Key Concepts of Section 24.3

• Dominant gain-of-function mutations in proto-oncogenes and recessive loss-of-function mutations in tumor-suppressor genes are oncogenic.

• Among the proteins encoded by proto-oncogenes are growth-promoting signaling proteins and their receptors, signal-transducing proteins, transcription factors, and anti-apoptotic proteins.

• An activating mutation of one of the two alleles of a proto-oncogene converts it into an oncogene. This can occur by point mutation, gene amplification, gene translocation, or mis-expression.

• Tumor-suppressor genes encode proteins that directly or indirectly control progression through the cell cycle, such as checkpoint pathway proteins that arrest the cell cycle if a previous step has occurred incorrectly, components of growth-inhibiting signaling pathways, and pro-apoptotic proteins.

• The first tumor-suppressor gene to be recognized, RB, is mutated in retinoblastoma and many other tumors; some component of the Rb pathway is altered in most tumors.

• Inheritance of a single mutant allele of RB greatly increases the probability that a specific kind of cancer will develop, as is the case for many other tumor-suppressor genes (e.g., APC and BRCA1).

• In individuals born heterozygous for a tumor-suppressor gene mutation, a somatic cell can undergo loss of heterozygosity (LOH) by mutation or deletion of the normal allele, chromosome mis-segregation, mitotic recombination, or gene silencing.

• Mutations affecting epigenetic regulators such as histone-modifying enzymes or chromatin remodelers are associated with a variety of tumors.

• MicroRNAs can promote or inhibit tumorigenesis by affecting the expression of multiple oncoproteins.

• Novel sequencing technologies have greatly accelerated the discovery of genes involved in cancer and are having a profound impact on cancer diagnosis and treatment.

• The advent of molecular techniques for characterizing individual tumors is allowing the application of drugs and antibody treatments that target the properties of a particular tumor. This strategy permits more effective treatment of individual patients and reduces the use of drugs or antibodies that will be ineffective and possibly toxic. These refinements have allowed substantial reduction in breast cancer mortality.

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• Novel shRNA and genome editing methods allow for the identification of genes specifically required for the survival of cancer cells, thereby facilitating the discovery of new therapeutic targets.