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PubMed2000

Molecular analysis reveals somatically mutated and unmutated clonal and oligoclonal B cells in T-cell-rich B-cell lymphoma.

This paper describes the immunohistology and molecular genetics of 18 cases of T-cell-rich B-cell lymphoma (TCRBL). In all cases, the large B cells stained strongly for CD20, with more variable expression of CD79a, and were negative for CD30 and CD15. The majority of T cells were predominantly positive for TIA-1 and negative for CD57; a large population of histiocytes was present in all cases. Epstein-Barr virus (EBV)-coded RNA (EBER) was found in B blasts from four cases and in one case was present among the background lymphoid cells. IgH PCR products were generated in 16/18 cases and revealed clonal, oligoclonal and polyclonal PCR products in 12, two and two cases, respectively. In addition, TCRG clonal gene rearrangements were identified in two cases. TCRB gene rearrangements were polyclonal. Sequence analysis of seven cases with clonal/oligoclonal IgH gene rearrangements revealed functional sequences with predominant V(H)3 gene usage associated with various D genes and J(H)4 or J(H)6 gene segments. Four cases displayed varying degrees of replacement and silent mutations (1.8-21%), with one case exhibiting intraclonal heterogeneity; the distribution of mutations was indicative of antigen selection in three cases. The remaining three cases, including two cases with functional oligoclonal IgH rearrangements, harboured unmutated V region genes. The EBV-positive cases were associated with clonal, oligoclonal and polyclonal PCR products and with mutated and germline clonal sequences. These data indicate that TCRBL may be a heterogeneous entity associated with clonal and oligoclonal B cells derived from both germinal centre and naïve B cells.

Adult↗
PubMed1992

Somatic mutations and human breast cancer. A status report.

A systematic study of primary human breast tumor DNA demonstrated that three proto-oncogenes or regions of the genome (c-myc, int-2, and c-erbB2) are frequently amplified and that there is loss of heterozygosity (LOH) on chromosomes 1p(37%), 1q(20%), 3p(30%), 7(41%), 11p(20%), 13q(30%), 17p(49%), 17q(29%), and 18q(34%). Specific subsets of tumors can be defined based on the particular collection of mutations they contain. For instance, LOH on chromosomes 11p, 17p, and 18q frequently occurs in the same tumor. A search for putative tumor suppressor genes within the regions of the genome affected by LOH has been started. In a comprehensive molecular analysis of the p53 gene on chromosome 17p, 46% of the tumors contained a point mutation in the p53 gene.

Breast Neoplasms↗
PubMed2000

Analysis of autoimmune bone marrow by antibody-phage display: somatic mutations and third complementarity-determining region arginines in anti-DNA gamma and kappa V genes.

OBJECTIVE: To examine anti-double-stranded DNA (anti-dsDNA) IgG autoantibodies from the bone marrow of individuals with systemic lupus erythematosus (SLE). METHODS: A library of single-chain variable fragments (scFv) was constructed from SLE bone marrow complementary DNA of gamma, kappa, and lambda isotype by cloning into the pHENIX phagemid vector. The library was screened with dsDNA in solution, and 2 anti-DNA phage, DNA1 and DNA4, were isolated and their Ig V genes sequenced. Soluble scFv corresponding to DNA1 and DNA4, and their heavy (H)- and light (L)-chain recombinants, were prepared, purified, and analyzed for binding to DNA by enzyme-linked immunosorbent assay. RESULTS: DNA1 and DNA4 used different Ig H-chain (3-30 and 5-51, respectively) and L-chain (DPK15 and DPK22, respectively) V genes. The ratios of replacement mutations to silent mutations in DNA1 and DNA4 suggest that their V genes were selected for improved antigen binding in vivo. The recombinant between DNA4VH and DNA1VL showed the highest relative affinity for both single-stranded DNA and dsDNA. These 2 Ig subunits contained third complementarity-determining region arginines and had acquired the majority of replacement mutations. CONCLUSION: Anti-dsDNA IgG autoantibodies from the bone marrow of SLE patients exploit diverse V genes and cationic V-D-J and V-J junctions for DNA binding, and accumulate replacement mutations that enhance binding.

Adult↗
PubMed2004

Somatic mutations in VHL germline deletion kindred correlate with mild phenotype.

Generally, von Hippel-Lindau (VHL) disease is caused by a germline mutation of the VHL gene (chromosome 3p), and tumorigenesis is initiated from a "second-hit" deletion. A subset of VHL patients have a germline deletion of the VHL gene, and the molecular events leading to tumorigenesis are not fully understood. To determine the molecular pathogenesis of tumor formation in this setting, we analyzed five central nervous system hemangioblastomas from three patients of a single VHL germline deletion kindred, all displaying mild clinical phenotype. Rather than loss of heterozygosity (the "second hit" in VHL germline mutation patients), all tumors from this kindred showed "second-hit" point mutations on the wild-type allele. Moreover, in two patients who each had two hemangioblastomas resected each tumor contained a unique mutation. The specific germline deletion and the overall genetic makeup of the patient did not predict these random "second-hit" point mutations. These results suggest that in patients with germline deletion of a tumor suppressor gene there is a unique genetic mechanism underlying tumorigenesis. This unique genetic mechanism correlates with and may help to understand the mild clinical phenotype seen in these patients.

Adult↗
PubMed1988

A 16/6 idiotype-positive anti-DNA antibody is encoded by a conserved VH gene with no somatic mutation.

Recently, the heavy chain of 16/6 idiotype-positive human anti-DNA antibodies was found to be similar, but not identical, to the VH26 gene. We resequenced the VH26 gene and found that its coding sequence is actually identical to the complementary DNA sequence of the anti-DNA antibodies previously described. Together with the previous data, our findings demonstrate that some human autoantibodies are encoded directly by immunoglobulin V region genes, and that these V region genes are remarkably conserved in populations.

Antibodies, Antinuclear↗
PubMed1985

T helper cell recognition of idiotopes on lambda 2 light chains of M315 and T952: evidence for dependence on somatic mutations in the third hypervariable region.

Previous work has indicated that BALB/c T helper cells (Th) recognize an idiotope expressed on a 88-114/117 fragment of V lambda 2 of BALB/c myeloma protein 315. In the present study the antigenic structure of this idiotope was further analyzed. Conventional carrier-specific Th elicited by immunization of BALB/c mice with free lambda 2(315) did not cross-react with the free lambda 2 chain of the BALB/c myeloma protein T952 which differs from lambda 2(315) in five amino acid positions (38, 94, 95, 96, 99). Similarly, Th primed with free lambda 2T952 did not respond to a boost with free lambda 2(315). Thus, BALB/c lambda 2(315)-specific Th recognize an idiotope that depends on some or all of the residues at positions 94, 95, 96 and 99. Furthermore, free lambda 2T952 contains an idiotope immunogenic to Th that depends on some or all of residues 38, 94, 95, 96 and 99. Th recognition of the free lambda 2T952 idiotope was quenched upon H + L chain assembly because Th elicited by free lambda 2T952 did not respond to a boost with the complete T952 myeloma protein. In contrast to the lack of Th cell cross-reactivity, some of the antisera from BALB/c mice immunized with free lambda 2T952 cross-reacted with free lambda 2(315), free lambda lJ558 and free lambda 3CBPC49 but not with free kappa W3129 or polyclonal L chains. The H chain of T952 (alpha, kappa 2) myeloma protein was abnormally short (Mr = 48 000) and T952 existed as a halfmere probably due to this H chain deletion. Furthermore, H and L chains were disulfide bonded to each other.

Animals↗
PubMed1988

Somatic mutation studies in human lymphoid cells: the detectability of quantitative genetic variants in two-dimensional gels.

The feasibility of detecting quantitative genetic variants based on a decrease in the integrated intensity of polypeptide spots in two-dimensional polyacrylamide gels of human lymphoblastoid cell clones was investigated. A battery of 65 spots on 115 gels was studied to determine the distribution of quantitative measures for spots where no mutation had occurred. The corresponding distribution for spots which have decreased integrated intensity as a result of a mutation at one of two alleles coding for the spot was investigated by quantitating spots for which mutations were known to have occurred. These two distributions allowed the estimation of the rates of false positive and false negative errors for any particular strategy aimed at detecting null mutations, and thus provides a basis for the design of efficient strategies. Our silver stained gels have sufficient reproducibility of spot integrated intensities so that, for situations in which the mutation rate is relatively high, it is practical to monitor a subset of spots for null variants using the same digitized images as are used to detect structural variants.

Clone Cells↗
PubMed1997

Detection of somatic mutations in the mitochondrial DNA control region of colorectal and gastric tumors by heteroduplex and single-strand conformation analysis.

Each entire hypervariable region of the mitochondrial DNA control region was screened for mutations from paired normal and tumor DNA corresponding to a group of 21 patients (13 colorectal and 8 gastric adenocarcinomas) using both heteroduplex analysis and single-strand conformation analysis. These two mutation scanning strategies allowed the identification of sequence alterations in 3/13 (23%) colorectal tumors and in 3/8 (37%) gastric tumors. Heteroduplex analysis showed the heteroplasmic state of the majority of these tumor mutations. Sequence analysis revealed two A:T/G:C transitions (nucleotide positions: 16241 and 16166) in hypervariable region 1 (HV1) and two C:G/T:A transitions (nucleotide positions: 76 and 312), one A:T/G:C transition (nucleotide position: 93), a 1-basepair C:G deletion (nucleotide position: 309), and a 2-base-pair CC:GG insertion (nucleotide position: 309) in the HV 2 region. A considerable proportion of these mutations was found in homopolymeric regions which are highly polymorphic among humans. Different mechanisms (clonal expansion, increased oxidative damage, and nuclear mutator mutations) were suggested to explain the increased mitochondrial DNA mutation rate observed in cancer.

Adenocarcinoma↗
PubMed2001

Further characterization and validation of gpt delta transgenic mice for quantifying somatic mutations in vivo.

The utility of any mutation assay depends on its characteristics, which are best discovered using model mutagens. To this end, we report further on the characteristics of the lambda-based gpt delta transgenic assay first described by Nohmi et al. ([1996]: Environ Mol Mutagen 28:465-470). Our studies show that the gpt transgene responds similarly to other transgenic loci, specifically lacZ and cII, after treatment with acute doses of N-ethyl-N-nitrosourea (ENU). Because genetic neutrality is an important factor in the design of treatment protocols for mutagenicity testing, as well as for valid comparisons between different tissues and treatments, a time-course study was conducted. The results indicate that the gpt transgene, like cII and lacZ, is genetically neutral in vivo. The sensitivities of the loci are also equivalent, as evidenced by spontaneous mutant frequency data and dose- response curves after acute treatment with 50, 150, or 250 mg/kg ENU. The results are interesting in light of transgenic target size and location and of host genetic background differences. Based on these studies, protocols developed for other transgenic assays should be suitable for the gpt delta. Additionally, a comparison of the gpt and an endogenous locus, Dlb-1, within the small intestine of chronically treated animals (94 microg/mL ENU in drinking water daily) shows differential accumulation of mutations at the loci during chronic exposure. The results further support the existence of preferential repair at endogenous, expressed genes relative to transgenes.

Animals↗
PubMed2006

3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice.

Xpc-null (Xpc-/-) mice, deficient in the global genome repair subpathway of nucleotide excision repair (NER-GGR), were exposed by intraperitoneal (i.p.) injection to a 300 mg/kg mutagenic dose of 3,4-epoxy-1-butene (EB), to investigate NER's potential role in repairing butadiene (BD) epoxide DNA lesions. Mutagenic sensitivity was assessed using the Hprt assay. Xpc-/- mice were significantly more sensitive to EB exposure, exhibiting an average 2.8-fold increase in Hprt mutant frequency (MF) relative to those of exposed Xpc+/+ (wild-type) mice. As a positive control for NER-GGR, additional mice were exposed by i.p. injection to a 150 mg/kg mutagenic dose of benzo[a]pyrene (B[a]P). The Xpc-/- mice had MFs 2.9-fold higher than those of exposed Xpc+/+ mice. These results suggest that NER-GGR plays a role in recognizing and repairing some of the DNA adducts formed following in vivo exposure to EB. Additional research is needed to examine the response of Xpc-/- mice, as well as other NER-deficient strains, to inhaled BD. Furthermore, it is likely that alternative DNA repair pathways also are involved in restoring genomic integrity compromised by BD-epoxide DNA damage. Collaborative studies are currently underway to address these critical issues.

Animals↗
PubMed1991

In vivo somatic mutation in the lymphocytes of Hodgkin's disease patients.

While current medical therapies for Hodgkin's disease are usually quite effective, it has become increasingly clear that some of the therapies utilized carry an inherent risk for the induction of secondary malignancies. In order to examine the cellular and genetic responses to therapy for Hodgkin's disease among individuals, we have determined the mutant frequency of T-lymphocytes in 3 cohorts of patients (N = 86) and in controls (N = 71) using a T-cell cloning assay selecting for 6-thioguanine resistance. The Hodgkin's disease cohorts studied include 1) new and untreated, 2) radiotherapy, and 3) combined modality therapy patients. Additionally, two patients receiving chemotherapy alone were studied. In untreated patients, 3 of 18 (17%) mutant frequencies were above the upper 95% confidence limit for mutant frequency in controls (12.6 x 10(-6]. After therapy, 14 out of 45 (31%) of those treated with X-rays only and 10 of 23 (44%) patients treated with both X-rays and chemotherapy had mutant frequencies greater than 12.6 x 10(-6). Overall, the results indicated that the individual response to Hodgkin's disease therapy was a heterogeneous one with a sub-population of persons having elevated mutant frequencies even many years after their last treatment. The larger frequency of elevated MFs in those patients who received intensive therapy (chemotherapy and radiotherapy) is consistent with their increased risk for second cancer induction.

Adult↗
PubMed1984

Somatic mutation and recombination test in Drosophila melanogaster.

A novel test system for the detection of mutagenic and recombinogenic activity of chemicals is described in detail. Drosophila melanogaster larvae trans-heterozygous for the mutations multiple wing hairs (mwh) and flare (flr) are exposed to the test compounds for various periods of time ranging from 96 hr to 1 hr. Induced mutations are detected as single mosaic spots on the wing blade of surviving adults that show either the multiple wing hairs or flare phenotype. Induced recombination leads to mwh and flr twin spots and also to a certain extent, to mwh single spots. Recording of the frequency and the size of the different spots allows for a quantitative determination of the mutagenic and recombinogenic effects. This and earlier studies with a small set of well-known mutagens indicate that the test detects monofunctional and polyfunctional alkylating agents (ethyl methanesulfonate, diepoxybutane, mitomycin C, Trenimon), mutagens forming large adducts (aflatoxin B1), DNA breaking agents (bleomycin), intercalating agents (5-aminoacridine, ICR-170), spindle poisons (vinblastine), and antimetabolites (methotrexate). In addition, the test detects mutagens unstable in aqueous solution (beta-propiolactone), gaseous mutagens (1,2-dibromoethane), as well as promutagens needing various pathways of metabolic activation (aflatoxin B1, diethylnitrosamine, dimethylnitrosamine, mitomycin C, and procarbazine). The rapidity and ease of performance as well as the low costs of the test necessitate a high priority for validation of this promising Drosophila short-term test.

Animals↗