Cancer is a genetic disease that arises as a consequence of the stepwise accumulation of disruptive mutations in genes that regulate cell life and death. Clonal expansion of cell populations bearing cancer gene mutations fuels the formation of malignant tumors capable of invasion and metastasis. This genetic model of cancer emerged in the latter 20th century as a product of advances in genetics, evolution, and cancer medicine. Small targeted gene sequencing studies conducted in colorectal cancer samples revealed that inactivating mutations in tumor suppressor genes (genes whose normal function serves to prevent aberrant cell growth) such as APC, TP53, and/or PTEN could drive malignant transformation of normal epithelium into an adenoma. Subsequent activating mutations in oncogenes (genes whose normal function is to accelerate cell growth) such as KRAS, BRAF, and/or PIK3CA coupled with additional cancer gene mutations were then shown to confer increasingly malignant phenotypes in the course of adenocarcinoma development and metastatic spread. Through this mutational process, cancers acquire specific key properties including self-sufficient growth signaling, resistance to growth inhibitory signaling, invasion and metastasis, unlimited replication potential, angiogenic signaling, immune modulation, DNA instability, metabolic dysregulation, and immune evasion. The genetic model and its downstream phenotypes have since been validated in many cancer types and provided a framework for our growing genomic understanding of cancer.
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