1. Human Genetics Concepts and Applications Tenth Edition RICKI LEWIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display PowerPoint ® Lecture Outlines Prepared by Johnny El-Rady, University of South Florida 18 Genetics of Cancer

2. 2 Introduction Cancer has been part of human existence for eons By 300 B.C., Hippocrates coined the term “cancer” to describe the crablike shape of a tumor invading normal tissue Cancer has or will affect one in three of us Diagnosis and treatment are becoming increasingly individualized

3. 3 Introduction Cancer is genetic, but is not usually inherited Carcinogens are substances that cause cancer - Most are mutagens (damage DNA) Cancer is a group of diseases caused by loss of cell cycle control - If a cell escapes normal control over its division rate, it forms a growth called a tumor

4. 4 Figure 18.1

5. 5 Introduction A tumor is benign if it does not spread or “invade” surrounding tissue A tumor is cancerous or malignant if it infiltrates nearby tissues Metastasis - The tumor spreads to other parts of the body via the blood or lymph vessels

6. 6 Cancer-Causing Genes Oncogenes - More than 100 - Cause cancer if inappropriately activated Tumor suppressor genes - More than 30 - Deletion or inactivation causes cancer - Cell cycle control/checkpoints In addition, changes in gene expression accompany cancer

7. 7 Cell Cycle Control Timing, rate, and number of cell divisions depend on: - Protein growth factors - Signaling molecules from outside the cell - Transcription factors within Checkpoints control the cell cycle - Ensure that mitotic events occur in the correct sequence

8. 8 Cell Cycle Control Figure 18.2

9. 9 Loss of Cell Cycle Control Many types of cancer result from faulty check points Cancer sends a cell down a pathway of unrestricted cell division Cancer cells either lose specializations or never specialize

10. 10 Figure 18.3

11. 11 Telomeres and Telomerase Loss of control of telomere length may also contribute to cancer Telomerase is the enzyme (complex of RNA and protein) that adds telomere sequences to the ends of chromosomes Normal, specialized cells have telomerase turned off, limits cell division Cancer cells have to express telomerase to be able to divide indefinitely

12. 12 Inherited vs. Sporadic Cancer Somatic mutations - Occur sporadically in nonsex cells - Result from a single dominant mutation or two recessive mutations in the same gene - Cancer susceptibility not passed on to offspring Germline mutations - Cancer susceptibility passed on to offspring - Usually requires second somatic mutation - Rarer but strike earlier than sporadic cancers

13. 13 Inherited vs. Sporadic Cancer Figure 18.4

14. 14 Origin of Cancer Cancer begins at the genetic and cellular levels If not halted, cancer spreads through tissues to take over organs and organ systems The origin and spread of cancer are summarized next

15. 15 Figure 18.5

16. 16 Characteristics of Cancer Cells Divide continually (given space and nutrients), and quicker than normal cells Contain heritable mutations Transplantable Dedifferentiated: lose their specialized identity Have a different appearance Cell surface has different types and/or number of antigen

17. 17 Characteristics of Cancer Cells Lack contact inhibition Induce angiogenesis: formation of local blood vessels Invasive: squeeze into any space available Metastasize: move to new location in body

18. 18 Figure 18.6

19. 19 Angiogenesis Nurtures a Tumor Figure 18.7

20. 20

21. 21 Table 18.2

22. 22 Origins of Cancer Cells Cancer can begin at the cellular level in at least four ways: - Activation of stem cells that produce cancer cells - Dedifferentiation - Increase in proportion of a tissue that consists of stem cells or progenitor cells - Faulty tissue repair

23. 23 Figure 18.8

24. 24 Cancer By Loss of Specialization Specialized cells lose some of their distinguishing features as mutations occur when they divide Result is dedifferentiation A biochemical “reversine” may stimulate differentiated cells to divide and produce progenitor cells in mice

25. 25 Dedifferentiation Reverses Specialization Figure 18.9

26. 26 Cancers from Shifting Balance of Cell Types in a Tissue Figure 18.10

27. 27 Uncontrolled Tissue Repair May Cause Cancer Figure 18.11

28. 28 Oncogenes Proto-oncogenes are normal versions of genes that promote cell division Expression at the wrong time or in the wrong cell type leads to cell division and cancer Proto-oncogenes are called oncogenes in their mutated form One copy of an oncogenic mutation is sufficient to promote cell division

29. 29 Oncogenes: Overexpression of a Normal Function Viruses integrated next to a proto-oncogene can cause transcription when the virus is transcribed Moving a proto-oncogene next to a highly transcribed gene can lead to overexpression of the proto-oncogene Example: Burkitt lymphoma - A translocation places a proto-oncogene next to an antibody gene

30. 30 Oncogenes: Overexpression of a Normal Function Figure 18.12 Chromosome 8 Chromosome 14

31. 31 Fusion Proteins Oncogenes are activated when a proto- oncogene moves next to another gene The gene pair is transcribed together The double gene product is a fusion protein - It activates or lifts control of cell division

32. 32 Acute Promyelocytic Leukemia Translocation between chromosomes 15 and 17 Combination of retinoic acid cell surface receptor and an oncogene, myl Fusion protein functions as a transcription factor - When overexpressed causes cancer Some patients respond to retinoid drugs

33. 33 Chronic Myelogenous Leukemia (CML) Most patients have a translocated Philadelphia chromosome (tip of 9 on 22) Abl (chromosome 9) and bcr (chromosome 22) genes produce a fusion protein BCR-ABL oncoprotein is a tyrosine kinase that excessively stimulates cell division Understanding cellular changes allowed development of new drug, Gleevec, for treatment

34. 34 Reading 18.1, Figure 2

35. 35 Her-2/neu Product of an oncogene Excessive levels in approximately 25% of breast cancer patients Too many receptors Too many signals to divide Monoclonal antibody drug, Herceptin, binds to receptors, blocking signal to divide

36. 36 Tumor Suppressor Genes Cancer can be caused by loss of genes that inhibit cell division Tumor suppressor genes normally stop a cell from dividing Mutations of both copies of a tumor suppressor gene is usually required to allow cell division Genes can also be lost by deletion or silenced by promoter hypermethylation

37. 37 Retinoblastoma (RB) A rare childhood cancer The RB gene is on chromosome 13 The RB protein binds transcription factors so that they cannot activate genes that carry out mitosis - Normally halts the cell cycle at G1 Study of RB was the origin of the “two-hit” hypothesis of cancer causation

38. 38 Two-Hit Hypothesis Two mutations or deletions are required - One in each copy of the RB gene For sporadic cases (non-inherited) - Retinoblastoma is a result of two somatic mutations For familial cases (inherited) - Individuals harbor one germline mutant allele for the RB gene in each of their cells - This is followed by a somatic mutation in the normal allele

39. 39 p53 The p53 gene is the “guardian of the genome” Determines if a cell has repaired DNA damage If damage cannot be repaired, p53 can induce apoptosis More than 50% of human cancers involve an abnormal p53 gene Rare inherited mutations in the p53 gene cause a disease called Li-Fraumeni syndrome - Family members have many different types of cancer at early ages

40. 40 Figure 18.13

41. 41 Breast Cancer Two main forms - Familial form: A germline mutation is inherited and then a somatic mutation occurs in a breast cell - Sporadic form: Two somatic mutations affect the same cell Mutations in many genes can cause cancer

42. 42 BRCA The two major breast-cancer susceptibility genes are BRCA1 and BRCA2 - Encode proteins that join two others to form a complex that allows repair of double-stranded DNA breaks Mutations in these genes have different incidences in different populations Inheriting BRCA mutations increases the risk of other types of cancer

43. 43 Other Genes Genes whose protein products affect those of BRCA1, BRCA2, and p53 can cause breast cancer Example: The ATM gene product adds a phosphate to the CHEK2 gene product, which then adds a phosphate to the BRCA1 protein - Mutations in ATM and CHEK2 can cause breast cancer

44. 44 MicroRNAs Revisited MicroRNAs normally control the expression of proto-oncogenes and tumor suppressor genes - Thus, when they are mutated or differentially expressed, cancer can result Patterns of microRNA expression change as a cancer progresses - This is being used to develop new, more sensitive ways to diagnose and treat cancer

45. 45 Types of Genes Gatekeeper genes - Directly control mitosis and apoptosis Caretaker genes - Control mutation rates and may have an overall effect, when mutant, in destabilizing the genome Most cancers are the culmination of a series of mutations in several genes

46. 46 Familial Adenomatous Polyposis (FAP) 5% of colon cancer cases are inherited 1 in 5000 in U.S. has FAP Causes multiple polyps at an early age Several mutations contribute - APC genes mutate - Activation of oncogenes (E.g. K-Ras) - Mutations in TGF, p53, and other genes - PRL-3 triggers metastasis - Caretaker genes cause genomic instability

47. 47 Figure 18.14

48. 48 The Cancer Genome Several large-scale projects are analyzing genomes of cancer cells - These allow construction of descriptive “atlases” containing different types of information Many mutations accompany cancer, but they interact in only a few pathways - Once a pathway is implicated, scientists can look for or develop drugs to target it

49. 49 Table 18.3

50. 50 Environmental Causes of Cancer Environmental factors contribute to cancer by mutating or altering the expression of genes that control the cell cycle, apoptosis, and DNA repair Inheriting a susceptibility gene places a person farther along the road to cancer - However, cancer can happen in somatic cells in anyone

51. 51 Environmental Causes of Cancer Individuals can lower the chance of developing cancer by: - Avoiding high-risk environmental factors, such as smoking and excess sun exposure - Taking “chemopreventative” nutrients such as folic acid and vitamin D

52. 52 Cruciferous Vegetables Can Lower Cancer Risk Figure 18.15

53. 53 Methods to Study Cancer- Environment Links Population Study: Compares incidence of a type of cancer among different groups of people Case Control: Identify differences between patients with a type of cancer and healthy individuals matched for multiple characteristics Prospective Studies: Two or more groups of individuals follow a specific regimen ( e.g., diet or activity plan) and are checked regularly for cancer

54. 54 Figure 18.16

55. 55 Cancer Diagnosis and Treatment Most often, discovery of cancer follows a screening test Oldest treatment is surgery, which removes the tumor Radiation and chemotherapy non-selectively destroy rapidly dividing cells Other drugs help patients tolerate the side effects

56. 56 Cancer Diagnosis and Treatment New types of cancer drugs: - Stimulate cells to regain specialized characteristics - Inhibit telomerase - Induce apoptosis - Inhibit angiogenesis Genomics information is increasingly used - Enables physicians to better match patient to treatment

57. 57 Table 18.6