title: Multiple mechanisms account for genomic instability and molecular mutation in neoplastic transformation.
abstract: Neoplastic cells typically possess numerous genomic mutations and chromosomal aberrations, including point mutations, gene amplifications and deletions, and replication errors. Acquisition of such genomic instability may represent an early step in the process of carcinogenesis. Proteins involved in DNA replication, DNA repair, cell cycle progression, and others are all components of complex overlapping biochemical pathways that function to maintain cellular homeostasis. Therefore, mutational alteration of genes encoding proteins involved in these cellular processes could contribute to genomic instability. Loss of normal cellular mechanisms that guard against genomic mutation and the ensuing genomic instability might lead to accumulation of multiple stable mutations in the genome of affected cells, perhaps resulting in neoplastic transformation when some critical number of transformation-related target genes become damaged. Thus, interactions of fundamental cellular processes play significant roles in sustaining cellular normality, and alteration of any of these homeostatic processes could entrain cells to the progressive genomic instability and phenotypic evolution characteristic of carcinogenesis. Here, we discuss possible molecular mechanisms governing DNA mutation and genomic instability in genetically normal cells that might account for the acquisition of genomic instability in somatic cells, leading to the development of neoplasia. These include (a) molecular alteration of genes encoding DNA repair enzymes, (b) molecular alteration of genes responsible for cell-cycle control mechanisms, and (c) direct molecular alteration of dominantly transforming cellular protooncogenes. We also discuss normal cellular processes involved with DNA replication and repair that can contribute to the mutational alteration of critical genes: e.g., slow repair of damaged DNA in specific genes, and the timing of normal gene-specific replication.
authors.affiliation: Department of Pathology, University of North Carolina School of Medicine, Chapel Hill 27599, USA.
authors.forename: W B
authors.initials: WB
authors.lastname: Coleman
authors.forename: G J
authors.initials: GJ
authors.lastname: Tsongalis
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D016678:Genome; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D011519:Proto-Oncogenes