Inactivation Of Suppressor Genes Research Articles

Evaluation of the replication error phenotype in relation to molecular and clinicopathological features in hereditary and early onset colorectal cancer

Mutations affecting human mismatch repair (MMR) genes (MLH1, MSH2, PMS1, PMS2, and MSH6) cause tumour predisposition in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and an association has been demonstrated with the replication error (RER) phenotype in most colorectal and some extracolonic neoplasms. A pathogenetic model for RER+ tumours through inactivation of suppressor genes has been hypothesised, and TGFβRII, BAX and IGFIIR genes have recently been proposed as targets of such inactivating mutations. In this study, a series of 47 tumours developed in patients with known MLH1/MSH2 status and a family history of HNPCC and/or early onset colorectal cancer were characterised for the RER phenotype through microsatellite analysis. The RER phenotype, displayed by 17 tumours, was then correlated with the presence of insertions/deletions at the TGFβRII, IGFIIR and BAX gene stretches, confirming that the TGFβRII inactivation may be particularly critical for the RER-associated tumorigenesis. RER+ colorectal cancers (CRCs) developed more frequently in patients from HNPCC families (72.7%) than in those from families not fulfilling the Amsterdam criteria (33.3% in suspected HNPCC and 20.8% in early onset CRC patients). A consistent fraction of either Amsterdam and non-Amsterdam patients developed RER− CRCs, pointing to the involvement of other genes not related to the MMR system. The RER phenotype was associated with younger age at diagnosis in familial cases, and there was a trend for an association with proximal CRC localisation and early Dukes’ stages. The RER status was also correlated with the presence and type of MLH1 and MSH2 alteration.

The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia.

An overall hypothesis for benzene-induced leukemia is proposed. Key components of the hypothesis include a) activation of benzene in the liver to phenolic metabolites; b) transport of these metabolites to the bone marrow and conversion to semiquinone radicals and quinones via peroxidase enzymes; c) generation of active oxygen species via redox cycling; d) damage to tubulin, histone proteins, topoisomerase II, other DNA associated proteins, and DNA itself; and e) consequent damage including DNA strand breakage, mitotic recombination, chromosome translocations, and aneuploidy. If these effects take place in stem or early progenitor cells a leukemic clone with selective advantage to grow may arise, as a result of protooncogene activation, gene fusion, and suppressor gene inactivation. Epigenetic effects of benzene metabolites on the bone marrow stroma, and perhaps the stem cell itself, may then foster development and survival of the leukemic clone. Evidence for this hypothesis is mounting with the recent demonstration that benzene induces gene-duplicating mutations in human bone marrow and chromosome-specific aneuploidy and translocations in peripheral blood cells. If this hypothesis is correct, it also potentially implicates phenolic and quinonoid compounds in the induction of "spontaneous" leukemia in man.

La citogenetica e la genetica molecolare nella prognosi del carcinoma della vescica: Cytogenetics and molecular genetics in bladder carcinoma prognosis

The use of cytogenetics in the characterization of bladder tumours has made it possible to demonstrate that chromosomal alterations are correlated with stage and grade of the tumour and have a predictive value as regards both tumour recurrences and progression. In the last decade the chromosomes involved in the main aberrations have been identified, and a negative prognostic significance has been suggested for some chromosomal aberrations. The knowledge of cytogenetics has been deepened by the sophisticated methods of molecular genetics, that have discovered many oncogenes and suppressor genes probably involved in the development of bladder tumours. The most characteristic molecular alterations of these tumours are losses of genetic information on chromosomes 9, 11 and 17, as a consequence of deletions and/or mutations. Such alterations probably cause the loss and/or the inactivation of suppressor genes (partly hypothetic still) and could represent important predictive factors of tumour progression.

Recessive oncogenes.

Tumor-suppressor genes (antioncogenes or recessive oncogenes) are cancer genes that achieve their oncogenic effect by mutational inactivation of both normal alleles. By contrast, oncogenes are created from protooncogenes by mutations that lead to aberrant functional activation. Mutation of multiple suppressor genes and/or oncogenes probably is required for the genesis of most human neoplasms. Two well-characterized tumor-suppressor genes, the retinoblastoma gene (rb) on chromosome 13q and p53 on chromosome 17p, frequently are mutated in a broad range of human cancer types. Mutations of these genes have been documented in prostate carcinoma but appear to affect only a subset of cases. Nevertheless, as in other cancers, introduction of normal copies of rb or p53 suppresses the neoplastic properties of prostatic tumor cells carrying mutated alleles of the relevant gene. These results suggest that mutation of rb or p53 is involved in the genesis or progression of some prostate cancers. Frequent allelic losses of certain chromosome arms (especially 8p, 10p and q, and 16q) from prostatic cancer cells may indicate the involvement of novel suppressor genes located in these regions. Although the inactivation of suppressor genes appears to be a common genetic mechanism in human oncogenesis, the rates of mutation of particular genes vary widely with the type of cancer. It is unknown whether prostate cancers with or without mutation of rb, p53, or other suppressor loci differ biologically or prognostically; this is an area of active investigation. Fundamental understanding of the genetic lesions that occur during human oncogenesis has great potential for clinical application in diagnosis, prognosis, and therapy.

Point Mutations, Deletions, and Radiation Carcinogenesis

A recent symposium summary and a letter in Radiation research prompt several comments. Fry, in his summary (1), asks: "Are deletions and perhaps changes in suppressor genes more important in radiation carcinogenesis than are point mutations?" Sentiments along similar lines have been expressed by Weischselbaum and his co-workers (2, 3). Rossi in his letter (4) based on microdosimetric considerations suggests that the production of point mutations is likely to be due to single ionization events, while large deletions are likely to be the result of "two-hit" processes, which can occur in much larger target volumes. He concludes that the event frequency (per gray) for large deletions is much higher than for point mutations and hence that suppressor genes frequently play the predominant role in radiation carcinogenesis. I should like to make the following points: (i) Carcinogenesis is generally regarded as a multistep process, involving various genetic changes, such as the activation of proto-oncogenes, the inactivation of suppressor genes, and the functional inactivation of genes which control cellular senescence [see for example Ref. (5); for review see Ref. (6)]. Each step is a sine qua non for full tumorigenicity; no event can be regarded as more significant than another. Indeed, studies of the clinical progression of colorectal tumors and of glioblastomas (7, 8) have identified genetic aberrations corresponding either to mutations or to deletions and even to amplifications, all of which appear to be equally important. (ii) DNA deletions and rearrangements can materially affect the expression (at the transcriptional and translational levels) of proto-oncogenes, thus converting them to full-blown oncogenes; such DNA deletions are thus not restricted to suppressor genes alone. A good case in point is the induction of skin tumors in rats (9, 10) by low-LET radiation (0.8-MeV electrons). DNA from 10 of the 12 tumors showed amplification of the third exon of the c-myc oncogene, and deletion of the first exon, which is known to regulate expression of the gene. (iii) Rossi (4) argues (correctly, I believe) that the production of point mutations is quite unlikely to be due to multiple ionization events. He then concludes that such production is therefore dose-rate independent and cannot be a major cause of radiation carcinogenesis when it is reduced by dose protraction. This point is open to question. It should be noted that point mutations are the result of the misrepair of a DNA lesion. It is conceivable that cellular repair processes (or a component thereof) are dose-rate dependent; in particular, at high dose rate error-prone repair pathways may predominate over high-fidelity repair mechanisms. A number of reports have demonstrated that mutation induction is in fact decreased when the radiation dose is fractionated or delivered at a low dose rate (11, 12). These studies involve traditional mutation assays, namely induction of resistance to selective agents, and it is not clear if the proliferating mutant cells are the result of gene deletion or of point mutations. Clarity on this issue awaits the results of DNA sequencing experiments. In the interim, a useful pointer can be obtained from Southern blot experiments. For example, Hill and Zhu (13) have shown that, of 21 independent mutations (in the HPRT gene) induced by 7 rays, fully one-third showed no observable change in the banding pattern of the gene. This implies that these mutants are due to extremely small deletions or to point mutatio s. In addition, a recent analysis' of the y-ray-induced mutations at the human HPRT locus showed that up to 50% were due to point mutations or small (2 bp) deletions. (iv) In a series of experiments, Pellicer and colleagues (14, 15) have identified activated K-ras oncogenes in four of seven radiation-induced mouse lymphomas. These genes were all activated by point mutations in the 12th codon of the gene. The work of Sawey et al. (9) is consistent with these findings; 6 out of 12 tumors exhibited point mutati ns in the K-ras gene. It is thus clear that point mutations are frequently found in tumors initiated by radiation. However, it is improbable that the incident radiation could have directly produced alterations in such a small DNA target with such a high (observed) frequency. This remains one of the basic conundrums of radiobiology. Perhaps the answer

Co-deletions of the Retinoblastoma Gene and Wilms' Tumor Gene and Rearrangement of the Krev-1 Gene in a Human Insulinoma

We found deletions of both alleles of the retinoblastoma gene (Rb) and the candidate Wilms' tumor gene (WT33) in a surgically resected human insulinoma by blot hybridization. Rearrangement of Krev-1, a transformation suppressor gene, was also detected in this case. The clinical and histological findings suggested that this tumor would be a benign insulinoma. The result suggests that the inactivation of multiple tumor suppressor genes could be involved even in the development of benign human tumors.