Mutations And Cancer

Mutation is the ultimate source of variability for individual cells (and organisms) and is an essential component of the

From: Molecular Diagnostics: For the Clinical Laboratorian, Second Edition

Edited by: W. B. Coleman and G. J. Tsongalis © Humana Press Inc., Totowa, NJ

process of natural selection (16). Tumorigenesis can be viewed simply as a process of natural selection in which cells develop a growth advantage that allows them to proliferate and invade under conditions where other (normal) cells cannot, and the acquisition of this ability is driven by mutation. In other words, tumor development and progression represents a form of somatic evolution, at the ultimate expense of the host organism (17). The idea that somatic mutation could significantly contribute to cancer development was suggested by Boveri early in the 20th century (18). At about the same time, De Vries proposed that certain forms of radiation (Röntgen rays) might be mutagenic (17), suggesting that mutation rates could be influenced by exogenous factors. Evidence in support of the idea that multiple somatic mutations occur in and contribute to the stepwise process of neoplastic transformation and tumorigene-sis has been provided by numerous investigators (19-22). In early studies, the nature of the mutations and the contribution of these mutations to tumorigenesis were not at all clear. Nonetheless, the presence of multiple mutations in cancer cells could be observed in the form of karyotypic alterations and abnormal chromosome numbers in tumor cells (23,24). More recent studies utilizing comparative genomic hybridization extended these observations by identifying both gross (cytoge-netically detectable) and subtle chromosomal abnormalities in several types of human neoplasm (25). Subsequently, numerous positive and negative mediators (proto-oncogenes and tumor suppressor genes) of cell growth and differentiation have been identified and characterized, defining the basic role for these critical genetic elements in neoplastic transformation and tumorigenesis (2,3,26). Very recently, microarray-based gene expression studies have provided definitive evidence that cancer is ultimately a disease of abnormal gene expression patterns (27-30). Somatic mutations occurring in developing cancers alter gene expression patterns, resulting in significant changes to cellular physiology, including unregulated (or abnormally regulated) cell proliferation and acquisition of invasive behaviors (31,32). These investigations have shown that the gene expression signature of a specific cancer can be used in differential diagnosis, prognostication, and prediction of responses to therapy (33,34).

The exact number of critical mutations required for neoplas-tic transformation of normal cells is not known. Investigations involving the statistical analysis of human tumor incidence and natural history in sporadic and inherited human tumors formed the basis for the two-hit model of cancer development (35,36). In this model, genetic predisposition for a specific type of neoplasm is conferred on an individual who either inherits or otherwise acquires a germline mutation in one allele of a critical target (such as a tumor suppressor gene), constituting the first "hit." The second "hit" represents an acquired somatic mutation in the remaining normal allele of the critical gene. Accumulation of two hits alters (or eliminates) normal gene function in affected cells, which proliferate to form a tumor. Although the kinetics of tumor formation for some neoplasms are consistent with this model, it is now recognized that neoplas-tic transformation involves the mutational alteration or aberrant expression of multiple genes that function in cell proliferation or differentiation. Furthermore, epigenetic mechanisms can contribute to the multihit model of cancer induction through the silencing of critical genes (37-39). In recent years, a reexamination of the number of critical mutations needed for cancer development has led to the suggestion that as many as six to eight mutations might be necessary for progression to an invasive tumor (5,10). These analyses provide estimates of the numbers of mutations involving genes that control proliferation and differentiation of specific cell types that might be necessary for neoplastic transformation of that cell type. However, numerous lines of evidence support the suggestion that tumors are mutation-prone and/or accumulate large numbers of mutations (12,40,41), and some investigators have estimated that tumor cells could contain thousands or tens of thousands of mutations (42,43).

Was this article helpful?

0 0
Get Pregnant - Cure Infertility Naturally

Get Pregnant - Cure Infertility Naturally

Far too many people struggle to fall pregnant and conceive a child naturally. This book looks at the reasons for infertility and how using a natural, holistic approach can greatly improve your chances of conceiving a child of your own without surgery and without drugs!

Get My Free Ebook

Post a comment