The rate of mortality from cancer changed very little over the past 50 years; however, during the past decade, perceptions about this situation have changed rapidly, primarily because the description of cancer in molecular terms has significantly improved the ways in which human cancers are detected (often in early stages), classified, monitored and, more importantly, treated. As a consequence, we are witnessing the start of a new exciting era in cancer research. A milestone has been the formalization of the concept that cancer is a genetic disease. This concept, however, lumps together two types of genetic diseases with the same outcome: the first linked to an entirely somatic cellgene deregulation and the second linked to genetic susceptibility. At the somatic cell level, deregulation of cancer genes that control the careful balance between increase in cell number and withdrawal from the cell cycle promotes neoplastic growth by disrupting this balance, which occurs as a result of circumvention of the apoptotic machinery, promotion of cell division and cell proliferation, loss of cell differentiation pathways, and disruption of cellcell communication and interaction. Thus, cancer represents the endpoint of a multistep process involving cancer genes and stimulatory and inhibitory signals provided by and controlled by products of the cancer genes. An additional feature of the cancer phenotype is the capability of cancer cells to modify their environment. This concept includes the promotion of angiogenesis, the degradation of stroma organization, and the production of factors related to inflammatory processes. In the first type of genetic disease, alterations in cancer genes can involve either dominant, gain-of-function mutations within proto-oncogenes that result in abnormal positive signals for cell proliferation or recessive, loss-of-function mutations within the tumor suppressor genes (TSG) that interfere with the negative regulation of cell growth. Mutations within TSG also may have a dominant-negative effect, one in which an altered protein is produced that competes with its wild-type counterpart and prevents its activity. Mutant versions of TSG TP53 provide an example of such a mechanism. A third type of cancer gene has been identified in colorectal tumors associated with hereditary nonpolyposis colorectal cancer (HNPCC). These genes control mismatch repair (MMR), a process associated with the fidelity of DNA replication, and have been designated mutator genes. Their alterations cause microsatellite instability (MSI), characterized by random contractions or expansions in the length of simple sequence repeats (SSR) or microsatellites, and may have important prognostic implications. The second type of genetic disease is based on the recognition of a genetic susceptibility in approximately 810% of patients with cancer. This latter disease results from the inheritance of altered alleles of genes, which are almost always TSG. With few relevant exceptions, such as RET proto-oncogene mutated in familiar medullary thyroid carcinomas and in tumors included in multiple neoplasia type-2 syndromes. Along with different penetrance, this tumor-suppressor type determines the genetic risk of cancer, which can be almost 100% during a lifetime. In all cases, including those genes that predispose to a genetic risk of cancer , alterations of cancer-associated genes define molecular markers Table 3.1. These markers are useful for novel diagnostic approaches and for genetic profiling of the tumor cell, with the aim of providing better prognostic evaluation and prediction of therapeutic drug response. In particular, the introduction into clinics of novel therapeutic molecules designed to interfere with target representing the altered genetic elements of the relevant pathogenetic pathway(s) in a given tumor, has increased the number of models of the so called "personalized or targeted therapy." To provide a more rational view of the problems, this chapter organizes the subject by discussing genetic markers from cancer-associated genes that were altered by point mutation, deletion, or inappropriate expression at somatic cell level. The classes of genetic markers derived from chromosomal instability and from nonrandom chromosomal abnormalities and generating tumor-specific fusion product are also discussed.
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