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The Genetics of Cancer
- 1. The Genetics of Cancer
- 2. Can you answer these questions? What is the leading cause of death in Western Countries? How many people will experience a diagnosis of cancer in his/her lifetime? (1 in ?) Approximately how many people die of cancer in the U.S. each year?
- 3. What research has taught us… Cancer is a genetic disease at the somatic cell level Characterized by the presence of gene products derived from mutated or abnormally expressed genes Leads to uncontrolled growth and spread of cancer cells
- 4. CANCER IS A GENETIC DISEASE AT THE LEVEL OF SOMATIC CELLS
- 5. What is Cancer? Cancer predominantly occurs in somatic cells Only ~1% are associated with germ- line mutations Rarely arises from a single mutation
- 6. Two fundamental properties: 1. abnormal cell growth and division (proliferation) 2. defects in normal restraints that keep cells from spreading and invading other parts of the body (metastasis)
- 9. Cancer is Clonal Come from one original cell Many result from reciprocal chromosomal translocations Ex. Burkitt’s lymphoma
- 13. Cancer Stem Cells Tumors are a mix of cells Only some proliferate – cancer stem cells ◦ Self-renewal More commonly found in leukemias and solid tumors
- 17. Multistep Process & Multiple mutations Progressive steps Age-related cancers Carcinogen exposure to cancer development ◦ Ex. Hiroshima & Nagasaki leukemias
- 18. Multistep Process & Multiple Mutations Tumorigenesis ◦ Driver mutations
- 19. Mutator Phenotype The high level of genomic instability seen is cancer cells is known as mutator phenotype
- 20. GENOMIC INSTABILITY & DEFECTIVE DNA REPAIR
- 21. Chronic Myelogenous Leukemia (CML) Translocation c-ABL on 9 into BCR on 22 Creates Philadelphia chromosome
- 23. Xeroderma Pigmentosum (XP) Defective in nucleotide excision repair
- 24. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Inactivation of DNA mismatch repair genes
- 25. Chromatin Modifications and Cancer Epigenetics Alterations in DNA methylation ◦ Overall less ◦ Promoters hypermethylated
- 27. Chromatin Modifications and Cancer Epigenetics Histone modifications Possibly more epigenetic modifications than gene mutations
- 28. CANCER CELLS CONTAIN GENETIC DEFECTS AFFECTING CELL-CYCLE REGULATION AND APOPTOSIS
- 29. Cell-Cycle and Signal Transduction Focus on G0 Phase ◦ Cancer cells can not enter G0 ◦ Rate of proliferation is not greater ◦ Not able to become quiescent
- 30. Cell Cycle and Signal Transduction Signal Transduction
- 31. Cell Cycle Control and Checkpoints Three important checkpoints: G1/S G2/M M
- 35. Proto-oncogenes Encode transcription factors that stimulate expression of other genes, signal transduction molecules that stimulate cell division, and cell-cycle regulators that move the cell through the cell cycle
- 36. Proto-oncogenes In normal cells, proto-oncogenes become quiescent and they the repress proto-oncogenes In cancer cells, one or more proto- oncogenes are altered ◦ Constantly “on” ◦ Mutated ◦ Aberrantly expressed
- 37. Proto-oncogenes
- 38. Oncogenes Cancer causing genes ◦ Dominant cancer phenotype
- 39. Tumor-Suppressor Genes Products normally regulate cell-cycle checkpoints or initiate apoptosis When inactivated, and other changes keep the cell growing and dividing, the cell may become tumorigenic
- 41. The ras Proto-Oncogenes Some the most frequently mutated genes in human tumors ◦ Mutated in more than 30% of human tumors ◦ Encode signal transduction molecules and regulate cell growth and division ◦ Get frozen in “on” position
- 44. The p53 Tumor-Suppressor Gene Most frequently mutated gene in human cancers ◦ In over 50% of cancers ◦ Encodes a nuclear protein that acts as a transcription factor, repressing or stimulating transcription of more than 50 different genes
- 46. Li Fraumeni Syndrome One mutant copy of the p53 gene Can lead to many different cancers ◦ Breast, leukemia, brain
- 47. The RB1 Tumor-Suppressor Gene Loss or mutation of the RB1 (retinoblastoma 1) tumor suppressor gene contributes to the development of many cancers Originally identified as a result of studies on retinoblastoma G1/S checkpoint control
- 49. Retinoblastoma
- 50. METASTASIS AND INVASION OF OTHER TISSUES
- 51. Metastasis Includes the ability to: ◦ disengage from the original tumor site ◦ enter the blood or lymphatic system ◦ invade surrounding tissues ◦ develop into secondary tumors
- 52. Tumor cells: Dissociate from other cells and digest components of the extracellular matrix and basal lamina
- 53. Proteolytic Enzymes E-cadherin glycoproteins – in low levels in epithelial tumors Metalloproteinases – in high levels in highly malignant tumors, not susceptible to TIMPs
- 54. Metastasis-Suppressor Genes Like tumor-suppressor genes Mutated or disrupted in metastatic tumors Less than 6 have been identified thus far Effects are often reduced by epigenetic mechanisms
- 56. Predisposition of Some Cancers Only a small percent of cancers are familial or hereditary Loss of heterozygosity: The phenomenon where a second, wild- type allele is mutated in a tumor ◦ Further mutations are needed for a tumor rot be malignant
- 57. Familial Adenomatous Polyposis (FAP) 1% of colon cancers Inherit 1 copy of the APC (adenomatous polyposis) gene on chromosome 5 Normally a tumor-suppressor gene for cell-to-cell contact and growth inhibition Leads to polyp (adenoma) formation Second gene often becomes mutated in later cancer stages
- 59. APC and ras proto- oncogenes Combined APC and ras mutations Develop intermediate adenomas Defects in cell differentiation Not growth inhibited Transformation occurs
- 60. DCC Third step in malignancy of polyps requires loss of both DCC (Deleted in Colon Cancer) genes Involved in cell adhesion and differentiation Late stage adenomas Usually loss of functional p53 genes
- 62. Viruses and Cancer ~15% of human cancers are associated with viruses DNA viruses, double-stranded DNA Most DNA viruses contain genes encoding products that stimulate cell growth Often inactivate tumor-suppressor genes
- 63. Viruses and Cancer Retroviruses RNA to DNA with reverse transcriptase Cause cancer by: ◦ Complete integration into host genome (provirus) ◦ Host DNA integrated into viral genome, DNA now under control of viral promotors ◦ Expression of viral genes
- 64. Retroviruses
- 66. Carcinogens Any substance can become carcinogenic Ex. about 30% of human cancer deaths are linked to cigarette smoking
- 67. Carcinogens Red meat and animal fats – imitate hormones or creation of carcinogens through cooking Alcohol – liver inflammation and liver cancer
- 68. Carcinogens Some of the most common carcinogens are natural Ex. aflatoxin – a component of mold that grows on peanuts and corn Nitrosamines Pesticides Antibiotics
- 69. Carcinogens It is estimated that the human body suffers about 10,000 damaging DNA lesions per day to the oxygen free radicals Repair enzymes handle most damage