Genetic alterations and DNA repair in human carcinogenesisGenetic alterations in cancerMutation spectraMutation avoidance: DNA repair and checkpoint pathwaysMutators, cell proliferation, and cancer development - how many mutations?Epigenetic mechanisms of gene activation and silencingConcluding remarksAcknowledgementsReferencesSeminars in Cancer Biology 14 (2004) 441–448Genetic alterations and DNA repair in human carcinogenesisKathleen Dixon∗, Elizabeth KoprasDepartment of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USAAbstractA causal association between genetic alterations and cancer is supported by extensive experimental and epidemiological data. Mutationalinactivation of tumor suppressor genes and activation of oncogenes are associated with the development of a wide range of cancers. Thelink between mutagenesis and carcinogenesis is particularly evident for cancers induced by chemical exposures, which, in some cases,lead to characteristic patterns of mutations. These “genotoxic,” direct-acting carcinogens form covalent adducts with DNA, which causemutations during DNA replication. The link between mutagenesis and carcinogenesis is also supported by the observation that DNA repairdefects are associated with an increased cancer risk. Normally, DNA repair mechanisms serve to suppress mutagenesis by correcting DNAdamage before it can lead to heritable mutations. It has been postulated that mutagenesis plays a role in both the initiation phase and theprogression phase of carcinogenesis, and that an essential step in the carcinogenic process is the development of a mutator state in whichthe normal cellular processes that suppress mutagenesis become compromised. Given the link between mutations and cancer, attemptshave been made to use the mutational profile of cancer cells as an indicator of the causative agent. While this may be a valid approach insome cases, it is complicated by the role of endogenous processes in promoting mutagenesis. In addition, many important carcinogenicagents may enhance mutagenesis indirectly through suppression of DNA repair functions or stimulation of inappropriate cell proliferation.Epigenetic phenomena may also suppress gene expression without causing overt changes in DNA sequence.© 2004 Elsevier Ltd. All rights reserved.Keywords: DNA repair; Mutagenesis; Tumor suppressors; Oncogenes1. Genetic alterations in cancerThe association between genetic alterations and humancancer was first observed decades ago [1]. Cytogenetic stud-ies revealed that specific chromosomal abnormalities werelinked to the development of certain cancers. For exam-ple, a chromosomal translocation (the Philadelphia chromo-some) was frequently found in white blood cells of leukemiapatients. In addition, tumor cells often exhibited extensivegenetic instability leading to chromosome aberrations, re-arrangements, and aneuploidy. However, it was not clearwhether this widespread genetic instability was a cause ora consequence of the cancer phenotype. An understand-ing of the role of genetic alterations in cancer developmentarose out of studies of oncogenic viruses and hereditarycancers. RNA tumor viruses were found to express certain“oncogenes” (e.g., c-ras and c-myc) that contributed to thetransforming activity of the viruses and that had homologouscounterparts (proto-oncogenes) in the human genome. Later,it was shown that RAS and MYC were over-expressed incancer cells, often due to genetic translocations that placed∗Corresponding author. Tel.: +1 513 558 1728; fax: +1 513 558 3509.E-mail address: [email protected] (K. Dixon).the genes under the control of strong heterologous promo-tors. The study of human retinoblastoma led to the discov-ery of the RB tumor suppressor gene; loss of function ofthis gene through inheritance of one mutant allele and thesomatic loss of the other allele lead to the formation of reti-nal tumors in children. Another important tumor suppressorprotein, p53, was first identified as a target for the SV40 tu-mor virus, and was later found to be inactivated in a varietyof tumor cells, and also in Li-Fraumeni syndrome, which isassociated with a high cancer risk. Both point mutations anddeletions are found among inherited and somatic mutationsthat inactivate RB and TP53; in addition, loss of the secondallele in the inherited cancers can often occur though lossof part or all of one of two homologous chromosomes.A large number of tumor suppressor genes and oncogeneshave now been identified and characterized through the anal-ysis of tumor cell DNA [1–4]. It has been postulated that theminimum constellation of mutations required for oncogenictransformation in humans includes inactivation of TP53 andRB, activation of RAS (or other members of that pathway),and constitutive expression of hTERT [5–7]. These genescontrol cellular functions that prevent uncontrolled prolif-eration (Fig. 1). The most prevalent mutations in humancancers occur in the tumor suppressor genes, TP53 and RB1044-579X/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.semcancer.2004.06.007442 K. Dixon, E. Kopras/Seminars in Cancer Biology 14 (2004) 441–448Fig. 1. Genetic alterations in cancer. Cancer develops over time as aconsequence of successive mutation and expansion of mutant clones. Mu-tations that inactivate tumor suppressor genes, activate proto-oncogenes,and turn on telomerase stimulate cell proliferation and inhibit cell death,providing a growth advantage.[5]. Both base substitution mutations and gene deletions inthese genes are found in a wide variety of cancer types [8].The Rb protein is a key regulator of the cell cycle, and lossof this function can lead to increased cell proliferation anda failure in terminal differentiation, i.e., an increase in the“birth rate” of cells [7]. The p53 protein is important in cel-lular responses to stress, controlling DNA repair, cell cyclecheckpoints, and apoptosis [9]. Perhaps, the most importantof these pathways for cancer development is apoptosis; lossof p53 function can lead to decreased apoptosis, i.e., a de-crease in the “death rate” of cells. Thus, loss of these two tu-mor suppressor genes leads to a net increase in cell numbersdue to an increased birth rate and a decreased death rate.Cancer development can also be promoted through mu-tations that activate the expression of proto-oncogenes thatregulate cell proliferation [5]. These are genes