Genomic instability: First step to carcinogenesis

Multiple genetic alterations are commonly observed in human cancers. It has been suggested that inactivation of DNA repair pathways, which leads to an increased nutrition rate and chromosomal instability, can initiate and accelerate the neoplastic process. Such a causality has been shown for DNA mismatch repair and Hereditary Nonpolyposis Colorectal Cancel (HNPCC), and evidence is accumulating that sever al other DNA repair pathways are frequently inactivated in different cancer types. In addition to genetic alterations, perturbations in DNA methylation patterns (epigenetic changes), which include both local hypermethylation and genome-wide hypomethylation, are frequently observed early in tumorigenesis. Therefore, genomic instability including genetic and/or epigenetic alterations may be the first step in carcinogenesis. Knowledge of these biochemical mechanisms nle likely to lead to more effective cancer diagnosis and therapy.