Novel genetic and epigenetic alterations in ... - Ous-research.no

IntroductionThe genes involved in maintaining homeostatis has traditionally been divided into twocategories, proto-oncogenes and tumor suppressor genes. Mutations or chromosomalrearrangements may either activate oncogenes, causing them to drive e.g. cell proliferationeven in absence of proliferative signals, and/or inactivate tumor-suppressor genes, leading todestruction of important checkpoints at which the cell may have time to perform DNArepair, align chromosomes or just wait for the beneficial environmental conditions for cellproliferation. Additionally, maintenance genes, or stability genes, are important forhomeostasis. Under normal circumstances these genes keep the genetic errors in the cell to aminimum[13]. The fact that 30% of our genes encode proteins involved in regulating theDNA fidelity clearly shows the importance of these stability genes[14].The impact of epigenetics on tumorigenesis is now widely demonstrated, and it is reckonedto play just as an important role in tumor development as genetics[15]. Promoterhypermethylation is a well known mechanism which may cause reduced or absence ofexpression of tumor suppressor and DNA repair genes while hypomethylation may activatea proto-oncogene into an oncogene[16]. As of this, both genome wide hypomethylation, andgene specific hypermethylation are involved in colorectal tumorigenesis[17].DNA mutations in cancerMutations include all stable, irreversible changes that alter the primary DNA sequence, andare seen in less than 1% of a population. Today the term “mutation” is often thought of assubtle sequence alterations such as base substitutions and small insertions and deletions(indels), but in genetics, gross chromosomal alterations such as chromosomal translocations,gene amplifications, large gene deletions, and gains and losses of large chromosomalstretches were also included in the term, and that the gross and subtle changes were twodifferent classes of mutations[18]. The different types of mutations and their timing in thecell cycle are illustrated in Figure 2. There are different categories of subtle mutations: pointmutation, defined by the exchange of a single base, includes both missense mutations(exchange of a base giving an amino acid change) which can affect protein folding andfunction, and non-sense mutations (exchange of a base which inserts a prematuretermination codon) leading to a truncated protein. If a point mutation does not give an13