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In the debate about the mechanism for the generation of immunological diversity, the initial positions of both 'somaticists' and 'germliners' were diametrically opposed. Then, as data developed favoring first one and then the other side, concessions were made, until the final solution showed that each had been at least partially correct.
The tumour suppressor gene PTEN/MMAC1, which is mutated or homozygously deleted in glioma, breast and prostate cancer, is mapped to a region of 10q which shows loss of heterozygosity (LOH) in bladder cancer. We screened 123 bladder tumours for LOH in the region of PTEN. In 53 informative muscle invasive tumours (> or = pT2), allele loss was detected in 13 (24.5%) and allelic imbalance in four tumours (overall frequency 32%). LOH was found in four of 60 (6.6%) informative, non-invasive tumours (pTa/pT1). We screened 63 muscle invasive tumours for PTEN mutations by single-strand conformation polymorphism (SSCP) analysis and for homozygous deletion by duplex quantitative polymerase chain reaction (PCR). Two homozygous deletions were identified but no mutations. Of 15 bladder tumour cell lines analysed, three showed homozygous deletion of all or part of the PTEN gene, but none had mutations detectable by SSCP analysis. Our results indicate that PTEN is involved in the development of some bladder tumours. The low frequency of mutation of the retained allele in tumours with 10q23 LOH suggests that there may be another predominant mechanism of inactivation of the second allele, for example small intragenic deletions, that hemizygosity may be sufficient for phenotypic effect, or that there is another target gene at 10q23.
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There is continued controversy as to the sequential steps and mechanism(s) responsible for the in vivo acquisition of multiple mutations during neoplastic transformation. We investigated the in vivo clonality and mutational spectra of hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations in T cells from children with acute lymphocytic leukemia (ALL) to gain insight into the mutagenic mechanisms associated with leukemogenesis. We observed several instances of multiple, independent HPRT mutations accumulating in vivo in T cell receptor (TCR) gene defined clones that had undergone extensive pre- and/or post-thymic expansion following chemotherapy. In addition, we also detected the accumulation of multiple unique single mutations within distinct expanding post-thymic T cell clones. This pattern of clonally restricted hypermutability is compatible with extensive cell proliferation and selection alone without postulating genomic instability. These observations provide a paradigm for a continuum of cellular events that eventually results in the clonal accumulation of mutations in selected populations of cells in vivo and may provide insight into the primary genetic events associated with leukemogenesis, as well as the development of second malignancies and drug resistance following chemotherapy.
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Previous studies have demonstrated frequent allelic losses of distal chromosome 11q in ovarian carcinomas. The tumor suppressor gene(s) presumably targeted by these losses have not yet been identified. PPP2R1B is a candidate tumor suppressor gene at 11q23 that has recently been shown to be mutated in a subset of colorectal and lung cancers. We evaluated 5 ovarian carcinoma cell lines and 27 primary ovarian carcinomas for allelic losses of 11q23 and for mutations in the open reading frame of PPP2R1B. We also evaluated the primary tumors for allelic losses at 17p13, another chromosomal region frequently affected by losses of heterozygosity (LOH) in ovarian cancers. 11q23 and 17p13 allelic losses were identified in 25% and 74% of the carcinomas, respectively. No mutations within PPP2R1B coding sequences were found. These findings indicate that mutations of the PPP2R1B gene are infrequent in ovarian cancer and that deletions affecting the distal portion of chromosome 11q in ovarian cancer likely target inactivation of other genes.
The naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility, in particular to basal cell carcinomas (BCCs). Medulloblastomas, primitive neuroectodermal tumours (PNETs) arising in childhood, occur in about 3-5% of NBCCS patients and a subset of PNETs was previously found with allelic imbalance at 9q22-q23, the region containing the gene for NBCCS (PTCH). We have analysed tumour DNA samples from 37 unrelated patients with sporadic PNETs and five medulloblastoma cell lines for PTCH mutations using an exon-by-exon single strand conformation polymorphism assay. We found three missense mutations, which affect conserved residues in transmembrane domains of the gene product and in the extracellular loop implicated in binding sonic hedgehog, one 2 bp deletion and an exon skipping splice site mutation. Most mutations were associated with the absence of the wild-type allele and were found in tumours exhibiting loss of heterozygosity (LOH) at loci flanking PTCH. The finding of LOH at 9q22-q23 in most mutated tumours while present in only three out of 26 tumours, in which a mutation was not identified, implicates PTCH as the target gene in PNETs with LOH at 9q22-q23 and deficient PTCH in the development of a subset of these tumours. Since all observed mutations were absent in the germ-line, a sporadic medulloblastoma developing as the first symptom of NBCCS is likely to be a very uncommon event.
Missense mutations in p53 frequently occur at 'hotspot' amino acids which are highly conserved and represent regions of structural or functional importance. Using the p53 mutation database and the p53 DNA sequences for 11 species, we more precisely defined the relationships among conservation, mutation frequency and protein structure. We aligned the p53 sequences codon-by-codon and determined the degree of substitution among them. As a whole, p53 is evolving at an average rate for a mammalian protein-coding gene. As expected, the DNA binding domain is evolving more slowly than the carboxy and amino termini. A detailed map of evolutionary conservation shows that within the DNA binding domain there are repeating peaks and valleys of higher and lower evolutionary constraint. Mutation hotspots were identified by comparing the observed distribution of mutations to the pattern expected from a random multinomial distribution. Seventy-three hotspots were identified; these 19% of codons account for 88% of all reported p53 mutations. Both high evolutionary constraint and mutation hotspots are noted at amino acids close to the protein-DNA interface and at others more distant from DNA, often buried within the core of the folded protein but sometimes on its surface. The results indicate that targeting highly conserved regions for mutational and functional analysis may be efficient strategies for the study of cancer-related genes.
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Paroxysmal nocturnal haemoglobinuria (PNH), aplastic anaemia (AA) and myelodysplastic syndrome (MDS) are haemopoietic stem cell disorders. These disorders have some features in common, and a percentage of cases progress to acute leukaemia. We speculated that changes in gene stability are involved in the pathogenesis of these haemopoietic stem cell disorders. Therefore we investigated in vivo mutation frequencies in these disorders by erythrocyte glycophorin A (GPA) mutation assay. The assay enumerates NO or NN variant cells in 106 erythrocytes of the MN type using a flowcytometric technique. Patients undergoing chemotherapy known to be at risk of hypermutageneity were also studied. Events exceeding the 95th percentile of healthy donors (> or = 32 and 34 events, respectively for NO and NN variants) were defined as abnormal. Abnormal events in the NO variants were found in three out of seven patients undergoing chemotherapy, two out of nine patients with AA, two out of seven patients with MDS, and four out of nine patients with PNH. Abnormal events in the NN variants were found in three out of seven patients undergoing chemotherapy, two out of nine patients with AA, one out of seven patients with MDS, and two out of nine patients with PNH. These results suggest that not only PIG-A, but also other genes including the GPA gene, are hypermutable in haemopoietic stem cell disorders, and that mutagenic pressure and/or gene instability can contribute to the pathogenesis of these disorders.
BACKGROUND: Lack of androgen receptor (AR) expression or mutation on the AR gene creates the tendency for androgen independence and progression of prostate cancer. However, the association between the progression and AR expression or mutations is still controversial. In this study, we evaluated the prognostic significance of AR expression and mutations in prostate cancers. METHODS: Forty-two prostate adenocarcinomas and three lymph node metastatic lesions sampled prior to hormonal therapy were included in this study; AR expression was analyzed immunohistochemically using an antibody against AR and the result was scored as the percentage of AR-positive tumor cells in the total tumor cells. Polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis and DNA sequencing were used to detect AR mutations. RESULTS: Our study revealed the average AR expression in the prostate adenocarcinoma was 52.2 +/- 27.1%, which was significantly lower than that in the adjacent non-tumorous prostate tissue (68.3 +/- 18.3% in average) (P < 0.001). A significant correlation was obtained between progression-free survival and AR expression (P < 0.01). By SSCP analysis, three silent mutations (T649T, E709E and E711E) were detected in three separate prostate carcinomas. CONCLUSION: : We conclude that AR expression is a useful prognostic indicator for tumor progression. Androgen receptor mutation may be an uncommon molecular event in untreated prostate cancer in Japanese men.
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