation. In some cases, this second hit eliminates the normal allele and the affected cells remain with a single allele, which is the inherited mutated copy, and we only visualize one allele after the amplification by polymerase chain reaction; this is called loss of heterozygosity (LOH). In this study we have analysed the DNA isolated from epitehlial cells from 164 cysts of 8 kidneys affected by ADPKD type I and 30 cysts form a kidney affected by ADPKD type II. We have demonstrated the presence of LOH in 20.1% of PKD1 cysts and in 10% of PKD2 cysts. We have also found eight other different mutations in PKD2 cysts without LOH; so the percentage of somatic mutations in the PKD2 kidney reaches 36.6% of cysts. In conclusion, our data suggest that a recessive mechanism at the cellular level is implicated in cyst formation in the PKD1 and the PKD2 disease. The loss of both copies of the gene triggers the proliferation of a single cell, resulting in the cyst formation.

Chromosomes, Human, Pair 16↗
PubMed1997

Somatic mutation of the MEN1 gene in parathyroid tumours.

Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 0.5 in 1,000 (ref. 1). In more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal, suggesting that one important step in tumour development is a mutation in a progenitor cell. Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene. We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10). We have studied parathyroid tumours not associated with MEN1 to determine whether somatic mutations in the MEN1 gene are present. Among 33 tumours we found somatic MEN1 gene mutation in 7, while the corresponding MEN1 germline sequence was normal in each patient. All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele. Thus, somatic MEN1 gene mutation for the mutant allele. Thus, somatic MEN1 gene mutation contributes to tumorigenesis in a substantial number of parathyroid tumours not associated with the MEN1 syndrome.

Chromosomes, Human, Pair 11↗
PubMed2002

Genetic analysis of de novo CD5+ diffuse large B-cell lymphomas suggests an origin from a somatically mutated CD5+ progenitor B cell.

CD5(+) diffuse large B-cell lymphomas (DLBLs) have recently been described as a particular subgroup of DLBLs. Classical banding and interphase cytogenetic analyses targeting ATM, TP53, and P16(INK4a) genes and the D13S25 locus from 13 CD5(+) DLBLs were compared with 55 CD5(-) DLBLs. Additionally, analysis of somatic mutations of the immunoglobulin heavy chain variable region (IgVH) genes were performed in CD5(+) DLBLs. CD5(+) DLBLs were somatically mutated (7 of 8 cases) and were negative for t(11;14)(q13;q32) and t(14;18)(q32;q21), whereas t(3;14)(q27;q32) was found in only one tumor. Trisomy 3 and gains on chromosomes 16/16p and 18/18q were significantly overrepresented in CD5(+) DLBLs. No ATM deletions were detected. The prevalence of deletions at the D13S25 locus was significantly higher in CD5(+) DLBLs (4 of 12 [33%]) compared with CD5(-) DLBLs (4 of 42 [10%]), as were p16(INK4a) deletions (33% versus 8%). On the basis of these findings, CD5(+) DLBLs are likely to arise from the same progenitor cell as the mutated variant of CD5(+) lymphocytic lymphoma/B-cell chronic lymphocytic leukemia (B-CLL).

B-Lymphocytes↗
PubMed2001

Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin's lymphoma.

Tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 (TRAIL-R1) and tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) are cell-surface receptors involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell-death signaling. TRAIL-R1 and TRAIL-R2 genes have recently been mapped to chromosome 8p21-22, which is a frequent site of allelic deletions in many types of human tumors, including non-Hodgkin's lymphoma (NHL). Because TRAIL/TRAIL receptor system plays an important role in lymphocyte homeostasis, we hypothesized that the mutations of TRAIL-R1 and TRAIL-R2 may be involved in the development of NHL and that such mutations may be responsible for the allelic losses of 8p21-22 in NHL. In this study, we analysed the entire coding region of TRAIL-R2 gene and the death domain region of TRAIL-R1 gene for the detection of the somatic mutations in a series of 117 human NHLs using polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) analysis. Overall, eight tumors (6.8%) were found to have two TRAIL-R1 gene mutations or six TRAIL-R2 gene mutations. Interestingly, of the eight mutations, six missense mutations (two TRAIL-R1 and four TRAIL-R2) were detected in the death domains and one nonsense mutation of TRAIL-R2 was detected just before the death domain. Our data suggest that somatic mutations of TRAIL-R1 and TRAIL-R2 genes may play a role in the pathogenesis of some NHLs and that TRAIL-R1 and TRAIL-R2 genes might be the relevant genes to the frequent loss of chromosome 8p21-22 in human NHL.

Humans↗
PubMed1992

Germinal and somatic mutation induction in Drosophila after treatment of larvae with tritiated water.

The present study was carried out to evaluate the mutagenicity of tritium, administered as tritiated water, in Drosophila melanogaster. Larvae were fed on tritium-treated medium during their development. Germinal and somatic mutation induction was detected by means of the sex-linked recessive lethal and the wing spot tests, respectively. Our results show that beta-radiation from tritium is able to induce significant increases in the frequency of both germinal and somatic mutations.

Animals↗
PubMed1993

The majority of human tonsillar CD5+ B cells express somatically mutated V kappa 4 genes.

We have fractionated human tonsillar B cells on the basis of CD5 expression and determined the nucleotide sequences of immunoglobin light chain variable (V) regions encoded by the single member of the V chi 4 gene family in both CD5+ and CD5- populations. The majority of cDNA from both CD5+ and CD5- B cells populations harbored somatic mutations. Thus, human tonsillar CD5+ B cells, unlike their murine counterparts, are capable of activating their somatic hypermutation mechanism, resulting in the accumulation of somatic mutation in the VL regions.

Amino Acid Sequence↗
PubMed1984

Somatic mutation creates diversity in the major group of mouse immunoglobulin kappa light chains.

Using a cloned cDNA of a mouse immunoglobulin kappa light chain synthesized in a myeloma MOPC321 (V kappa-21 subgroup C) as a probe we could detect 13 germ line V kappa gene segments. 11 of these were isolated. Using a set of overlapping cloned segments, we showed that nine of these germ line V kappa genes are arranged in two linkage clusters and that they all have the same transcriptional orientation (11, 12, 22). These two clusters occupy 90 and 30 kb of chromosomal DNA and contain six and three V kappa's, respectively. We determined the complete nucleotide sequences of five germ line V kappa's and showed that three of them encode the prototype sequence of V kappa-21 subgroups B, C, and E. None of these five germ line V kappa's encodes the variant amino acid sequences of known V kappa-21 subgroups. We thus conclude that, as in the lambda 1 light chains, the variant V regions are encoded by gene segments derived by a few somatic mutations from the corresponding germ line DNA. Such somatic mutations are not restricted to sequences encoding the hypervariable regions: they also occur in sequences encoding framework regions.

Amino Acid Sequence↗
PubMed2006

Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human cancers.

Tyrosine kinases are major regulators of signal transduction cascades involved in cellular proliferation and have important roles in tumorigenesis. We have recently analyzed the tyrosine kinase gene family for alterations in human colorectal cancers and identified somatic mutations in seven members of this gene family. In this study we have used high-throughput sequencing approaches to further evaluate this subset of genes for genetic alterations in other human tumors. We identified somatic mutations in GUCY2F, EPHA3, and NTRK3 in breast, lung, and pancreatic cancers. Our results implicate these tyrosine kinase genes in the pathogenesis of other tumor types and suggest that they may be useful targets for diagnostic and therapeutic intervention in selected patients.

Adenocarcinoma↗
PubMed1998

Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors.

Germ-line mutations in a serine/threonine kinase gene, LKB1, were recently shown to underlie Peutz-Jeghers syndrome (PJS), a hereditary disorder that predisposes to benign and malignant tumors of multiple organ systems. Most mutations that have been described thus far dramatically change the predicted protein and are likely to be of an inactivating nature. This observation and a previous observation that the LKB1 locus is often deleted in PJS polyps suggest that the gene may function as a tumor suppressor. We examined whether somatic mutations in this gene are present in sporadic carcinomas of the colon and testis, tumors that are characteristic of PJS. First, 20 randomly selected colorectal and 28 testicular tumors were analyzed by single-strand conformation polymorphism analysis. No mutations in LKB1 were found in colorectal tumors. One testicular tumor displayed a heterozygous missense type variant, in which glycine 163 was changed to aspartic acid. This change was absent in the DNA of normal tissue. To better focus our efforts, we tested 75 additional colon carcinomas for loss of heterozygosity at 19p, where LKB1 is localized. Of 75 samples analyzed, 50 were informative with a closely linked marker, D19S886, and 13 (26%) of these displayed loss of heterozygosity. The 13 tumors were scrutinized for LKB1 mutations by genomic sequencing. This analysis revealed no changes. Together, these findings suggest that somatic mutations of LKB1 are not frequent in colorectal and testicular cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed2001

Somatic mutations in MEN type 1 tumors, consistent with the Knudson "two-hit" hypothesis.

MEN type 1 is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroids, anterior pituitary, and pancreatic islet cells. The MEN1 gene, which is located on chromosome 11q13, consists of 10 exons and encodes a 610-amino acid protein named MENIN. The observation of LOH involving 11q13 in MEN type 1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the "two-hit" model of hereditary cancer. The second hit in MEN type 1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur, and the other mechanisms, such as intragenic deletions or point mutations that inactivate the gene, have not been reported in MEN type 1 tumors. We have therefore undertaken studies to search for such mutations in six MEN type 1 tumors (four parathyroid tumors, one insulinoma, and one lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883 and PYGM centromerically and D11S449 and D11S913 telomerically. This revealed four somatic mutations, which consisted of two missense mutations and two frameshift mutations in two parathyroid tumors, one insulinoma, and one lipoma. Thus, our results, which represent the first small intragenic somatic mutations reported in MEN type 1 tumors, provide further evidence that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by Knudson's "two-hit" hypothesis.

Adult↗
PubMed2001

Somatic mutations in the death domain of the Fas (Apo-1/CD95) gene in gastric cancer.

It is now believed that genes regulating apoptosis are also important variables in cancer development. Fas, a transmembrane protein of the tumour necrosis factor receptor family, is a key molecule for cell death signalling. The mutation of the primary structure of the Fas gene might also be one of the possible mechanisms that disrupt Fas-mediated apoptosis in tumour cells. The purpose of this study was to determine whether somatic mutation of the Fas gene could be involved in the tumourigenesis of gastric cancer. Polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) analysis with two intragenic polymorphic markers, and mutation analysis for the entire coding regions of the Fas gene were performed in 43 cases of gastric cancer, using PCR-single-strand conformational polymorphism sequencing. Five (11.6%) missense mutations were detected, only in the death domain of the Fas gene. Although these mutations were observed only in intestinal-type gastric cancers, there was no statistically significant difference in the frequency of Fas mutation between intestinal- and diffuse-type gastric cancer (p=0.068). Nine LOH out of 22 informative cases were also detected with one or both markers (41%). Three of them demonstrated a somatic mutation in the remaining allele, indicating the inactivation of both alleles. These results suggest that genetic alterations of the Fas gene may not only be limited to gastric cancer cell protection through Fas resistance, but may also play an important role in tumour promotion and/or progression in a subset of gastric cancer.

Adenocarcinoma↗
PubMed1991

Characterization of somatically mutated S107 VH11-encoded anti-DNA autoantibodies derived from autoimmune (NZB x NZW)F1 mice.

We have studied 19 S107 heavy chain variable region gene (VH11)-encoded monoclonal antibodies from NZBWF1 mice. These studies show that a single VH gene can encode both antibodies to foreign antigens (anti-phosphorylcholine) and to self antigens (anti-double-stranded DNA) in the same animal. All of the anti-DNA antibodies contain many somatic mutations compared with the relevant germline genes. Since the anti-DNA antibodies were extensively somatically mutated and had undergone isotype switching, the response seems to be T cell dependent. While some of the antibodies appear to be the products of an antigen-driven and antigen-selected response, a number of characteristics of the antibodies suggest that forces other than antigen are contributing to the stimulation and selection of this response.

Amino Acid Sequence↗
PubMed1997

Intragenic Tsc2 somatic mutations as Knudson's second hit in spontaneous and chemically induced renal carcinomas in the Eker rat model.

We searched for the rat homologue of the human tuberous sclerosis (TSC2) gene mutations in loss of heterozygosity (LOH)-negative Eker rat renal carcinomas (RCs) by polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis using 45 primer sets covering all 41 coding exons and one leader exon including splicing donor/acceptor sites. We have identified intragenic somatic mutations in 7 of 21 spontaneous RCs, including one cell line (33%), and in 3 of 9 (33%) N-ethyl-N-nitrosourea (ENU)-induced LOH-negative RCs. Interestingly, five mutations in the spontaneous RCs were either deletion or duplication (5/7 = 71%). In contrast, all three in ENU-induced RCs were base substitutions (3/3 = 100%), as expected. Thus, a qualitative difference in the second hit might exist between spontaneous and ENU-induced mutations (e.g., deletion or duplication versus point mutation). By a direct cloning approach utilizing the restriction length difference caused by germline insertional mutation or reverse transcriptase-PCR analysis in two applicable cases, we could clearly show the presence of intragenic somatic mutations in the second copy (wild-type) of the Tsc2 gene. This is the first demonstration at the DNA sequence level of the validity of Knudson's two-hits hypothesis in the Tsc2 gene.

Alleles↗
PubMed2001

BCL10 somatic mutations rarely occur in gastric lymphoma: detection of high frequency of polymorphisms in BCL10 coding region.

The BCL10 gene, recently isolated due to its involvement in the t(1;14)(p22;q32) of mucosa-associated lymphoid tissue B cell non-Hodgkin lymphoma (MALToma), was shown to have frequent somatic mutations and short deletions within the coding region in MALToma and a variety of other lymphomas and solid tumors. These observations have been recently questioned. In this study, we examined BCL10 gene mutations by direct sequencing of the entire coding region of the BCL10 gene, amplified from paired normal and tumor genomic DNAs, as well as tumor cDNAs, in 23 cases of primary gastric B cell non-Hodgkin lymphomas, comprising of 6 cases of MALToma and 17 cases of diffuse large cell (DLC) lymphoma. Heterozygosity due to three types of known polymorphisms in codon 5 (17.3%), codon 8 (21.7%), and codon 213 (8.6%) were observed in both normal germline DNA and tumor DNAs and tumor cDNAs in individual cases. In one case (4.3%) G/C heterozygosity in codon 8 in normal germline DNA was reduced to homozygosity (LOH) in tumor DNA and cDNA. Mutations inactivating BCL10 gene product function were not found in any of these cases. Moreover, post-transcriptional alterations were not indicated by abnormalities in BCL10 mRNA sequence in tumor cDNAs in these gastric lymphoma cases. Our results show that somatic mutations in the BCL10 gene rarely occur in gastric lymphoma and indicate that this gene is unlikely to be of pathogenetic significance in the majority of gastric lymphomas.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Somatic mutations and single nucleotide polymorphisms of base excision repair genes involved in the repair of 8-hydroxyguanine in damaged DNA.

To elucidate the involvement of 8-hydroxyguanine (oh(8)G) repair genes in human lung carcinogenesis, 47 lung cancer cell lines and 55 primary lung cancers were examined for somatic mutations and genetic polymorphisms in all coding exons of the MYH and APEX genes, and exon 8 of the OGG1 gene by polymerase chain reaction-single strand conformation polymorphism analysis. In the MYH gene, one missense mutation was detected in a cell line, NCI-H157, whereas no mutations were detected in primary cancers. There were no mutations in the APEX and OGG1 genes in the cell lines or primary cancers. Ten single nucleotide polymorphisms (SNPs) were identified, and seven of them were accompanied by amino acid substitutions. Differences in the oh(8)G repair activities of MYH, APEX and OGG1 proteins due to somatic mutations and SNPs can be involved in human carcinogenesis.

Carbon-Oxygen Lyases↗
PubMed2000

Aneuploidy, the somatic mutation that makes cancer a species of its own.

The many complex phenotypes of cancer have all been attributed to "somatic mutation." These phenotypes include anaplasia, autonomous growth, metastasis, abnormal cell morphology, DNA indices ranging from 0.5 to over 2, clonal origin but unstable and non-clonal karyotypes and phenotypes, abnormal centrosome numbers, immortality in vitro and in transplantation, spontaneous progression of malignancy, as well as the exceedingly slow kinetics from carcinogen to carcinogenesis of many months to decades. However, it has yet to be determined whether this mutation is aneuploidy, an abnormal number of chromosomes, or gene mutation. A century ago, Boveri proposed cancer is caused by aneuploidy, because it correlates with cancer and because it generates "pathological" phenotypes in sea urchins. But half a century later, when cancers were found to be non-clonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer although, (1) many carcinogens do not mutate genes, (2) there is no functional proof that mutant genes cause cancer, and (3) mutation is fast but carcinogenesis is exceedingly slow. Intrigued by the enormous mutagenic potential of aneuploidy, we undertook biochemical and biological analyses of aneuploidy and gene mutation, which show that aneuploidy is probably the only mutation that can explain all aspects of carcinogenesis. On this basis we can now offer a coherent two-stage mechanism of carcinogenesis. In stage one, carcinogens cause aneuploidy, either by fragmenting chromosomes or by damaging the spindle apparatus. In stage two, ever new and eventually tumorigenic karyotypes evolve autocatalytically because aneuploidy destabilizes the karyotype, ie. causes genetic instability. Thus, cancer cells derive their unique and complex phenotypes from random chromosome number mutation, a process that is similar to regrouping assembly lines of a car factory and is analogous to speciation. The slow kinetics of carcinogenesis reflects the low probability of generating by random chromosome reassortments a karyotype that surpasses the viability of a normal cell, similar again to natural speciation. There is correlative and functional proof of principle: (1) solid cancers are aneuploid; (2) genotoxic and non-genotoxic carcinogens cause aneuploidy; (3) the biochemical phenotypes of cells are severely altered by aneuploidy affecting the dosage of thousands of genes, but are virtually un-altered by mutations of known hypothetical oncogenes and tumor suppressor genes; (4) aneuploidy immortalizes cells; (5) non-cancerous aneuploidy generates abnormal phenotypes in all species tested, e.g., Down syndrome; (6) the degrees of aneuploidies are proportional to the degrees of abnormalities in non-cancerous and cancerous cells; (7) polyploidy also varies biological phenotypes; (8) variation of the numbers of chromosomes is the basis of speciation. Thus, aneuploidy falls within the definition of speciation, and cancer is a species of its own. The aneuploidy hypothesis offers new prospects of cancer prevention and therapy.

Aneuploidy↗