Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

The Genetics of Cancer

10,026 views

Published on

The Genetics of Cancer - Chapter 16

Published in: Science
  • Manifestation Magic� - $27 - By Alexander Wilson - 96% Off  http://t.cn/AiuvUCDd
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • Manifestation Magic� - $27 - By Alexander Wilson - 96% Off ♣♣♣ https://bit.ly/30Ju5r6
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • Use this weird secret involving text messages to get your Ex to come crawling back! Learn how ●●● http://t.cn/R50e2MX
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

The Genetics of Cancer

  1. 1. The Genetics of Cancer
  2. 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. 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. 4. CANCER IS A GENETIC DISEASE AT THE LEVEL OF SOMATIC CELLS
  5. 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. 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)
  7. 7. Benign vs. Malignant
  8. 8. Benign vs. Malignant
  9. 9. Cancer is Clonal  Come from one original cell  Many result from reciprocal chromosomal translocations  Ex. Burkitt’s lymphoma
  10. 10. Burkitt’s Lymphoma
  11. 11. X chromosome inactivation
  12. 12. X chromosome inactivation
  13. 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
  14. 14. Cancer Stem Cells
  15. 15. Cancer Stem Cells
  16. 16. Cancer Stem Cells
  17. 17. Multistep Process & Multiple mutations  Progressive steps  Age-related cancers  Carcinogen exposure to cancer development ◦ Ex. Hiroshima & Nagasaki leukemias
  18. 18. Multistep Process & Multiple Mutations  Tumorigenesis ◦ Driver mutations
  19. 19. Mutator Phenotype  The high level of genomic instability seen is cancer cells is known as mutator phenotype
  20. 20. GENOMIC INSTABILITY & DEFECTIVE DNA REPAIR
  21. 21. Chronic Myelogenous Leukemia (CML)  Translocation c-ABL on 9 into BCR on 22  Creates Philadelphia chromosome
  22. 22. Chronic Myelogenous Leukemia (CML)
  23. 23. Xeroderma Pigmentosum (XP)  Defective in nucleotide excision repair
  24. 24. Hereditary Nonpolyposis Colorectal Cancer (HNPCC)  Inactivation of DNA mismatch repair genes
  25. 25. Chromatin Modifications and Cancer Epigenetics  Alterations in DNA methylation ◦ Overall less ◦ Promoters hypermethylated
  26. 26. Chromatin Modifications and Cancer Epigenetics  Histone modifications  Possibly more epigenetic modifications than gene mutations
  27. 27. CANCER CELLS CONTAIN GENETIC DEFECTS AFFECTING CELL-CYCLE REGULATION AND APOPTOSIS
  28. 28. 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
  29. 29. Cell Cycle and Signal Transduction  Signal Transduction
  30. 30. Cell Cycle Control and Checkpoints  Three important checkpoints:  G1/S  G2/M  M
  31. 31. Cyclins and Cyclin-dependent Kinases
  32. 32. Control of Apoptosis
  33. 33. PROTO-ONCOGENES AND TUMOR- SUPPRESSOR GENES
  34. 34. 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
  35. 35. 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
  36. 36. Proto-oncogenes
  37. 37. Oncogenes  Cancer causing genes ◦ Dominant cancer phenotype
  38. 38. 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
  39. 39. Tumor-Suppressor Genes
  40. 40. 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
  41. 41. The ras Proto-Oncogenes
  42. 42. 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
  43. 43. The p53 Tumor-Suppressor Gene
  44. 44. Li Fraumeni Syndrome  One mutant copy of the p53 gene  Can lead to many different cancers ◦ Breast, leukemia, brain
  45. 45. 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
  46. 46. The RB1 Tumor-Suppressor Gene
  47. 47. Retinoblastoma
  48. 48. METASTASIS AND INVASION OF OTHER TISSUES
  49. 49. Metastasis  Includes the ability to: ◦ disengage from the original tumor site ◦ enter the blood or lymphatic system ◦ invade surrounding tissues ◦ develop into secondary tumors
  50. 50. Tumor cells:  Dissociate from other cells and digest components of the extracellular matrix and basal lamina
  51. 51. Proteolytic Enzymes  E-cadherin glycoproteins – in low levels in epithelial tumors  Metalloproteinases – in high levels in highly malignant tumors, not susceptible to TIMPs
  52. 52. 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
  53. 53. Metastasis-Suppressor Genes
  54. 54. 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
  55. 55. 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
  56. 56. Familial Adenomatous Polyposis (FAP)
  57. 57. APC and ras proto- oncogenes  Combined APC and ras mutations  Develop intermediate adenomas  Defects in cell differentiation  Not growth inhibited  Transformation occurs
  58. 58. 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
  59. 59. VIRUSES AND CANCER
  60. 60. 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
  61. 61. 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
  62. 62. Retroviruses
  63. 63. ENVIRONMENTAL AGENTS AND CANCER
  64. 64. Carcinogens  Any substance can become carcinogenic  Ex. about 30% of human cancer deaths are linked to cigarette smoking
  65. 65. Carcinogens  Red meat and animal fats – imitate hormones or creation of carcinogens through cooking  Alcohol – liver inflammation and liver cancer
  66. 66. Carcinogens  Some of the most common carcinogens are natural  Ex. aflatoxin – a component of mold that grows on peanuts and corn  Nitrosamines  Pesticides  Antibiotics
  67. 67. 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

×