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PubMed2000

Diverse roles for the third complementarity determining region of the heavy chain (H3) in the binding of immunoglobulin Fv fragments to DNA, nucleosomes and cardiolipin.

Autoantibodies to DNA and chromatin employ junctional diversity and somatic mutations to generate or enhance antigen recognition. To define the role of diversity generating mechanisms in the etiology of autoantibodies to nuclear antigens, the heavy (H) chain of a murine autoantibody, 3H9, was used in its somatically mutated or germ-line form in conjunction with its own or with heterologous CDR3 (H3) domains. The resulting H chains were expressed together with the 3H9 light (L) chain as single-chain Fv (scFv) in Escherichia coli and assayed for binding to DNA, nucleosomes, or cardiolipin by enzyme-linked immunosorbent assay. All recombinant scFv exhibited nearly identical binding to cardiolipin. In contrast, the binding to nuclear antigens was drastically reduced by the reversion of mutations in 3H9 or the exchange of H3, such that only 3H9 itself bound strongly to single-stranded DNA, double-stranded DNA and nucleosomes. The results illustrate diverse interactions between a single combining site and different autoantigens. The analysis of these interactions suggests that the 3H9 VH domain, as encoded by the germ line, directs binding to cardiolipin, whereas structural determinants of H3, in concert with the remainder of the combining site, guide the maturation of antibody binding toward nuclear autoantigens.

Amino Acid Sequence↗
PubMed2000

Cultivated H-RS cells are resistant to CD95L-mediated apoptosis despite expression of wild-type CD95.

OBJECTIVE: In most cases of classic Hodgkin's disease (HD), Hodgkin and Reed-Sternberg (H-RS) cells clonally derive from germinal-center B cells. Within their rearranged immunoglobulin genes, somatic mutations rendering potentially functional immunoglobulin gene rearrangements nonfunctional were detected, indicating that H-RS cells do not express a B-cell receptor. Under physiologic conditions, these cells would undergo apoptosis within the germinal center. However, H-RS cells clonally expand, disseminate, and lead to clonal relapse of HD, indicating their resistance to induced programmed cell death. The underlying mechanism remains to be elucidated. MATERIALS AND METHODS: [corrected] Analysis of receptor-ligand interactions in primary H-RS cells is difficult to perform due to their scarcity in vivo and their low proliferation rate in vitro. Therefore, two [corrected] B-cellular H-RS cell lines (L1236 and L428) were used to test for the expression of CD95 by flow cytometry and for the induction of apoptosis after incubation with CD95L obtained from retrovirally transduced murine myoblasts. Sequence analysis of CD95 cDNA obtained from these H-RS cell lines was performed. RESULTS: Expression of CD95 on the cell surface was detected in both cell lines. However, after incubation with CD95L, the cells did not undergo apoptosis. To test whether mutations within the CD95 cDNA sequence caused resistance to apoptosis in H-RS cells, sequence analysis of CD95 cDNA obtained from L1236 and L428 was performed. In both cell lines, CD95 was not affected by somatic mutations. CONCLUSIONS: Our results indicate that the two H-RS cell lines L1236 and L428 are resistant to CD95-mediated apoptosis induced via CD95L, although wild-type CD95 is expressed. For further characterization of the mechanisms leading to prevention of apoptotic cell death in H-RS cells, it is necessary to determine impairments within the signaling cascade following CD95 activation.

Apoptosis↗
PubMed2006

CancerGenes: a gene selection resource for cancer genome projects.

The genome sequence framework provided by the human genome project allows us to precisely map human genetic variations in order to study their association with disease and their direct effects on gene function. Since the description of tumor suppressor genes and oncogenes several decades ago, both germ-line variations and somatic mutations have been established to be important in cancer-in terms of risk, oncogenesis, prognosis and response to therapy. The Cancer Genome Atlas initiative proposed by the NIH is poised to elucidate the contribution of somatic mutations to cancer development and progression through the re-sequencing of a substantial fraction of the total collection of human genes-in hundreds of individual tumors and spanning several tumor types. We have developed the CancerGenes resource to simplify the process of gene selection and prioritization in large collaborative projects. CancerGenes combines gene lists annotated by experts with information from key public databases. Each gene is annotated with gene name(s), functional description, organism, chromosome number, location, Entrez Gene ID, GO terms, InterPro descriptions, gene structure, protein length, transcript count, and experimentally determined transcript control regions, as well as links to Entrez Gene, COSMIC, and iHOP gene pages and the UCSC and Ensembl genome browsers. The user-friendly interface provides for searching, sorting and intersection of gene lists. Users may view tabulated results through a web browser or may dynamically download them as a spreadsheet table. CancerGenes is available at http://cbio.mskcc.org/cancergenes.

Databases, Genetic↗
PubMed1998

The origin of Hodgkin and Reed/Sternberg cells in Hodgkin's disease.

One of the characteristic features of Hodgkin's disease (HD) is the presence of a small population of often bizarre-looking large mono- or multinucleated Hodgkin and Reed-Sternberg (HRS) cells within the affected tissue. Recent cytogenetic investigations, studies of Epstein-Barr virus (EBV) genomes present in HRS cells, and analyses of Ig gene rearrangements amplified from single, micromanipulated HRS cells show that these cells largely represent clonal populations. The finding of Ig gene rearrangements in HRS cells in most cases of HD identifies B cells as the precursors of HRS cells in most if not all cases. Furthermore, the presence and pattern of somatic mutations within the rearranged Ig genes show that HRS cells in classical (i.e. nodular sclerosis, mixed cellularity, and lymphocyte depletion HD) as well as lymphocyte predominant (LP) HD originate from germinal center (GC) B cells. Ongoing somatic mutation and evidence for selection link HRS cells from LP HD to a mutating, antigen-selected GC B cell. In classical HD, the finding of "crippling" mutations and lack of stringent selection for antigen receptor expression suggests that in this case HRS cells are derived from a compartment of GC B cells that were destined to die but escaped apoptosis by some transforming event. One candidate for the latter is EBV infection.

Animals↗
PubMedDate not supplied

Defect in the generation of light-chain diversity in bursectomized chickens.

The avian bursa of Fabricius has been regarded as a central organ for B-cell development, but there is controversy about the existence of other sites for differentiation of B cells. We have recently shown that chickens surgically bursectomized as early embryos, before the bursal primordium appears, can produce cytoplasmic, surface and serum immunoglobulins of IgM, IgG and IgA classes but are unable to generate specific antibodies in response to antigen. We have therefore examined the structure and diversity of immunoglobulins of bursectomized chickens. Analysis of serum IgG revealed normal gamma-heavy chains but altered light chains with more basic and less diverse isoelectric points than normal. These light chains may represent germ-line specificities not diversified by somatic mutations. Thus the bursa of Fabricius appears not to be necessary for the production of immunoglobulin molecules as such but to function in the creation and expansion of the antibody repertoire, possibly by providing a microenvironment for somatic mutations.

Animals↗
PubMed2002

McCune-Albright syndrome: molecular genetics.

McCune-Albright syndrome (MAS) is a rare disorder characterized by the association of precocious puberty (mostly in girls), polyostotic fibrous dysplasia and café-au-lait pigmented skin lesions. In addition to this classical triad, several endocrine disorders, all due to autonomous hormonal hyperproduction, can also be associated, such as pituitary adenomas secreting growth hormone, hyperthyroid goiters, or adrenal hyperplasia. The distribution pattern of skin lesions and the sporadic character of MAS have led to the hypothesis that this syndrome is due to a dominant somatic mutation early in the course of development. Furthermore, the diverse endocrine hyperactivity syndromes observed in MAS have in common the involvement of cells that respond to extracellular signaling by activating the adenyl cyclase system. The identification of somatic mutations of the Gsalpha gene have shown that MAS is due to a post-zygotic activating mutation of the Gsalpha subunit leading to a mosaic distribution of cells bearing constitutively active adenyl cyclase activity. In all patients reported to date, the mutation is a substitution of the arginine residue at position 201 most often into histidine or cysteine. We present here some of the results we have obtained in studying 80 patients presenting one or several signs of MCA for identification of the Arg201 mutation. We used a PCR-based method that allows selective enrichment of mutated DNA. This study, and data in the literature during the last decade, has widened the definition of MAS. Affections as clinically different as somatotropic or thyrotropic adenomas, isolated polyostotic fibrous dysplasia, isolated peripheral precocious puberty and the classic McCune-Albright syndrome all appear to be elements of a wide spectrum of disease based on the same molecular defect. The developmental moment at which the mutation occurs determines both the number of tissues affected and the severity of expression. The application of tools from molecular genetics to the study of this syndrome confirms their essential contribution to a deeper understanding of endocrine pathologies.

Child↗
PubMed2000

Identification of three subgroups of B cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes.

Although B cell chronic lymphocytic leukemia (B-CLL) has been traditionally viewed as a tumor of virgin B cells, this notion has been recently questioned by data suggesting that a fraction of B-CLL derives from antigen experienced B cells. In order to further clarify the histogenetic derivation of this lymphoproliferation, we have analyzed the DNA sequences of the 5' non-coding region of BCL-6 proto-oncogene in 28 cases of B-CLL. Mutations of BCL-6 proto-oncogene, a zinc finger transcription factor implicated in lymphoma development, represent a histogenetic marker of B cell transit through the germinal center (GC) and occur frequently in B cell malignancies derived from GC or post-GC B cells. For comparison, the same tumor panel was analyzed for somatic mutations of the rearranged immunoglobulin variable (IgV) genes, which are known to be acquired at the time of B cell transit through the GC. Sequence analyses of BCL-6 and IgV genes allowed the definition of three groups of B-CLL. Group I B-CLL displayed mutations of both BCL-6 and IgV genes (10/28; 36%). Group II B-CLL displayed mutated IgV genes, but a germline BCL-6 gene (5/28; 18%). Finally, group III B-CLL included the remaining cases (13/28; 46%) that were characterized by the absence of somatic mutations of both BCL-6 and IgV genes. Overall, the distribution of BCL-6 and IgV mutations in B-CLL reinforce the notion that this leukemia is histogenetically heterogeneous and that a substantial subgroup of these lymphoproliferations derives from post-germinal center B cells.

Base Sequence↗
PubMed1995

Retinoblastoma: a model for deriving the mutation rate without using any estimate of the size of the population at risk.

Paediatric cancer of the retinae arises from a transient population of stem cells whose growth and decay are responsible for the development of the fully differentiated photo-receptors and nerve cells. A model is described which fits the data on the incidence of bilateral retinoblastoma and gives the somatic mutation rate without using an estimate of the size of the population at risk. It also gives the shape of the retinoblast growth/decay curve. The model has been tested on two independent sets of data from the USA, and given that both sets are representative of the USA as a whole, there seems to have been little change in the somatic mutation rate over the last 30 or so years. For a total retinoblast formation of 4 x 10(6) cells, the average mutation rate is 2.94 x 10(-7) per cell per year.

Age Factors↗
PubMed1989

Tumour suppressor genes: oncogenesis update.

Evidence for tumour suppressor genes (anti-oncogenes, hemerogenes, flatogenes) has been obtained from the behaviour of familial childhood tumours in man, tumours in Drosophila caused by recessive mutations, experiments on fusing tumour cells to normal cells in tissue culture and revertants of oncogene-transformed cells. They may comprise more than one class of genes, one of which is likely to consist of genes responsible for normal differentiation. In large long-lived animals like man, which have a large potential somatic mutational load, mutant genes are associated with autosomal dominant behaviour in families. The susceptible individuals inherit heterozygosity of the tumour gene but the emergence of a tumour appears to follow a second somatic mutational event which results in homozygosity or hemizygosity. Hence, in tumour cells the mutations behave in a recessive manner. Success in isolating the normal genes may provide new tools for antenatal diagnosis of carriers and open up the possibility of developing new gene therapy.

Animals↗
PubMed1996

Activation but not inactivation of the MTS1 gene is associated with primary colorectal carcinomas.

Several investigators have reported that alterations of the multiple tumor suppressor 1 (MTS1) gene frequently occurred in certain types of tumors. We examined the expression levels and somatic mutations of the MTS1 gene in primary colorectal carcinomas. The MTS1 transcript was quantitatively detected in 14 of 17 tumors, but in only one case of adjacent normal mucosa. Direct sequencing of the amplified MTS1 gene showed no somatic mutation in 17 primary colorectal carcinomas. These results indicate that inactivation of the MTS1 gene is not involved in pathogenesis of primary colorectal carcinomas, and that its enhanced expression is, instead, associated with primary colorectal carcinomas, especially markedly in the early stage of tumor progression.

Base Sequence↗
PubMed1977

Frequency of occurrence of idiotypes associated with anti-p-azophenylarsonate antibodies arising in mice immunologically suppressed with respect to a cross-reactive idiotype.

Inoculation of rabbit anti-idiotypic (anti-id) antibodies suppresses the subsequent appearance of a cross-reactive idiotype (CRI) associated with the anti-p-azophenylarsonate (anti-Ar) antibodies of A/J mice. Such suppressed mice produce normal concentrations of anti-Ar antibodies which lack the CRI, but against which anti-id antisera can be prepared. The anti-Ar antibodies of an individual, suppressed mouse do not in general share idiotype with anti-Ar antibodies of other A/J mice, either suppressed or nonsuppressed. The present experiments were undertaken to quantitate several "private idiotypes" in a large number of hyperimmunized A/J mice. Anti-Ar antibodies of three mice, suppressed for the CRI, were labeled with 125I and subjected to isoelectric focusing. Four single peaks, that were over 90% reactive with autologous antiid, were randomly selected for use as ligands in a radioimmunoassay, and ascitic fluids containing anti-Ar antibodies from 181 A/J mice were tested as inhibitors. Two of the four idiotypes could not be detected in any mouse other than the donor. The concentration of the idiotype was less than 1 part in 1,250 to less than 1 part in 25,000 of the anti-Ar antibody population; these are minimum values. A third idiotype was detected in 3 of the 181 mice, but at very low concentrations. The fourth idiotype was present in 28% of the mice, again at a low concentration. The data support the existence of a very large repertoire of anti-Ar antibodies in the A/J strain and are consistent with a process of random somatic mutation for generating diversity in hypervariable regions. It is proposed that the cross-reactive idiotype may be controlled by a germ line gene or a gene related to a germ line gene through a small number of somatic mutations; and that the idiotypes that were not detectable in other mice were the products of genes that had undergone extensive mutations, with a low probability of recurrence in other mice.

Animals↗
PubMed1992

[Rheumatoid factors].

Rheumatoid factors (RF), which are auto-antibodies recognising the Fc fragment of IgGs, are the commonest auto-antibodies in man. They are present in polyclonal form in a large number of auto-immune disorders as well as in certain inflammatory states. In monoclonal form, they are frequently the product of "mature" malignant (chiefly Waldenström's macroglobulinemia and chronic lymphoid leukemia) and allegedly benign (such as cryoglobulinemias) lymphoid proliferations. In addition, RF account for a significant part of the normal antibody repertory, notably during the fetal and neonatal periods, suggesting that they may play an important role in the development and regulation of the immune system. As a result, RF are an excellent model for the analysis of auto-immunity in man. Thus many indirect (analysis of antigens recognised and of idiotopes carried) and, more recently, direct (protein or nucleotide sequencing of their various regions) studies have now provided the following conclusions. RF are coded by a very limited repertory of V genes. These genes are present in the normal genome and appear to be highly preserved in the human species. They are used with very few somatic mutations by monoclonal B proliferations (which opens up valuable therapeutic possibilities) as well as probably by RF producing B lymphocytes in normal individuals. In contrast, in the context of auto-immune disorders, these same genes have many somatic mutations suggesting maturation governed by the antigen and/or escape from idiotype control.

Autoimmune Diseases↗
PubMed2002

Identification of single nucleotide polymorphisms in the human kallikrein 10 (KLK10) gene and their association with prostate, breast, testicular, and ovarian cancers.

BACKGROUND: The KLK10 gene (also known as the normal epithelial cell-specific 1 gene) is a member of the expanded human kallikrein gene family. Recently, it has been reported that KLK10 is a tumor suppressor gene and that its expression is downregulated in various forms of cancer and cancer cell lines. KLK10 is also upregulated in ovarian cancer. We thus hypothesized that the KLK10 gene may be a target for mutations in various cancers. METHODS: We sequenced the five coding exons of the KLK10 gene using genomic DNA from various tumors, normal tissues, and blood, by PCR amplification and automated sequencing. RESULTS: In none of the tumor-derived DNAs, we identified somatic mutations that could inactivate this gene. However, we identified a prevalent germline single nucleotide variation at codon 50 (exon 3) of this gene [GCC (alanine) to TCC (serine)]. The GCC genotype was less prevalent in prostatic cancer patients in comparison to control subjects (P = 0.027) but no differences were seen with testicular, ovarian, and breast cancer. We also identified four genetic variations in exon 4, at codons106 [GGC (glycine) to GGA (glycine)], codon 112 [ACG (threonine) to ACC (threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and at codon 149 [CCG (proline) to CTG (leucine)]. None of these variations was significantly different between normal subjects and cancer groups. CONCLUSIONS: We found no evidence for somatic mutations of the KLK10 gene in cancers of the prostate, breast, ovary, and testis. The single nucleotide variation at codon 50 appears to be associated with prostate cancer risk.

Breast Neoplasms↗
PubMed2003

Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants.

Deciding whether a missense allelic variant affects protein function is important in many contexts. We previously demonstrated that a detailed analysis of p53 intragenic conservation correlates with somatic mutation hotspots. Here we refine these evolutionary studies and expand them to the p16/Ink4a gene. We calculated that in order for 'absolute conservation' of a codon across multiple species to achieve P<0.05, the evolutionary substitution database must contain at least 3(M) variants, where M equals the number of codons in the gene. Codons in p53 were divided into high (73% of codons), intermediate (29% of codons), and low (0 codons) likelihood of being mutation hotspots. From a database of 263 somatic missense p16 mutations, we identified only four codons that are mutational hotspots at P<0.05 (8 mutations). However, data on function, structure, and disease association support the conclusion that 11 other codons with > or =5 somatic mutations also likely indicate functionally critical residues, even though P0.05. We calculated p16 evolution using amino acid substitution matrices and nucleotide substitution distances. We looked for evolutionary parameters at each codon that would predict whether missense mutations were disease associated or disrupted function. The current p16 evolutionary substitution database is too small to determine whether observations of 'absolute conservation' are statistically significant. Increasing the number of sequences from three to seven significantly improved the predictive value of evolutionary computations. The sensitivity and specificity for conservation scores in predicting disease association of p16 codons is 70-80%. Despite the small p16 sequence database, our calculations of high conservation correctly predicted loss of cell cycle arrest function in 75% of tested codons, and low conservation correctly predicted wild-type function in 80-90% of codons. These data validate our hypothesis that detailed evolutionary analyses help predict the consequences of missense amino-acid variants.

Amino Acid Sequence↗
PubMed2002

Lack of somatic hypermutation of IG V(H) genes in lymphoid malignancies with t(2;14)(p13;q32) translocation involving the BCL11A gene.

The t(2;14)(p13;q32.3) involving the BCL11A and IGH genes is a rare but recurrent chromosomal aberration in B-cell malignancies. Hitherto, juxtaposition of BCL11A and IGH has only been described in B-cell chronic lymphocytic leukemia (B-CLL) and immunocytoma. As subgroups of B-CLL can be distinguished by the pattern of somatic mutation of immunoglobulin variable (V) genes we investigated four lymphomas with IGH/BCL11A involvement for IGH hypermutation. Clonal V(H) gene rearrangements were amplified; in all four cases, sequencing of the amplificates revealed the rearranged V(H) genes to lack somatic mutations. These results suggest that t(2;14)(p13;q32.3) is associated with a subset of B-CLL/immunocytoma characterized by non-mutated IG genes deriving from pre-germinal center B cells. As the translocations in both informative cases are targeted to the switch regions of the IGG2 gene, which is mainly used in T cell-independent immune responses, these translocations presumably occurred in activated B cells in the course of T cell-independent immune responses outside the germinal center.

Carrier Proteins↗
PubMed1993

Analysis of somatic hypermutation in mouse Peyer's patches using immunoglobulin kappa light-chain transgenes.

We have exploited mice transgenic for an immunoglobulin kappa light chain in order to show that immunoglobulin genes in the B cells of Peyer's patches in unimmunized mice carry a high level of somatic mutations. Most of the mutations are found in the subpopulation of B cells which, based on peanut agglutinin binding, derive from the germinal centers. The number of mutations per clone and their distribution along the variable gene segment (indicative of untemplated point mutations) are very similar to those found in antigen-specific splenic B cells of normal mice after secondary immunization. The mutations accumulate mainly in complementarity-determining region 1, in particular in some specific codons (Ser-26, Ser-31, and Ser-77) which have been previously recognized as intrinsic hypermutational hotspots. These results suggest that, as in the spleen, somatic mutation occurs in B cells which have migrated to the germinal centers, probably as a consequence of stimulation by antigens present in the gut environment. Transgenic animals are increasingly being used to define the signals involved in hypermutation. However, their subsequent study is very time-consuming because it is based on immunization and analysis of hybridomas or antigen-selected cells. We propose that the use of Peyer's patches of unimmunized adult mice offers a reliable and simple approach to analyze hypermutation of transgenes.

Amino Acid Sequence↗
PubMed2001

DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes.

To determine whether DNA polymerase eta plays a role in the hypermutation of immunoglobulin variable genes, we examined the frequency and pattern of substitutions in variable VH6 genes from the peripheral blood lymphocytes of three patients with xeroderma pigmentosum variant disease, whose polymerase eta had genetic defects. The frequency of mutation was normal but the types of base changes were different: there was a decrease in mutations at A and T and a concomitant rise in mutations at G and C. We propose that more than one polymerase contributes to hypermutation and that if one is absent, others compensate. The data indicate that polymerase eta is involved in generating errors that occur predominantly at A and T and that another polymerase(s) may preferentially generate errors opposite G and C.

Animals↗
PubMed1996

Maturation of the antibody response to the major epitope on the self antigen mouse cytochrome c. Restricted V gene usage, selected mutations, and increased affinity.

Most B lymphocytes recognizing the major epitope on the self Ag mouse cytochrome c (CYT) express one particular VH gene (19.1.2) in combination with one of two Vkappa genes (R9 or 2G5). This restriction made it possible to observe changes in the primary structure of mouse CYT-specific mAb as the B cell response to mouse CYT (coupled to OVA) progressed. Thus, somatic mutations at positions 31 and 58 in the VH gene complementarity-determining regions (CDR) 1 and 2, respectively, and tyrosine at position 96 in the Vkappa-Jkappa join were frequently selected during the response. The affinity constant (ka), which increased as much as 90-fold due to a decrease in the off-rate constant, correlated with the number of somatic mutations but not strictly with the commonly selected changes. There appears to be little selection for a particular H chain CDR3 in the mouse CYT-specific mAb since it is extremely variable, in sequence and length, throughout the response. This variability may reflect that mouse CYT is a self Ag. Otherwise, the Ab response to this protein Ag is consistent with the paradigm for affinity maturation that is well established for Ab responses to haptens.

Amino Acid Sequence↗