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PubMed1981

Toward a system for detecting somatic-cell mutations. V. Preparation of fluorescent antibodies to hemoglobin hasharon, a human alpha-chain variant.

Antibodies against the abnormal human hemoglobin, Hb Hasharon (alpha 47 Asp leads to His), were raised in horse and purified by absorption against Sepharose 4B to which normal hemoglobins or Hb Hasharon were bound. The purified, non-precipitating antibodies were tested for specificity against normal hemoglobins and Hb Hasharon by immunodiffusion in the presence of anti-horse IgG, and by exposing mixtures of normal and Hb Hasharon-containing red cells to the antibodies after conjugation of the latter with fluorescein isothiocyanate. The ease with which antibodies specific for different variant hemoglobins have been prepared, and their potential for identifying individual erythrocytes that contain these hemoglobins by virtue of somatic mutation, underscore their value as aids to detection and analysis of mutational events in human subjects.

Chemical Precipitation↗
PubMed2004

Somatic mutation-mediated evolution of herbicide resistance in the nonindigenous invasive plant hydrilla (Hydrilla verticillata).

Hydrilla (Hydrilla verticillata L.f. Royle) was introduced to the surface water of Florida in the 1950s and is today one of the most serious aquatic weed problems in the USA. As a result of concerns associated with the applications of pesticides to aquatic systems, fluridone is the only USEPA-approved chemical that provides systemic control of hydrilla. After a decrease in fluridone's efficacy at controlling hydrilla, 200 Florida water bodies were sampled to determine the extent of the problem and the biological basis for the reduced efficacy. Our studies revealed that hydrilla phenotypes with two- to six-fold higher fluridone resistance were present in 20 water bodies. Since fluridone is an inhibitor of the enzyme phytoene desaturase (PDS), the gene for PDS (pds) was cloned from herbicide-susceptible and -resistant hydrilla plants. We report for the first time in higher plants three independent herbicide-resistant hydrilla biotypes arising from the selection of somatic mutations at the arginine 304 codon of pds. The three PDS variants had specific activities similar to the wild-type enzyme but were two to five times less sensitive to fluridone. In vitro activity levels of the enzymes correlated with in vivo resistance of the corresponding biotypes. As hydrilla spread rapidly to lakes across the southern United States in the past, the expansion of resistant biotypes is likely to pose significant environmental challenges in the future.

Base Sequence↗
PubMed1993

Use of the most JH-proximal human Ig H chain V region gene, VH6, in the expressed immune repertoire.

VH6, the most 3' human H chain V region gene, is preferentially expressed in the preimmune repertoire of the developing human fetus. To determine whether VH6 contributes to the immune repertoire, we amplified and sequenced from human spleen RNA VH6 rearrangements that were isotype-switched to IgG. Eighteen distinct in-frame VH6 clones were sequenced. Definitive assignment to C gamma 1 could be made in the majority of clones, and all had undergone extensive somatic hypermutation in the V region with an average of 14 (range, 2 to 25) mutations/281 bp in the VH6 segment. The overall frequency of somatic mutation was 5.2% of the total nucleotides sequenced. Replacement somatic mutations were targeted to the complementarity determining region, and the complementarity determining region had higher replacement to silent mutation ratios, consistent with antigenic selection. Silent somatic mutations were also significantly more frequent in the complementarity determining region compared to the framework region. Five clones were derived from the same VH6Dxp'1JH6 rearrangement, each containing unique and shared mutations. All DH segments used by independently arising clones were unique, and all DH reading frames were seen. N segments were lacking at either the 5'DH-JH junction or the 3'DH-JH junction in 7 of 13 independent rearrangements. DH-DH recombinations were frequently observed, and there was biased usage of JH3b and JH4b in the clones. The data imply that a high degree of diversity arises from use of this 3'-VH gene in the immune repertoire.

Amino Acid Sequence↗
PubMed1996

[Adenine phosphoribosyltransferase (APRT)].

Adenine phosphoribosyltransferase (APRT) is a purine metabolic enzyme that salvages adenine moiety generated via the polyamine synthetic pathway. Adenine is produced by the cleavage of methylthiodenosine (MTA), a by-product of the polyamine synthesis. None of the normal somatic cells but about 23% of human malignant cells lack the enzyme MTA phosphorylase because of the homozygous deletion of 9p21 and are deficient in the salvage route of the adenine molecule. APRT gene is located at 16q24, is about 2200 bp long and is composed of 5 exons. The cDNA codes for 180 amino acids which include a PRPP binding domain. The Met at the N-terminal is removed and the Ala is next acetylated. The protein is cleaved into two peptides at amino acid 136 (Met) by BrCN treatment and the N-terminal peptide includes the PRPP binding domain. Although most of the somatic cells express APRT gene, some cells do not, even in normal subjects. This is because of somatic mutations. APRT locus is one of a few genetic loci where human somatic mutations can be observed. We can observe loss of heterozygosity (LOH) and point mutational events at the somatic cell level at this locus. The mode of the somatic mutations is quite similar to that observed in neoplastic cells at the tumor-suppressor loci.

Adenine↗
PubMed1997

Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).

Sporadic aggressive fibromatosis (also called desmoid tumor) is a monoclonal proliferation of spindle (fibrocyte-like) cells that is locally invasive but does not metastasize. A similarity to abdominal fibromatoses (desmoids) in familial adenomatous polyposis and a cytogenetic study showing partial deletion of 5q in a subset of aggressive fibromatoses suggests that the adenomatous polyposis coli (APC) gene plays a role in its pathogenesis. APC helps regulate the cellular level of beta-catenin, which is a downstream mediator in Wnt (Wingless) signaling. beta-Catenin has a nuclear function (binds transcription factors) and a cell membrane function (is a component of epithelial cell adherens junctions). Six cases of aggressive fibromatosis of the extremities from patients without familial adenomatous polyposis, or a family history of colon cancer, were studied. Immunohistochemistry, using carboxy and amino terminus antibodies to APC, and DNA sequencing showed that three of the six contained an APC-truncating mutation, whereas normal tissues did not contain a mutation. Western blot and Northern dot blot showed that all six tumors had a higher level of beta-catenin protein than surrounding normal tissues, despite containing similar levels of beta-catenin mRNA. Immunohistochemistry localized beta-catenin throughout the cell in tumor tissues, although it localized more to the periphery in cells from normal tissues. Reverse transcription polymerase chain reaction showed that the tumors expressed N-cadherin but not E-cadherin (a pattern of expression of proteins making up adherens junctions similar to fibrocytes), suggesting that the specific adherens junctions present in epithelial cells are not necessary for beta-catenin function. Increased beta-catenin may cause the growth advantage of cells in this tumor through a nuclear mechanism. The increased protein level, relative to the RNA level, suggests that beta-catenin is degraded at a lower rate compared with normal tissues. In some cases, this is caused by a somatic mutation resulting in a truncated APC protein.

Adenomatous Polyposis Coli Protein↗
PubMed2002

Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis.

EXT1 and EXT2 are genes that have been shown to cause hereditary multiple exostosis (HME), a syndrome marked by the formation of bony growths juxtaposed to the growth plate. These genes are members of a growing family of proteins with glycosyltransferase activity required for the synthesis of heparan sulfate chains. This protein activity is predicted to play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. We and others have previously suggested that a two-hit mutational model applies to the development of an exostosis where a germline mutation coupled with a somatic mutation results in the loss of EXT1 or EXT2 function and subsequent tumor formation. We report the direct sequencing and loss of heterozygosity (LOH) analysis of 12 exostoses from 10 HME families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, we find only one solitary case in which two somatic mutations, a deletion and an LOH, are present. This provides limited support for the two-hit hypothesis involving the EXT1 and EXT2 genes for the development of an exostosis. Alternative models are developed based on the functional significance of EXT proteins in heparan sulfate biosynthesis.

Exostoses, Multiple Hereditary↗
PubMed1989

Relationship of variable region genes expressed by a human B cell lymphoma secreting pathologic anti-Pr2 erythrocyte autoantibodies.

To study the biology of cold agglutinin disease we previously established EBV-transformed B cell clones isolated from a patient with splenic lymphoma of an early plasmacytic cell type and immune hemolysis due to an anti-Pr2 cold agglutinin. These clones had an aberrant chromosomal marker identical to the patient's B cell lymphoma and each secreted IgMk anti-Pr2 similar to the pathologic autoantibody in the serum of the patient. In this study, we have further investigated the Pr2-specific autoimmune response through nucleotide sequencing of VH and VL region genes. We have shown that the seven clones share the same VDJ/VJ gene segments and junctional elements confirming their clonal origin. The VH sequences were 88% homologous to a VHI germline gene while the VL sequences were 97% homologous to a VkIII germline gene. Only 4 somatic mutations (3 silent and 1 conservative) were found in greater than 5,000 bp sequenced, suggesting that a low mutation rate existed. Based on a tumor mass of 10(12) cells and a minimum of 40 divisions, we estimated the somatic mutation rate to be 4.45 x 10(-5) m/bp/d. This somatic mutation rate is similar to those estimated for acute lymphocytic leukemia (pre-B cell) and chronic lymphocytic leukemia (intermediate B cell), but significantly lower than the mutation frequency in follicular lymphomas (activated B cell). We propose that the difference in somatic mutation frequency of a B cell tumor may be related to the stage of B cell differentiation. In addition, the low mutation frequency observed in the Pr2-specific B cell tumor may also reflect, in part, selection by autoantigen to conserve sIg structure and specificity.

Agglutinins↗
PubMedDate not supplied

Somatic DNA alterations in endometriosis: high frequency of chromosome 17 and p53 loss in late-stage endometriosis.

PROBLEM: Genetic predisposition to endometriosis is well established, but the gene(s) involved largely remain unknown. Although endometriosis is considered a benign disease, it displays several features similar to malignancy: altered morphology, disregulated growth, invasion. We hypothesize endometriosis arises as result of somatic DNA alterations occurring in a multi-step process, analogous to origin of neoplasia. Since chromosome 17 and TP53 tumor suppressor gene (TSG) alterations occur frequently in premalignant and malignant tissues, including endometrial and ovarian epithelial carcinomas, we sought to determine if similar somatic changes occur in late stage endometriosis. METHOD OF STUDY: To determine the frequencies of monosomy for chromosome 17, as well as for perturbations of p53 and other loci on 17, two different approaches were used. Fluorescent in situ hybridization (FISH) analysis was used to detect monosomy for the 17 centromere and for the p53 locus. For FISH, archival tissue (n=6) and fresh endometriotic touch preparations were prepared from women (n=8) undergoing extirpation of advanced stage endometriosis. Direct-labeled probes specific for p53 (17p13.1) and for the chromosome 17 alpha-satellite centromere region (1711.1-q11.1) were used to compare single glandular and stromal cells from endometriosis and normal tissue. DNA analysis of polymorphic DNA loci were used to detect loss of heterozygosity (LoH) for other loci on 17. We assessed matched endometriotic and normal DNA (peripheral blood) from women with severe/late stage disease (n=15), studying these dinucleotide markers: HGH (located on 17q22-24), D17S250 (17q11.2-q12) and CHRNB1 (17p13.1). RESULTS: Loss of the chromosome 17 centromere (monosomy) was shown by FISH in some cells from all 14 endometriosis specimens, although in no case did every cell show monosomy 17. In 12 of 14 specimens, significant proportions of cells not only were monosomic for the chromosome 17-centromere (8 to 42% of cells) but also showed loss of p53 locus. In the two remaining cases, p53 loss alone was observed in 8 and 14%. LoH for other alleles on chromosome 17 was observed less often, namely only 3 of 15 specimens for HGH, 1 of 15 for D17S250, and 0 of 15 for CHRNB1. CONCLUSIONS: Our study indicates that perturbations of chromosome 17 in general and the p53 locus in particular occur frequently in severe/late stage endometriosis. That not all cells show loss of whole chromosome 17 or the p53 locus suggests somatic mutation, perhaps occurring late in the pathogenesis of endometriosis. Clonal evolution of endometriosis must depend not only on somatic mutations for p53 but also on other oncogenes or TSG. Alternatively, the clone could begin with a germline or somatic mutation involving a nonneoplastic process, followed by one or more somatic mutations involving an oncogene or TSG like p53. Additional candidate genes clearly must be evaluated in order to determine the precise role chromosome 17 and p53 alterations play in endometriosis; however, additional genes seem unlikely to involve region connoted by HGH, D17S250 or CHRNB1.

Chromosomes, Human, Pair 17↗
PubMed2005

Cutaneous melanoma susceptibility and progression genes.

This review aims to provide an up-to-date view on our understanding of the molecular genetics of melanoma development. It gives an overview of genes (and loci) currently known to be substantially involved in melanoma predisposition and progression. Broadly, the review falls into 3 sections: genes/loci involved in melanoma susceptibility through germline mutation, tumor suppressor genes somatically mutated or deleted in melanoma, and oncogenes mutated somatically in melanoma. The main cellular pathways in which these genes are involved are summarized and discussed. From this it is evident that abberations of cell cycle regulation, DNA repair and receptor-mediated signal transduction are important for melanocytic neoplasia.

Animals↗
PubMed2004

Protein dynamics and the immunological evolution of molecular recognition.

While it is accepted that protein flexibility plays a role in protein folding, catalysis, and molecular recognition, few techniques are capable of the rigorous measurement of protein motions required to quantify flexibility. Three-pulse photon echo shift spectroscopy can be used to measure the time scale of protein motions, and we have used this technique, along with steady-state spectroscopy and binding and structural data, to examine the immunological evolution of protein flexibility in an anti-fluorescein antibody. Two light chain somatic mutations increase affinity for fluorescein by 12-fold but also significantly affect flexibility. Specifically, a rigidification of the protein is seen in each of three observable motions; two slower motions undergo decreased amplitudes of displacement, by 3- and 20-fold, respectively, in response to an applied force, and the distribution associated with the amplitude of a faster motion is narrowed upon somatic mutation. The somatic mutations appear to rigidify the antibody-fluorescein complex by more strongly anchoring fluorescein to the protein and by more tightly packing the complex. The data demonstrate that in addition to affinity, antibody dynamics are systematically manipulated during affinity maturation, and they imply that the evolution of protein flexibility may be a central component of the immune response. The results also reflect the type of protein rigidification that may be important for other biological interactions, such as protein-protein, protein-ligand or protein-drug, and enzyme-substrate recognition.

5' Untranslated Regions↗
PubMed2004

Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers.

Lysyl oxidase (LOX) and HRAS-like suppressor (HRASLS) are silenced in human gastric cancers and are reported to have growth-suppressive activities in ras-transformed mouse/rat fibroblasts. Here, we analyzed whether or not LOX and HRASLS are tumor suppressor genes in human gastric cancers. Loss of heterozygosity and promoter methylation of LOX were detected in 33% (9 of 27) and 27% (26 of 96) of gastric cancers, respectively. Biallelic methylation and loss of heterozygosity with promoter methylation were also demonstrated in gastric cancers. Silencing of LOX was also observed in colon, lung, and ovarian cancer cell lines. As for mutations, only one possible somatic mutation was found by analysis of 96 gastric cancer samples and 58 gastric and other cancer cell lines. When LOX was introduced into a gastric cancer cell line, MKN28, in which LOX and HRASLS were silenced, it reduced the number of anchorage-dependent colonies to 57 to 61%, and the number of anchorage-independent colonies to 11 to 23%. Sizes of tumors formed in nude mice were reduced to 19 to 26%. Growth suppression in soft agar assay was also observed in another gastric cancer cell line, KATOIII. On the other hand, neither loss of heterozygosity nor a somatic mutation was detected in HRASLS, and its introduction into MKN28 did not suppress the growth in vitro or in vivo. These data showed that LOX is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in gastric cancers, and possibly also in other cancers.

Animals↗
PubMed1994

Epigenetic nature of radiation carcinogenesis at low doses.

The present paradigm of radiation-induced carcinogenesis has been based on somatic mutation theory initiating a mutation in somatic cells derived from DNA damage by ionizing radiation. A non-threshold linear model has been assumed from high doses to low doses. As an alternative to this, we are proposing a new model that epigenetic changes induced by low dose irradiation may be a first step of carcinogenesis. Our preliminary data suggesting the epigenetic nature and reports on various stress response to ionizing radiation are presented.

Animals↗
PubMed2000

Analysis of expressed immunoglobulin heavy chain genes in familial B-CLL.

In this study, we wished to determine whether familial chronic lymphocytic leukemia of B-cell phenotype (CLL) shares with sporadic B-CLL the same immunoglobulin (Ig) heavy chain variable region (VH) gene usage and occurrence of somatic mutation, to gain insight into the pathogenetic relatedness of these epidemiologically distinct forms of CLL. We therefore analyzed the expressed Ig heavy chain genes in 23 cases (11 families) of familial CLL, and compared these results with data previously reported for sporadic CLL. In addition, we assessed the relationship of the occurrence of somatic mutation to several clinical and phenotypic features. The distribution of V genes among these cases was similar to that observed in sporadic CLL: VH3 > VH1 > VH4. Thirteen of the 23 cases (57%) showed germ line VH gene sequences, whereas somatic mutations were detected in 10 cases (43%). The average mutation frequency of these latter 10 cases of was 6.7% (ranging from 1.7% to 8.8%), and evidence of antigen selection was noted in 6. Intraclonal variation, followed by clonal evolution and the appearance of a second clone over a 20-year period was observed in 1 case, suggesting that mutations can continue to accumulate after neoplastic transformation. The presence of somatic mutations correlated with age at presentation, low white blood cell (WBC) count, and low fluorescence intensity of surface CD5, and the potential significance of these relationships is discussed. Our data indicate that familial and sporadic B-CLL display a similar pattern of immunoglobulin gene usage and frequency of somatic mutation, and are consistent with a common ontogeny and immunogenetic origin for these 2 epidemiologically distinct forms of CLL. (Blood. 2000;95:1413-1419)

Adult↗
PubMed2000

CXCR5-deficient mice develop functional germinal centers in the splenic T cell zone.

The chemokine receptor CXCR5 is thought to be essential for the migration of B cells into the network of follicular dendritic cells in the spleen. However, as shown here, B cells and follicular dendritic cells do co-localize, albeit aberrantly, even in the absence of CXCR5. In mice lacking CXCR5 both cell types are found in a broad ring around the sinuses of the marginal zones. Upon immunization with the T cell-dependent antigen 2-phenyl-oxazolone, ectopic germinal centers develop in the periarteriolar lymphocyte sheath. A network of follicular dendritic cells forms in the vicinity of the central arteriole within which the antigen-activated B cells proliferate. The analysis of the expressed V gene repertoire revealed that during B cell proliferation, hypermutation is activated and V region genes accumulate somatic mutations. The pattern of somatic mutations suggests that affinity selection may occur. This analysis confirms that in CXCR5-deficient mice, the organization of splenic primary follicles is severely impaired. However, within the T cell zone a micro-environment is built up, which provides all requirements needed for the affinity maturation to take place.

Animals↗
PubMed1996

Activating mutations of Gs protein in monostotic fibrous lesions of bone.

Activating mutations of the alpha chain of the heterotrimeric signal transducer Gs disrupt the inherent guanosine triphosphatase activity of the alpha chain, stimulate adenylyl cyclase, and can result in independent cell proliferation. Such mutations are identified in a number of endocrine disorders, including McCune-Albright syndrome, which is a triad of endocrinopathy, café au lait spots, and polyostotic fibrous dysplasia. The mutation in this syndrome is a missense point mutation in exon 8 that results in the substitution of either histidine or cysteine for arginine at position 201. Monostotic fibrous dysplasia is a nonhereditary isolated bone lesion. Other isolated bone lesions that share some cytologic and clinical similarities to fibrous dysplasia are osteofibrous dysplasia and aggressive fibromatosis involving bone. Four cases of monostotic fibrous dysplasia, four cases of aggressive fibromatosis involving bone, and one case of osteofibrous dysplasia were studied to determine if a mutation was present in exon 8 of the alpha chain of Gs. A missense mutation was present in all of the fibrous dysplasias. The other fibrous lesions and uninvolved tissue did not contain a mutation. Somatic activating mutations of Gs differentiate fibrous dysplasia from the other lesions and may be responsible for the loss of control of local proliferation and growth factor expression.

Adolescent↗
PubMed2006

Germline ATBF1 mutations and prostate cancer risk.

BACKGROUND: ATBF1 has been recently identified as a candidate prostate tumor suppressor gene. In addition to more unique mutations, two somatic mutations (shortening of a polypyrimidine tract [Poly(T)n] and a deletion beginning at codon 3381 (3381del)) were each observed in multiple prostate cancer samples and both appear to have an impact on ATBF1 gene function and expression. METHODS: We assayed two recurrent sequence variants in germline DNA from prostate cancer cases and controls, and examined whether carriers of these variants are at increased risk for prostate cancer. RESULTS: We found Poly(T)n variants in both normal and matched tumor DNA samples from multiple patients, indicating a germline origin in each case. Genotyping germline DNA samples indicated that 3381del was significantly associated with prostate cancer risk among sporadic cases (P = 0.03), but not among men with hereditary disease. CONCLUSIONS: Our study indicates that the germline 3381del allele may influence prostate cancer susceptibility.

Alleles↗
PubMed2005

Genetic alterations of the KLF6 gene in gastric cancer.

The KLF6 is a zinc-finger tumor suppressor that is frequently mutated in several human cancers and broadly involved in differentiation and development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. To determine whether genetic alterations of KLF6 gene are involved in the development and/or progression of gastric cancer, we have screened a set of 80 sporadic gastric cancers for mutations and allele loss of the KLF6 gene. Four missense mutations, S155R, P172 T, S180L, and R198 K, were detected in transactivation domain of the KLF6 gene and one of them had biallelic mutations with somatic mutation of one allele and loss of the remaining allele. All of the cases with mutation were of advanced intestinal-type gastric cancer with lymph node metastasis. In addition, 16 (43.2%) of 37 informative cases showed allelic loss at KLF6 locus. Interestingly, allelic loss was also frequent in intestinal-type gastric cancer. Therefore, our data suggest that genetic alterations of KLF6 gene might play an important role in the development or progression of sporadic gastric cancers.

Humans↗
PubMed1986

Identification of a unique tumor antigen as rejection antigen by molecular cloning and gene transfer.

Tumor-specific transplantation antigens are antigens that can lead to complete immunological destruction of a transplanted cancer by the syngeneic host. When such antigens are expressed on cancers induced by chemical or physical carcinogens, then they are usually unique, i.e., antigenically different for each independently induced tumor. In this study, we show that the product of a gene encoding a novel MHC class I molecule and isolated from the murine UV light-induced regressor tumor 1591 represents one such unique tumor-specific transplantation antigen that causes tumor rejection. The major evidence comes from our finding that 1591 progressor variants regularly lost the gene encoding this antigen that is expressed in the parental tumor that regresses in normal mice; furthermore, reintroduction of this gene into a 1591 progressor variant by DNA transfection caused the progressor variant to regress in normal immunocompetent mice. Thus, the progressor tumor reverted to the parental regressor phenotype following transfection. Consistent with the conclusion that the expression of the novel MHC class I gene following transfection was responsible for the regressor phenotype is also our finding that a variant of the transfected tumor that had lost expression of the transfected gene resumed its progressive growth behavior. Finally, we show that the molecule encoded by the novel class I gene is specifically recognized by a syngeneic tumor-specific cytolytic T cell clone that we have previously shown to select in vitro for progressor variants from the parental regressor tumor cell line. It remains to be determined to what extent unique tumor-specific rejection antigens of other highly immunogenic regressor tumors are encoded by novel MHC class I genes and whether these genes represent germline mutations or somatic mutations caused by the carcinogen treatment.

Animals↗