Chapter 23: Genetic Basis of Cancer

Cancer is recognized fundamentally as a genetic disease resulting from malfunctions that deregulate the systems controlling cell division and growth, often triggered or exacerbated by environmental carcinogens. This group of diseases involves critical genomic changes, including the failure of mechanisms like programmed cell death (apoptosis), which normally dispose of superfluous or abnormal cells. Normal cell-cycle progression, regulated by checkpoints (like the mid-G1 START checkpoint) and complexes formed between cyclins and cyclin-dependent kinases (CDKs), is characteristically defective in cancer cells. Genetic defects fall into two major categories: oncogenes and tumor suppressor genes. Oncogenes are hyperactive, mutant versions of proto-oncogenes (like c−H−ras or c−src), which normally function in signaling or regulation. Mutations in proto-oncogenes often act as dominant activators of cell growth, such as the c−H−ras mutation that impairs GTP hydrolysis, keeping the protein constitutively active, thereby stimulating uncontrolled division. Oncogene activation can also result from chromosomal rearrangements, notably the bcr/c−abl fusion creating the Philadelphia chromosome in Chronic Myelogenous Leukemia (CML) or the juxtaposition of c−myc in Burkitt’s lymphoma. Conversely, tumor suppressor genes (TSGs) function to repress cell growth, and their inactivation requires two mutational "hits" to eliminate both functional copies, validating Knudson’s two-hit hypothesis. Critical TSGs include RB, which produces pRB protein to arrest the cell cycle by binding E2F transcription factors, and TP53 (p53 protein), the most frequently mutated TSG in human cancers, which initiates either DNA repair (via p21 activation) or apoptosis (via BAX activation) in response to DNA damage. Other TSGs involved in hereditary cancers are APC, which controls cell proliferation in the intestines by regulating β-catenin degradation, and DNA repair genes like BRCA1 and hMSH2. The ultimate development of malignancy typically requires the accumulation of multiple mutations in both oncogenes and tumor suppressor genes, eventually resulting in the six defining hallmarks of cancer: achieving self-sufficiency in growth signaling, insensitivity to inhibitory signals, evasion of apoptosis, acquiring limitless replicative potential (immortality), inducing new blood vessel growth (angiogenesis), and the ability to metastasize and colonize new tissues.