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PubMed2000

Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer.

Inactivation of p53, which represents the most prevalent genetic alteration in lung cancer, has been shown to play a crucial role in the acquisition of genomic instability. We examined 44 lung cancer specimens to search for mutations in the CHK1 and CHK2 genes, which have been suggested to play roles in regulating p53 after DNA damage. We found that the CHK2 gene was somatically mutated in lung cancer in vivo, although at a low frequency, and that a previously undescribed shorter isoform of CHK1 was expressed preferentially in small cell lung cancer in a tumor-predominant manner. Additional studies are warranted to investigate the functional significance of these changes as well as the potential involvement of other components in this important pathway to maintain genomic stability.

Amino Acid Sequence↗
PubMed2002

Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation.

The breast cancer predisposition gene BRCA2 encodes a protein involved in the repair of DNA double-strand breaks, which arise spontaneously and following exposure to ionizing radiation (IR). To develop a mouse model that examines the effect of BRCA2 mutation and IR exposure on in vivo somatic mutation acquisition, we crossed mice with targeted disruption of Brca2 with a LacZ transgenic mutation reporter strain. Loss of both wild-type Brca2 alleles caused a 2.3-fold increase, equivalent to an extra 100 mutations per cell, in the in vivo acquisition of spontaneous somatic mutation by 2 weeks gestation. IR (4 Gy) had a disproportionate effect on animals homozygous for Brca2 disruption, inducing 3.4-fold more mutations compared with wild-type animals. These data provide the first evidence that loss of Brca2 increases in vivo somatic mutation acquisition and synergizes with IR exposure, with potential attendant implications for mammographic screening and therapeutic IR in mutation carriers.

Animals↗
PubMed2006

Germinal center function in the spleen during simian HIV infection in rhesus monkeys.

Infection with HIV-1, SIV, or simian HIV is associated with abnormalities in the number, size, and structure of germinal centers (GCs). To determine whether these histopathologic abnormalities are associated with abnormalities in Ab development, we analyzed nucleotide sequences of Igs from splenic GCs of simian HIV-infected macaques. Virus-specific GCs were identified in frozen splenic tissue sections by inverse immunohistochemistry using rHIV-1 gp120 as a probe. B cells from envelope-specific GCs were isolated from these sections using laser capture microdissection. Their Igs were amplified from cDNA using nested PCR, then cloned and sequenced. Nucleotide sequences were recovered from nine multimember clonal lineages. Within each lineage, sequences had similar V-D-J or V-J junctions but differed by somatic mutations distributed throughout the variable domain. The clones were highly mutated, similar to that previously reported for HIV-1-specific human IgG Abs. The average clone had 37 mutations in the V region, for a frequency of 0.11 mutations/base. The mutational pattern was strikingly nonrandom, with somatic mutations occurring preferentially at RGYW/WRCY hotspots. Transition mutations were favored over transversions, with C-->T and G-->A replacements together accounting for almost one-third of all mutations. Analysis of replacement and silent mutations in the framework and CDRs suggests that the Igs were subjected to affinity selection. These data demonstrate that the process of Ab maturation is not seriously disrupted in GCs during the early stages of immunodeficiency virus infection, and that Env-specific Igs developing in GCs are subject to extensive somatic mutation and profound selection pressures.

Amino Acid Sequence↗
PubMed2001

Enforced expression of Bcl-2 selectively perturbs negative selection of dual reactive antibodies.

We investigated the role of apoptosis in the development of B cell memory by analyzing the (p-azophenylarsonate) Ars response in a line of A strain mice in which expression of human Bcl-2 was enforced in the B cell compartment. Previous studies of the Ars immune response in these A. Bcl-2 mice, demonstrated that a large percentage of the antibodies expressed by the Ars induced memory B cell compartment had accumulated point mutations via somatic hypermutation that increased their affinity for both Ars and the autoantigen DNA ("dual reactive" antibodies). This was in sharp contrast to normal A strain mice which displayed no dual reactive B cells in their Ars induced memory B cell compartment. These data suggested that interference with apoptotic pathways regulated by Bcl-2 allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. Further studies of these mice, reported here, demonstrate that enforced expression of Bcl-2 does not alter serum antibody affinity maturation nor positive selection of B cells expressing somatically mutated antibody with an increased affinity for Ars. Moreover, the somatic hypermutation process was unaffected in A. Bcl-2 mice. Thus, enforced expression of Bcl-2 in A. Bcl-2 mice appears to selectively alter a negative selection process that operates during memory B cell differentiation.

Animals↗
PubMed1998

Immunoglobulin transgenes as targets for somatic hypermutation.

This review describes studies on somatic hypermutation of immunoglobulin genes that were started in the mid-80s in collaboration with Ralph Brinster. Almost all of the experiments were carried out using Ig transgenes as targets for the somatic mutation mechanism. Ig transgenes can be very good targets of somatic mutation, despite many different transgene integration sites. Thus, the required cis-acting elements must be present within the approximately 10 kb of the transgene. Only the Ig variable region and its proximate flanks are mutated, not the constant region in unmanipulated sequences. Several Ig gene enhancers are permissive for somatic mutation and they do not have to be associated with the Ig promoter they normally interact with. However, the mutation process does seem to be specific for Ig genes. No mutations were found in several housekeeping genes isolated from cells that had very high levels of somatic hypermutation of their Ig genes. This suggests that the Ig enhancers provide the lg gene specificity. An exception is the Bcl-6 gene, encoding a transcription factor, which was found to be mutated in normal human memory B cells. When the transcriptional promoter that is located upstream of the variable region is duplicated upstream of the constant region, this region is mutated as well. This suggests a transcription coupled model in which a mutator factor associates with the RNA polymerase at the initiation of transcription, travels with the polymerase during elongation, and causes mutations during polymerase pausing. Our recent data with an artificial substrate for somatic mutation suggest that the mutations are increased by increased stability of the secondary structures in the nascent RNA, and the specific nucleotides that are mutated are due to preferences of a mutator factor.

Animals↗
PubMed2005

[Heteroplasmy: a common phenomenon of mitochondrial genome mutations in human tumor tissues].

To explore the status of heteroplasmy and homoplasmy of Mitochondrial DNA somatic mutations in different tumors. DNA from 149 tumors and corresponding normal tissues were extracted and entire mitochondrial genome was amplified using 32 pairs of overlapping primers. The somatic mutations were screened by temporal temperature gradient gel electrophoresis and their heteroplasmic statute were identified by sequencing. The results showed that the incidence rate of heteroplasmy of mitochondrial DNA somatic mutations varies in different tumors. There is a high rate of heteroplasmic mutation in oral cancer (65%) and esophageal cancer (64%), followed by breast cancer (45%). The frequency of four transfer types is Hm (homoplasmy)-->Hm (heteroplasmy) > Hm-->Ht > Ht-->Hm > Ht-->Ht. The main transfer forms of transition and transversion mutations are Hm-->Hm and Hm-->Ht respectively. Heteroplasmy is a common phenomenon in mitochondrial DNA somatic mutations of human tumors.

Breast Neoplasms↗
PubMed2005

Absence of pathogenic mitochondrial DNA mutations in mouse brain tumors.

BACKGROUND: Somatic mutations in the mitochondrial genome occur in numerous tumor types including brain tumors. These mutations are generally found in the hypervariable regions I and II of the displacement loop and unlikely alter mitochondrial function. Two hypervariable regions of mononucleotide repeats occur in the mouse mitochondrial genome, i.e., the origin of replication of the light strand (OL) and the Arg tRNA. METHODS: In this study we examined the entire mitochondrial genome in a series of chemically induced brain tumors in the C57BL/6J strain and spontaneous brain tumors in the VM mouse strain. The tumor mtDNA was compared to that of mtDNA in brain mitochondrial populations from the corresponding syngeneic mouse host strain. RESULTS: Direct sequencing revealed a few homoplasmic base pair insertions, deletions, and substitutions in the tumor cells mainly in regions of mononucleotide repeats. A heteroplasmic mutation in the 16srRNA gene was detected in a spontaneous metastatic VM brain tumor. CONCLUSION: None of the mutations were considered pathogenic, indicating that mtDNA somatic mutations do not likely contribute to the initiation or progression of these diverse mouse brain tumors.

Animals↗
PubMed1997

Confirmation of a double-hit model for the NF1 gene in benign neurofibromas.

Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called "neurofibromin." It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the "two hit" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NF1 locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NF1 markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.

Alleles↗
PubMed1998

Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity.

Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of the Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somatic Fas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity.

Adult↗
PubMed1994

Kniest dysplasia is caused by dominant collagen II (COL2A1) mutations: parental somatic mosaicism manifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia.

We describe two unrelated children with Kniest dysplasia, a severe autosomal dominant form of chondrodysplastic dwarfism associated with cleft palate, progressive arthropathy, myopia and retinal detachment. In the first patient the disorder was caused by a 28 base pair exon 12/intron 12 deletion in the gene coding for type II collagen. Her mother had mild abnormalities of the vertebral bodies and long bones compatible with abnormalities seen in Stickler arthro-ophthalmopathy. The second child had a transition of AG to GG at the 3' splice site of intron 20 of the COL2A1 gene. Her father had premature polvarthrosis interpreted as a sequela of mild spondyloepiphyseal dysplasia. Molecular studies revealed that the mother of the first and the father of the second child each had somatic mosaicism of the same mutation as their children. Heterozygous mutations of the gene coding for type II collagen can cause Kniest dysplasia, and somatic mosaicism for the same mutations can result in the Stickler phenotype or in mild spondyloepiphyseal dysplasia leading to premature polyarthrosis.

Adult↗
PubMed2002

Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion.

The majority of patients with Von Hippel-Lindau (VHL) disease are affected by a VHL germline mutation involving one copy of the VHL gene. Loss of heterozygosity of the second VHL allele can be consistently demonstrated in tumor tissue from these patients, suggesting that allelic deletion is a very early or even initiating event for tumorigenesis. Approximately 20% of VHL disease patients, however, exhibit germline deletion of one entire copy or at least a substantial part of the VHL gene. To investigate the nature of the "second genetic hit" in this patient population, we analysed two renal cell carcinomas and one CNS hemangioblastoma from three unrelated patients for genetic changes of the second copy of the VHL gene. All three tumors showed retention of one VHL allele by FISH. Single-strand conformation polymorphism and mutation analysis of microdissected tumor DNA revealed somatic point mutations of the wild-type VHL copies in each of the three tumors. The results indicate that the "two hit model" is equally applicable to patients with VHL germline mutation and VHL germline deletion. In contrast to tumors from patients with VHL germline mutation, however, point mutations of the wild-type allele can be detected in tumors from patients with VHL germline deletion.

Alleles↗
PubMed2006

[Frequency of RET/PTC rearrangement and somatic BRAF mutation in papillary thyroid cancer].

Frequency of RET/PTC rearrangement and somatic BRAF mutation was investigated in patients with papillary thyroid cancer (PTC) vis-a-vis relevant demographic and clinico-pathological features. The study group included 76 patients with a female/male ratio of 4.8:1; mean age - 45.7 +/- 9.7 yrs. BRAF mutation was identified in 49 (65%) (V600E--47, KSRWS600--1 and E585K--1). RET rearrangement was detected in 9 (12%): RET/PTC1--5, RET/PTC3--2, unspecified RET/PTC--1 and delta RET/PTC--1. It was age at diagnosis alone that proved to be consistently associated with BRAF mutations (p = 0.017). Younger tumor patients were mostly prone to RET/PTC rearrangement (p = 0.08). No correlation between mutation and clinico-pathological features was established.

Adult↗
PubMed2006

Comprehensive NF1 screening on cultured Schwann cells from neurofibromas.

Neurofibromatosis type 1 (NF1) is mainly characterized by the occurrence of benign peripheral nerve sheath tumors or neurofibromas. Thorough investigation of the somatic mutation spectrum has thus far been hampered by the large size of the NF1 gene and the considerable proportion of NF1 heterozygous cells within the tumors. We developed an improved somatic mutation detection strategy on cultured Schwann cells derived from neurofibromas and investigated 38 tumors from nine NF1 patients. Twenty-nine somatic NF1 lesions were detected which represents the highest NF1 somatic mutation detection rate described so far (76%). Furthermore, our data strongly suggest that the acquired second hit underlies reduced NF1 expression in Schwann cell cultures. Together, these data clearly illustrate that two inactivating NF1 mutations, in a subpopulation of the Schwann cells, are required for neurofibroma formation in NF1 tumorigenesis. The observed somatic mutation spectrum shows that intragenic NF1 mutations (26/29) are most prevalent, particularly frameshift mutations (12/29, 41%). We hypothesize that this mutation signature might reflect slightly reduced DNA repair efficiency as a trigger for NF1 somatic inactivation preceding tumorigenesis. Joint analysis of the current and previously published NF1 mutation data revealed a significant difference in the somatic mutation spectrum in patients with a NF1 microdeletion vs. non-microdeletion patients with respect to the prevalence of loss of heterozygosity events (0/15 vs. 41/81). Differences in somatic inactivation mechanism might therefore exist between NF1 microdeletion patients and the general NF1 population.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Phenotypic and molecular characterization of human peripheral blood B-cell subsets with special reference to N-region addition and J kappa-usage in V kappa J kappa-joints and kappa/lambda-ratios in naive versus memory B-cell subsets to identify traces of receptor editing processes.

We identified a population of IgM+IgD+ B-cells in the peripheral blood (PB) of humans that express somatically mutated V-region genes like classical class switched or IgM-only memory B-cells and comprise around 15% of PB B-cells in adults. Mutated IgM+IgD+ cells differ from unmutated naive IgM+IgD+ cells in that they express the CD27 cell surface antigen. In addition, a very small subset of IgD-only B-cells was identified in the PB that carried rearranged VH-genes with an extremely high load of somatic mutations (up to 60 mutations per gene). A common characteristic of the four somatically mutated subsets, which altogether comprise 40% of PB B-lymphocytes in adults, is the surface expression of CD27. This antigen may thus represent a general marker for memory B-cells in the human. Somatically mutated and unmutated PB B-cell subsets were analyzed for N-region addition and J kappa-usage in V kappa J kappa-joints, and in addition for the respective kappa/lambda-ratios: N-nucleotides could be identified in a large fraction of V kappa-regions of all B-cell subsets, indicating that N-region insertion already occurs in the pre-germinal center (GC) phase of B-cell development. Both the J kappa-usage in expressed V kappa J kappa-joints and the kappa/lambda-ratio from somatically mutated B-cells do not differ substantially from those of the unmutated cells, so that in terms of these parameters, a contribution of secondary V kappa J kappa-rearrangements in shaping the memory B-cell repertoire is not detectable.

Adult↗
PubMed1997

Immunoglobulins D and M multiple myeloma variants are heavily mutated.

Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of malignant plasma cells within the bone marrow. Previous studies that have examined the Ig VH genes of IgG and IgA MMs have shown the presence of somatic mutations, suggesting that in these cases, the myeloma precursor cell passed through the phase of antigenic selection within the germinal center but is no longer exposed to the somatic mutation process. However, no information about this matter is available in the rare IgD and IgM MM variants. Therefore, we have analyzed the Ig VH genes of three IgD, one IgM, and one biclonal (IgG and IgM) MM for the presence of somatic mutations. Our study demonstrates that all of these myeloma clones have accumulated a high number of somatic mutations within their Ig VH genes but show no intraclonal variation. Moreover, proof that the clone sustained a strong antigenic selection pressure could be provided in three cases (one IgD and two IgMs). Therefore, this study strongly implies that IgD and IgM MMs emerge from a postgerminal center preswitched B cell that is no longer exposed to the somatic mutation process or able to undergo further isotype switching in vivo.

Amino Acid Sequence↗
PubMed2003

Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder.

Deletions of the long arm of chromosome 9 are the most common genetic alteration in transitional cell carcinoma (TCC) of the bladder. Several regions of deletion on 9q have been mapped by loss of heterozygosity (LOH) analysis, one of which encompasses one of the two loci for tuberous sclerosis, TSC1, at 9q34. Tuberous sclerosis complex (TSC) is an autosomal dominant condition in which affected individuals develop benign tumors (hamartomas) in many organs. There is a small increase in risk of renal cell carcinoma (<2%), but the hamartomas are of stromal origin and patients do not develop an excess of epithelial malignancies. However, during a search for candidate bladder tumor suppressor genes within the 9q34 region of LOH, we previously found a small number of mutations of TSC1, raising the possibility that this represents a bladder tumor suppressor. Here, we have carried out mutation analysis of 62 bladder tumors and 33 bladder tumor-derived cell lines to establish the frequency and spectrum of TSC1 mutations in TCC. Twelve percent of samples contained mutations. We found 10 somatic mutations, 9 of which are novel mutations not found previously in TSC cases. Two of these were missense mutations, a type of change only rarely observed in the germ line in TSC. We also identified a bladder tumor patient carrying a germ-line mutation but with no symptoms of TSC. The tumor in this case and in two other cases with somatic mutations retained the wild-type allele. Thus 3 cases with mutation retained heterozygosity for TSC1 despite our selection of tumors mostly with 9q LOH (>80%) for the study. This may indicate that haploinsufficiency for TSC1 can contribute to the development of bladder cancer and, if so, that the LOH of TSC1 observed in >50% of TCCs is biologically significant.

Amino Acid Sequence↗
PubMed1993

Molecular and kinetic analysis of an epitope-specific shift in the B cell memory response to a multideterminant antigen.

Our previous studies showed that the primary and memory B cell responses to the multideterminant antigen poly-(L-Tyr, L-Glu)-poly-D,L-Ala-poly-L-Lys ((T,G)-A-L), differ. The primary response is dominated by antibodies binding side-chain epitopes; there is little antibody response to epitopes on the poly-D,L-Ala-poly-L-Lys backbone of (T,G)-A-L. In contrast, B cells producing A-L+ antibodies constitute approximately a third of the memory response to (T,G)-A-L. To determine the basis of this epitope-specific repertoire shift, we have examined the kinetics of expression of A-L+ B cells and antibodies after in vivo antigen priming and identified VH and V kappa genes used by A-L+ hybridoma antibodies derived from primary vs memory B cells. Kinetic studies, using the splenic focus assay, showed that the clonal frequency of A-L+ B cells remains low (<3% of (T,G)-A-L-specific B cells) 1 wk after Ag priming, increases (9%) by 2 wk, but does not reach the memory frequency (30%) until at least 3 wk after immunization. Molecular analyses showed that both the primary and memory A-L+ antibody responses are heterogeneous, using different VH and V kappa gene families as well as different germ-line genes within a VH gene family. Both H and L chain gene sequences showed somatic mutations in primary as well as memory antibodies. Analysis of antibody binding patterns and somatic mutations in a set of clonally related B cells that use a new germ-line VH gene in the VGAM3.8 family (VGK7, described here), showed a direct correlation between somatic mutation and change in antibody binding specificity. Our results demonstrate how somatic mutation and Ag selection play a role in the development of the memory response to a multideterminant Ag. The data are discussed in the context of the single vs dual lineage models for memory B cell generation.

Animals↗
PubMed1991

A somatic point mutation in a putative ligand binding domain of the TSH receptor in a patient with autoimmune hyperthyroidism.

Nucleotide sequence analysis of PCR fragments of TSH receptor cDNA synthesized from thyroid RNA of a patient with autoimmune hyperthyroidism, revealed two different sequences in the first position of codon 36. In one of the sequences, there was a C for G substitution leading to the D36----H substitution in the predicted peptide. Both variants were also found in genomic DNA of thyroid tissue. However, only the germ line sequence was found in other tissues representing all three different germ layers. The novel sequence is therefore likely to represent a somatic mutation in the thyroid tissue, of possible relevance for the pathogenesis of the patient's thyroid disorder.

Adult↗