Cancer: a genetic disease of inherited and somatic mutations n Gene mutations and/or genetic instability are involved in many cancers. n Viruses and environmental agents implicated in cancer are believed to act by causing mutations. n Mutated gene include those classified as “gatekeepers” (oncogenes and tumor suppressor genes) or “caretakers” (encoding proteins involved in DNA repair and chromosome segregation). n For the most part, these genes confer predisposition or susceptibility to cancer.

Cancer and the Cell Cycle n Understanding the cell cycle is key to understanding cancer. n Misregulation of the cell cycle is a frequent event in tumorigenesis. n The cell cycle is controlled at several key “checkpoints”: G1/S and G2/M.

Familial Retinoblastoma and the Two-Hit Hypothesis n A clear-cut case of inherited prediposition due to a single gene is retinoblastoma, providing evidence for a “two-hit” model in which both alleles must be mutated to express cancer. n Familial retinoblastoma: inheritance of single mutant allele and spontaneous somatic mutation of other n Sporadic retinoblastoma: inheritance of two normal alleles and sequential spontaneous somatic mutation of both

Most cancers require sequential somatic mutation of several genes n A well-studied example is colon cancer, studied by Vogelstein and Kinzler. n Several different genes, including p53, are mutated in a sequential order. n These basic findings of Vogelstein and Kinzler have revolutionized clinical diagnosis and prevention of death.

Genomic instabilities can activate cancer n Somatic chromosome translocations can juxtapose sequences, leading to activation of of tumor promoters. n Failure to monitor DNA change can lead to somatic mutation and cancer, such as hereditary nonpolyposis colon cancer.

“Gatekeeper” genes n The “gatekeeper” gene monitor cell proliferation and death. They include: –“oncogenes” which are cell growth promoters, where dominant mutations lead to uncontrolled growth, and –“tumor suppressor” genes which are negative regulators of cell growth, where recessive mutation can lead to uncontrolled cell growth (e.g., p53).

“Caretaker” genes n The “caretaker” genes include genes that regulate DNA repair and chromosome segregation in mitosis. Mutation of of these genes can cause abnormal gatekeeper function because of mutation or abnormal gene content. The “caretaker” genes include: –DNA repair genes, whose mutations lead to genetic instability (more mutations), and –genes that regulate chromosome segregation, whose mutations lead to abnormal chromosome content, or chromosomal instability.