Mechanisms of Oncogene Activation Mechanisms that upregulate (or activate) cellular oncogenes fall into three broad categories: point mutation, DNA amplification, and chromosomal rearrangement. Point Mutation Point mutation is a common mechanism of oncogene activation. For example, mutations in one of the RAS genes (HRAS, KRAS, or NRAS) are present in up to 85% of pancreatic cancers and 50% of colon cancers but are relatively uncommon in other cancer types. Remarkably—and in contrast to the diversity of mutations found in tumor-suppressor genes (Fig. 79-4)—most of the activated RAS genes contain point mutations in codons 12, 13, or 61 (which convey resistance to. | Chapter 079. Cancer Genetics Part 7 Mechanisms of Oncogene Activation Mechanisms that upregulate or activate cellular oncogenes fall into three broad categories point mutation DNA amplification and chromosomal rearrangement. Point Mutation Point mutation is a common mechanism of oncogene activation. For example mutations in one of the RAS genes HRAS KRAS or NRAS are present in up to 85 of pancreatic cancers and 50 of colon cancers but are relatively uncommon in other cancer types. Remarkably and in contrast to the diversity of mutations found in tumor-suppressor genes Fig. 79-4 most of the activated RAS genes contain point mutations in codons 12 13 or 61 which convey resistance to GAP a protein that interacts with RAS and inactivates it through substitution of the GTP cofactor with GDP . The restricted pattern of mutation compared to tumor-suppressor genes reflects the fact that gain-of-function mutations of oncogenes are more difficult to attain than simple inactivation. Indeed inactivation of a gene can be attained through the introduction of a stop codon anywhere in the coding sequence whereas activations require precise substitutions at residues that normally downregulate the activity of the encoded protein. The specificity of oncogene mutations provides specific diagnostic opportunities as it is much simpler to find mutations at specified positions than it is when mutations can be scattered throughout the gene as in tumor-suppressor genes . DNA Amplification The second mechanism for activation of oncogenes is DNA sequence amplification leading to overexpression of the gene product. This increase in DNA copy number may cause cytologically recognizable chromosome alterations referred to as homogeneous staining regions HSRs if integrated within chromosomes or double minutes dmins if extrachromosomal in nature. The recognition of DNA amplification is accomplished through various cytogenetic techniques such as comparative genomic hybridization CGH and fluorescence
