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 MutationPoint 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...
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Chapter 079. Cancer Genetics (Part 7) Chapter 079. Cancer Genetics (Part 7) Mechanisms of Oncogene Activation Mechanisms that upregulate (or activate) cellular oncogenes fall into threebroad categories: point mutation, DNA amplification, and chromosomalrearrangement. Point Mutation Point mutation is a common mechanism of oncogene activation. Forexample, mutations in one of the RAS genes (HRAS, KRAS, or NRAS) are presentin up to 85% of pancreatic cancers and 50% of colon cancers but are relativelyuncommon in other cancer types. Remarkably—and in contrast to the diversity ofmutations found in tumor-suppressor genes (Fig. 79-4)—most of the activatedRAS genes contain point mutations in codons 12, 13, or 61 (which conveyresistance to GAP, a protein that interacts with RAS and inactivates it throughsubstitution of the GTP cofactor with GDP). The restricted pattern of mutationcompared to tumor-suppressor genes reflects the fact that gain-of-functionmutations of oncogenes are more difficult to attain than simple inactivation.Indeed, inactivation of a gene can be attained through the introduction of a stopcodon anywhere in the coding sequence, whereas activations require precisesubstitutions at residues that normally downregulate the activity of the encodedprotein. The specificity of oncogene mutations provides specific diagnosticopportunities, as it is much simpler to find mutations at specified positions than itis when mutations can be scattered throughout the gene (as in tumor-suppressorgenes). DNA Amplification The second mechanism for activation of oncogenes is DNA sequenceamplification, leading to overexpression of the gene product. This increase inDNA copy number may cause cytologically recognizable chromosome alterationsreferred to as homogeneous staining regions (HSRs), if integrated withinchromosomes, or double minutes (dmins), if extrachromosomal in nature. Therecognition of DNA amplification is accomplished through various cytogenetictechniques such as comparative genomic hybridization (CGH) and fluorescence insitu hybridization (FISH), which allow the visualization of chromosomalaberrations using fluorescent dyes. With these techniques, the entire genome canbe surveyed for gains and losses of DNA sequences, thus pinpointingchromosomal regions likely to contain genes important in the development orprogression of cancer. Noncytogenetic, molecular techniques for identifyingamplifications have more recently become available. Numerous genes have been reported to be amplified in cancer. Severalgenes, including NMYC and LMYC, were identified through their presence withinthe amplified DNA sequences of a tumor and had homology to known oncogenes.Because the region amplified often extends to hundreds of thousands of base pairs,more than one oncogene may be amplified in some cancers (particularlysarcomas). Genes simultaneously amplified in many cases include MDM2, GLI,CDK4, and SAS. Demonstration of amplification of a cellular gene is often apredictor of poor prognosis. For example, ERBB2/HER2 and NMYC are oftenamplified in aggressive breast cancers and neuroblastoma, respectively. Chromosomal Rearrangement Chromosomal alterations provide important clues to the genetic changes incancer. The chromosomal alterations in human solid tumors such as carcinomasare heterogeneous and complex and likely reflect selection for the loss of tumor-suppressor genes on the involved chromosome. In contrast, the chromosomealterations in myeloid and lymphoid tumors are often simple translocations, i.e.,reciprocal transfers of chromosome arms from one chromosome to another.Consequently, many detailed and informative chromosome analyses have beenperformed on hematopoietic cancers. The breakpoints of recurring chromosomeabnormalities usually occur at the site of cellular oncogenes. Table 79-3 listsrepresentative examples of recurring chromosome alterations in malignancy andthe associated gene(s) rearranged or deregulated by the chromosomalrearrangement. Translocations are particularly common in lymphoid tumors,probably because these cell types normally rearrange their DNA to generateantigen receptors. Indeed, antigen receptor genes are commonly involved in thetranslocations, implying that an imperfect regulation of receptor generearrangement may be involved in the pathogenesis. An example is Burkittslymphoma, a B cell tumor characterized by a reciprocal translocation betweenchromosomes 8 and 14. Molecular analysis of Burkitts lymphomas demonstratedthat the breakpoints occurred within or near the MYC locus on chromosome 8 andwithin the immunoglobulin heavy chain locus on chromosome 14, resulting in thetranscriptional activation of MYC. Enhancer activation by trans ...