Genetic and Epigenetic Alterations in Cancer
Summary of Key Points
• A root cause of cancer is the accumulation of genetic and epigenetic defects in key cellular pathways regulating proliferation, differentiation, and death. The defects in cancer cells are of two types: gain-of-function alterations affecting oncogenes and loss-of-function alterations affecting tumor suppressor genes. Regardless of whether the defects are genetic or epigenetic in nature, a common net consequence is dysregulation of gene expression in cancer cells.
• Clinical and pathological studies indicate that many cancers arise from preexisting benign lesions, and numerous cooperating genetic and epigenetic defects affecting multiple independent signaling pathways are likely needed for development of most clinically recognizable cancers.
• A process termed clonal selection has a key role in determining the particular constellation of genetic and epigenetic defects present in a cancer cell. Clonal selection is essentially an evolutionary process that promotes outgrowth of precancerous and cancerous cells carrying those mutations and gene expression changes that confer the most potent proliferative and survival properties upon the cancer cells in a given context.
• Although a sizeable and diverse array of mutations and gene expression changes have been implicated in cancer pathogenesis, the defects appear to affect a more limited number of conserved signaling pathways or networks. A relatively small collection of oncogenes and tumor suppressor genes is recurrently deranged in cancer cells of various types and includes the RAS, PIK3CA, EGFR, RAF, β-catenin, and MYC oncogene proteins and the p53, p16Ink4a, ARF, RB1, PTEN, APC, and NF1 tumor suppressor proteins. The proteins that are recurrently targeted by mutations in cancer likely represent particularly critical hubs in the cell’s regulatory circuitry.
• Although cancer represents a very heterogeneous collection of diseases, the development of all cancers, regardless of type, appears to be critically dependent on the acquisition of certain traits that allow the cancer cells to grow in an unchecked fashion in their tissue of origin and to grow as metastatic lesions in distant sites in the body. Signature traits that are likely to be inherent in the majority, if not all, cancers include the following: (1) an increased tendency to manifest a stem cell or progenitor-like phenotype; (2) an enhanced response to growth-promoting signals; (3) a relative resistance to growth inhibitory cues; (4) an increased mutation rate to allow for the rapid generation of new variant daughter cells; (5) the ability to attract and support a new blood supply (angiogenesis); (6) the capacity to minimize an immune response and/or evade destruction by immune effector cells; (7) the capacity for essentially limitless cell division; (8) a failure to respect tissue boundaries, allowing for invasion into adjacent tissues and organs, as well as blood vessels and lymphatics; and (9) the ability to grow in organ sites with microenvironments that are markedly different from the one where the cancer cells arose.
