Concepts Summary

• Cancer is fundamentally a genetic disorder, arising from somatic mutations in multiple genes that affect cell division and proliferation. If one or more mutations are inherited, then fewer additional mutations are required for cancer to develop.
• A mutation that allows a cell to divide rapidly provides the cell with a growth advantage; this cell gives rise to a clone of cells having the same mutation. Within this clone, other mutations occur that provide additional growth advantages, and cells with these additional mutations become dominant in the clone. In this way, the clone evolves.
• Environmental factors play an important role in the development of many cancers by increasing the rate of somatic mutations.
• Oncogenes are dominant mutated copies of normal genes (proto-oncogenes) that stimulate cell division. Tumor-suppressor genes normally inhibit cell division; recessive mutations in these genes may contribute to cancer. Sometimes, the mutation of a single allele of a tumor-suppressor gene is sufficient to cause cancer, a phenomenon known as haploinsufficiency.
• The cell cycle is controlled by cyclins and cyclin-dependent kinases. Mutations in genes that control the cell cycle are often associated with cancer.
• Signal-transduction pathways conduct external signals to intracellular responses. These pathways consist of a series of proteins that are activated and inactivated in a cascade of reactions. Mutations in the components of signal-transduction pathways disrupt the cell cycle and may contribute to cancer.
• Defects in DNA-repair genes often increase the overall mutation rate of other genes, leading to defects in proto-oncogenes and tumor-suppressor genes that can contribute to cancer progression.
• Mutations in sequences that regulate telomerase allow cells to divide indefinitely, contributing to cancer progression.
• Tumor progression is also affected by mutations in genes that promote vascularization and the spread of tumors.
• Many tumor cells exhibit a widespread reduction in the expression of many miRNAs, suggesting that a reduction in miRNA control of gene expression may play a role in tumor progression.
• Epigenetic changes to chromatin structure, including DNA methylation and histone modification, are often associated with cancer.
• Colorectal cancer offers a model system for understanding tumor progression in humans. Initial mutations stimulate cell division, leading to a small benign polyp. Additional mutations allow the polyp to enlarge, invade the muscle layer of the gut, and eventually spread to other sites. Mutations in particular genes affect different stages of this progression.
• Some cancers are associated with specific chromosome mutations, including chromosome deletions, inversions, and translocations. Deletions may cause cancer by removing or disrupting genes that suppress tumors; inversions and translocations may break tumor-suppressing genes or they may move genes to positions next to different regulatory sequences, which alter their expression.
• Mutations in some genes cause or allow chromosomes to segregate improperly, leading to aneuploidy that can contribute to cancer.
• Viruses are associated with some cancers; they contribute to cell proliferation by mutating and rearranging host genes or by altering the expression of host genes.