Cancer surveys最新文献

There is strong evidence that DNA methylation is not a neutral bystander in carcinogenesis, but actively contributes to the process. Methylation of cytosine is known to promote mutation to thymine, and there are many examples of tumours in which tumour suppressor proteins have been rendered functionless by methylation induced mutations of this kind. There is also evidence that tumour suppressor genes can be silenced epigenetically by de novo methylation of their CpG islands in the absence of any predisposing mutation. Although the experimental results in favour of the idea are becoming highly suggestive, it is too early to consider involvement of purely epigenetic processes as proven. New data bearing on this subject will doubtless be forthcoming.

Telomere attrition may regulate the proliferative life span of somatic cells and contribute to the genetic instability of tumour cells, and telomere maintenance is required for cell survival. The ample, but mainly correlative, evidence in support of these hypotheses is now beginning to be complemented by experimental results. There have also been unexpected findings that attest to the complexity of the biological processes and systems under study. Mammalian telomere biology has definitely entered into an exciting phase. Given the increasing pace of research on this topic, it seems most likely that a not too distant future will provide us with answers to many of the unresolved issues mentioned in this article.

All types of neoplasia that have been extensively examined, be they benign or malignant, are characterized by acquired chromosomal aberrations. In many instances, the changes are specific for the tumour type in question. Some tumours, even among the most malignant ones, have only a single chromosomal abnormality, whereas others have numerous secondary aberrations. Although an overall parallel exists between a tumour's malignancy and the number and complexity of its chromosomal changes, in some situations altered selection pressure may give rise to reduced karyotypic complexity with time. The effective causes of both primary and secondary chromosomal changes of neoplastic cells are largely unknown. In some special situations, in particular therapy induced acute leukaemias, exposure to a carcinogenic agent seems to have specifically induced the leukaemogenic genetic rearrangement. Patients carrying malignant neoplasms have in most studies been found to have normal chromosomal stability in their non-neoplastic somatic cells, both generally and at the genomic regions that are rearranged in their tumours. Although abnormal chromosomal fragility of cells belonging to the neoplastic parenchyma has not been convincingly demonstrated, the existence of such instability remains a viable, perhaps even necessary, hypothesis. To look for a unifying mechanism common to all neoplastic processes seems simplistic: specific mutagenesis giving rise to both primary and secondary chromosomal changes is likely to occur in some tumours, whereas in others random aberrations are generated, and at least as far as the secondary ones are concerned often at a higher than normal rate, followed by Darwinian selection for fitness within the host organism.

In this chapter we describe an assay for lymphocyte specific antigen receptor transrearrangements mediated by the V(D)J recombinase complex. Such transrearrangements occur in all normal individuals, are capable of increasing the immune repertoire and can be viewed as a readily available baseline measure of a type of genetic instability. In human and murine systems, the absolute number of some of these transrearrangements correlates at the population level with risk for the development of lymphoid malignancy.

Mutations that constitutively activate the alpha chains of Gs and Gi2 by inhibiting their intrinsic GTPase activity are present in human endocrine tumours. The gsp oncogene is mainly found in pituitary GH secreting tumours and thyroid hyperfunctioning adenomas, where it induces a constitutive activation of the adenylyl cyclase-cAMP pathway. In pituitary and thyroid cells, this signal leads to abnormal proliferation and a persistent activation of differentiated functions. The gip2 oncogene has been identified in tumours of the ovary and adrenal cortex. Although the mechanisms of the oncogenic action of mutationally activated alpha i2 are less clear than those of alpha s, the protein can induce transformation of certain cell types. At least five other alpha chains, which share with alpha s and alpha i2 common structural and functional mechanisms of GTP hydrolysis, activate mitogenic pathways leading to transformation. In addition, the G protein beta gamma subunits clearly control signals involved in cell growth. So far, there is no evidence for mutations of these molecules in human tumours. Further studies will tell us whether at present we know of only two members of a much larger family of G protein oncogenes.