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PubMed1980

Development of a somatic mutation screening system using Hb mutants. IV. Successful detection of red cells containing the human frameshift mutants Hb Wayne and Hb Cranston using monospecific fluorescent antibodies.

The production and purification of antibodies detecting Hb Wayne, an alpha-globin frameshift mutant, and Hb Cranston, a beta-globin frameshift mutant, are described. The antibodies are of a nonprecipitating nature, and they permit strong fluorescent labeling of erythrocytes containing Hb Wayne or Hb Cranston. Studies using artificial mixtures containing cells with either of the two mutants in frequencies ranging from 1 in 10(2) to 1 in 10(5) showed that fluorescent antibodies can detect rare mutant red cells in the presence of vast excesses of normal erythrocytes. On the basis of the structures and the molecular lesions underlying production of the two abnormal hemoglobins, we predict that the anti-Hb Wayne antibody will detect several frameshift mutants resulting from deletion of 3n + 1 nucleotides or insertion of 3n + 2 nucleotides at the 5' side of the codon normally specifying residue 139 of the alpha chain. The anti-Hb Cranston antibody should be capable of detecting beta chains, the corresponding genes of which have sustained insertions of 3n + 2 nucleotides or deletions of 3n + 1 nucleotides on the 5' side of the codon normally specifying residue 144. The two antibodies may, therefore, prove to be valuable in the development of a system aimed at detecting rare erythrocytes that express mutations which arise in the hemopoietic stem cells of normal individuals and subjects exposed to mutagens.

Antibodies↗
PubMed1995

Somatic mutations of the WAF1/CIP1 gene in primary prostate cancer.

The WAF1/CIP1 gene, a potential tumor suppressor gene, has recently been cloned and identified as a p53 mediator and an inhibitor for G1 cyclin-dependent kinases (CDKs). We undertook this study to investigate the possible role of the WAF1/CIP1 gene in human prostatic carcinoma. Matched normal and cancer tissues from 18 patients with prostate cancer were screened for WAF1/CIP1 mutation by nested reverse transcription-polymerase chain reaction/single strand conformational polymorphism (RT-PCR/SSCP) and DNA sequencing. Shifted bands from three tumor, but not the matched normal specimens, were observed. Subsequent direct DNA sequencing of the PCR fragments identified four sequence alterations including a cytosine (C) to adenine (A) transversion and a guanine (G) to A transition and two A insertions. Our results demonstrated that mutations of the WAF1/CIP1 gene occur and may be important during the pathogenesis of human prostate cancer. This is the first report of WAF1/CIP1 mutation in a primary human cancer.

Base Sequence↗
PubMed1995

Burkitt's lymphomas express VH genes with a moderate number of antigen-selected somatic mutations.

The normal counterpart of the neoplastic B cells occurring in Burkitt's lymphomas (BL) is an issue of controversial debate. To clarify this matter, a semi-nested primer polymerase chain reaction was performed to amplify the VDJ rearrangements of the immunoglobulin heavy chain (VH) gene of DNA extracts from 10 (8 sporadic and 2 endemic) BL cases. The resulting amplificates were sequenced for comparison with known germ line VH segments. The control cases comprised six cases of B cell chronic lymphocytic leukemia and six cases of mantle cell lymphoma known to display naive nonmutated, ie, pre-germinal center VH configurations; and eight cases of follicular center lymphoma known to display mutated VH genes with signs of a still-ongoing mutation reaction, characteristic for germinal center cells and lymphomas that derive therefrom. The results of this approach revealed that both sporadic and endemic BL express mutated VH genes with a mutation frequency considerably lower (4.9% and 5.4%, respectively) than that observed in follicular center lymphoma (11.8%). In addition, after subcloning the amplificates, sequence analysis revealed no signs of ongoing mutations. These results led us to conclude that the derivation of neoplastic B cells in BL is definitely not from naive, nonmutated pre-germinal center B cells. Instead, our findings support the view that BL cells stem either from early centroblasts that are arrested after an initial hypermutation reaction, or from germinal center B cells that have differentiated in terms of surface immunoglobulin profile and mutation pattern but not in terms of morphology and proliferation toward SIgM+ IgD- memory B cells because of the deregulated c-myc gene expression.

Burkitt Lymphoma↗
PubMed1995

Monoclonal IgM rheumatoid factor secreted by CD5-negative B cells during mixed cryoglobulinemia. Evidence for somatic mutations and intraclonal diversity of the expressed VH region gene.

Mixed cryoglobulinemia is usually considered to be a nonmalignant human B cell proliferation that produces a monoclonal IgM rheumatoid factor (RF). Important immunologic similarities and differences were described between the monoclonal B cells during mixed cryoglobulinemia and during malignant chronic lymphocytic leukemia (CLL):high frequency of the same VH and V kappa gene usage by both types of monoclonal B cells producing IgM with RF activity, apparent intraclonal homogeneity, but different expression of the pan T cell CD5 Ag. The description of an unusual CD5-negative B cell CLL case secreting a mutated IgM RF led the authors to suggest that the usage of non-mutated germline Ig genes is a property of cells derived from the CD5 lineage or stage of differentiation, rather than an intrinsic property of CLL or of IgM RF-producing cells in general. Because mixed cryoglobulinemia cells are usually CD5-negative, it was of interest to test for the existence of mutations in the VH and V kappa regions, as well as for the intraclonal homogeneity of the expressed Ig genes. In this study, we used the PCR technique to analyze the monoclonal rheumatoid factor (mRF) V genes from a patient with mixed cryoglobulinemia. We show that the CD5-negative monoclonal B cells express a slightly mutated V kappa 3 gene, but a more mutated VH1 gene whose genomic counterpart was shown to be the 51p1 germline gene. The sequence analysis of several independent clones shows some degree of intraclonal diversity, suggesting the existence of a clonal filiation. These results are discussed in terms of the origin of the monoclonal B cell during mixed cryoglobulinemia and CLL.

Antibodies, Monoclonal↗
PubMed1995

Somatic mutations detected by mini- and microsatellite DNA markers reveal clonal intratumor heterogeneity in gastrointestinal cancers.

We investigated clonal intratumor heterogeneity by comparing different areas of each tumor in 20 gastrointestinal cancers from female patients (1 esophageal cancer, 5 stomach cancers, and 14 colorectal cancers). In all 19 cases informative for X-inactivation analysis with the M27 beta and/or the phosphoglycerate kinase probes, the tumors were clonal. Separate areas from a given tumor showed identical X-inactivation patterns, providing evidence for its single-cell origin. Of 20 cancers, 11 showed p53 gene mutations (base pair insertions, point mutations, and one case of a base pair deletion) in exons 5-8. A particular p53 gene mutation was identical in all tumor areas investigated per case. The minisatellite probes detected loss of heterozygosity or new mutant alleles at 1p33, 1q21, 5q35, 17p13, or 18q21. In seven cases mutations at particular loci were restricted to one or two areas per tumor, while in another seven cases they were common to all tumor areas. Loss of heterozygosity or new alleles detected at the microsatellite loci D2S123, D3S1611, D5S107, D17S261, or D18S34 [(CA)n repeats] were common to all tumor areas in 7 of 19 cases. In another seven cases, however, microsatellite mutations at these loci were restricted to one to three areas per tumor. Tracing clonal intratumor heterogeneity would permit one to study the hierarchy of mutational events in cancers where no premalignant lesions can be harvested. Most important, our study indicates that clonal intratumor heterogeneity might lead to sampling errors in the molecular diagnosis of cancer biopsy specimens when using mini- or microsatellite markers.

Alleles↗
PubMed1994

Database of p53 gene somatic mutations in human tumors and cell lines.

A data base is described in which over 2,500 mutations in the p53 gene of human tumors and tumor cell lines are compiled from a systematic search of reports published before 1 January 1994. Data from 1994 are being added intermittently, with a systematic search and update scheduled for December, 1994. The compilation has been deposited with the EMBL Data Library and is available in electronic form free of charge. This report contains a rationale for the compilation, a brief summary of the major findings and a description of the data base.

DNA Mutational Analysis↗
PubMed1994

IgMs produced by two acquired immune deficiency syndrome lymphoma cell lines: Ig binding specificity and VH-gene putative somatic mutation analysis.

Two B-cell lines, 2F7 and 10C9, were established by single cell cloning from biopsies obtained from two acquired immune deficiency syndrome patients with Burkitt's lymphoma. Representation of the original tumors was verified by demonstration of (1) identical biallelic rearrangement of Ig genes for 2F7 and (2) shared idiotype for 10C9. Both cell lines displayed cell-surface Ig and secreted Ig (IgM lambda for 2F7, IgM kappa for 10C9). IgMs from both cell lines immunoprecipitated actin; in addition, 2F7 IgM lambda immunoprecipitated recombinant human immunodeficiency virus type 1 (HIV-1) gp 160. 2F7 IgM lambda did not react with other autoantigens (double-stranded and single-stranded DNA, actin, bovine serum albumin, IgG), whereas 10C9 IgM kappa reacted with human IgG. The 2F7 IgM heavy-chain variable region (VH) showed a 95% nucleotide homology with a previously sequenced VHIII germline gene, hv3019b9, whereas the 10C9 IgM VH showed a 95% homology with a previously sequenced VHIV germline gene, VH4.21. Use of minimally modified VH genes and demonstration of reactivity with chronically present antigens (ie, actin, HIV-1 gp 160, or human IgG) suggests that B cells in HIV-1-infected individuals proliferating in response to chronic antigenic stimulation may be at increased risk for lymphomagenesis.

Amino Acid Sequence↗
PubMed1995

Infrequent somatic mutations of the p16 and p15 genes in human bladder cancer: p16 mutations occur only in low-grade and superficial bladder cancers.

A recently identified gene, p16, located on chromosome 9p21, has been shown to be deleted and/or mutated in various types of human cancers. To investigate structural alterations of p16 and a neighboring gene, p15, we examined human bladder cancers for mutations in the entire coding region of these genes using polymerase chain reaction and single-strand conformational polymorphism analysis. Of 50 samples obtained from patients with bladder cancer, 3 (6%), all low-grade and superficial tumors, were found to have p16 gene alterations. The alterations included 1 missense mutation and 2 single-base deletions. We found no p15 gene mutations in these 50 bladder cancers. Our results suggested that p16 gene mutations, although they occurred at low frequency, are involved in some low-grade and early stage bladder cancers.

Base Sequence↗
PubMed1997

Somatic mutations of PTEN in glioblastoma multiforme.

Alterations of the PTEN gene occur in glioblastoma multiforme. To determine the frequency of PTEN alteration, 34 consecutive glioblastomas were studied in detail. Sequencing each of the nine exons amplified from tumor DNA revealed 11 mutations. Analysis of polymorphic markers within and surrounding the PTEN gene identified an additional four homozygous deletion mutations. Loss of heterozygosity (LOH) was observed in 25 of 34 (74%) cases. All mutations occurred in the presence of LOH. PTEN was mutated in 44% (15 of 34) of all glioblastomas studied and 60% (15 of 25) of tumors with LOH on 10q. Thus, PTEN appears to be the major target of inactivation on chromosome 10q in glioblastoma multiforme.

Astrocytoma↗
PubMed1998

Somatic mutations that contribute to breast cancer.

Cytogenetic and molecular analyses of primary sporadic human breast carcinomas have documented at least 12 different chromosome arms affected by loss of heterozygosity (LOH). This has been taken as evidence for the presence of putative tumour suppressor genes in the remaining allele within the affected regions. We have previously identified three regions on chromosome 17q that are affected by LOH in primary human breast tumours. A physical map of one of these regions (17q21) has been prepared. The putative target gene appears to be located between the D17S846 and D17S746 loci. We are currently determining whether either of two genes located in this region is the target for LOH. The mouse mammary tumour model system provides an approach for identifying genes which, when activated or inactivated by mouse mammary tumour virus (MMTV) integration, contribute to specific stages of mammary tumorigenesis. Using this approach we have identified two genes, designated NOTCH4/INT3 and INT6 respectively. Interruption of NOTCH4/INT3 by MMTV represents a gain-of-function mutation that has profound consequences for mammary gland development and tumorigenesis. INT6 was found to be interrupted by an integrated MMTV genome in a mammary hyperplastic outgrowth line and two independent mammary tumours. In each case the transcriptional orientation of the viral genome was opposite to that of INT6. The rearranged allele was expressed as a truncated chimaeric RNA species composed of INT6 coding sequences, intron sequences and MMTV sequences. Since the non-rearranged allele contained no mutations, we conclude that MMTV integration into INT6 causes a dominant-negative mutation or biologically activates its function. The nucleotide sequence of INT6 is unrelated to any of the known genes in the GenBank database, but is evolutionarily highly conserved.

Animals↗
PubMed1998

New somatic mutation in the PIG-A gene emerges at relapse of paroxysmal nocturnal hemoglobinuria.

We report a detailed longitudinal study of the first patient to be treated (in 1973) for paroxysmal nocturnal hemoglobinuria (PNH) with syngeneic bone marrow transplantation (BMT). The patient subsequently relapsed with PNH in 1983, and still has PNH to date. Analysis of the PIG-A gene in a recent blood sample showed in exon 6 an insertion-duplication causing a frameshift. Polymerase chain reaction (PCR) amplification of the PIG-A exon 6 from bone marrow (BM) slides obtained before BMT showed that the duplication was not present; instead, we found several single base pair substitutions in exons 2 and 6. Thus, relapse of PNH in this patient was not due to persistence of the original clones; rather, it was associated with the emergence of a new clone. These findings support the notion that the BM environment may create selective conditions favoring the expansion of PNH clones.

Adolescent↗