1. Genes and Cancer Chapter 12

2. Cancer Is a Genetic Disorder of Somatic Cells  Somatic cells – any cell of the body except sperm and egg  Cancer is a complex disease characterized by two main properties:  Uncontrolled cell division  The ability of these cells to spread to other sites in the body (metastasis)  Each year, more than one million new cancer cases are diagnosed and approximately 500,000 people will die from the disease

3. Estimated Cases of Cancer in the US, 2015

4. Age is a Leading Risk Factor for Cancer 10,000 1,000 100 KEY 10 Cancer deaths (per 100,000) Female Male 1 <1 1– 5–9 10 15–19 20 25–34 35– 45–54 55– 75–84 –24 65–74 85+ 4 –14 4464 Age groups in years

5. Cancer and Genetics  A predisposition to more than 50 forms of cancer are inherited to one degree or another  Most chemicals that cause cancer are also mutagens  Some viruses carry genes that promote cancer  Gardasil is effective against HPV types 16 and 18 which cause approximately 70% of cervical cancers, and against HPV types 6 and 11 which cause approximately 90% of genital warts.  Specific chromosomal changes are found in certain cancers  Mutations are the ultimate cause of cancer

6. Cancer Begins in a Single Cell  Cancer cells are clonal descendants from one mutant cell  The cell accumulates specific mutations over a long period of time  Cancer cells that escape control of the cell cycle divide continually  Mutations continue to accumulate  Cancer cell scan can be either:  Non-invasive (benign) or  Invasive and spread to other sites (metastatic)

7. ANIMATION: Cancer and metastasis To play movie you must be in Slide Show Mode PC Users: Please wait for content to load, then click to play Mac Users: CLICK HERECLICK HERE

8. Metastasis Cancer cells break away from their original tissue. The metastasizing cells become attached to the wall of a blood vessel or lymph vessel. They secrete digestive enzymes to create an opening. Then they cross the wall at the breach. Cancer cells creep or tumble along inside blood vessels, then leave the bloodstream the same way they got in. They start new tumors in new tissues. 2 1 3

9. Cancers: Sporadic and Inherited  Sporadic cancer - Cancer caused by accumulation of a number of mutations in somatic cells  Mutation occurs in a single somatic cell  Additional mutations accumulate  Inherited cancer syndromes - Inherited mutant genes cause a predisposition to cancer  Mutations are carried in all cells in a heterozygous state  The normal allele is lost in the cancer cell (loss of heterozygosity)

10. 3D ANIMATION: Cancer

11. ANIMATION: The cell cycle and cancer— Phases To play movie you must be in Slide Show Mode PC Users: Please wait for content to load, then click to play Mac Users: CLICK HERECLICK HERE file:///D:/Media/PowerPoint_Lect ures/chapter12/videos_animatio ns/4_2_1.html

12. ANIMATION: The cell cycle and cancer— Growth factor control To play movie you must be in Slide Show Mode PC Users: Please wait for content to load, then click to play Mac Users: CLICK HERECLICK HERE file:///D:/Media/PowerPoint_Lect ures/chapter12/videos_animatio ns/4_2_2.html

13. The Eukaryotic Cell Cycle G1/S Checkpoint Cell proceeds to S phase or enters inactive G0 state G1 Interval of cell growth before DNA replication (chromosomes unduplicated) S Interval of cell growth when DNA replication is completed (chromosomes duplicated) Each daughter cell starts interphase CYTOKINESIS Telophase M Checkpoint Cell monitors attachment of spindle fibers to chromosomes Prophase G2 Interval following DNA replication; cell prepares to divide Interphase ends for parent cell G2/M Checkpoint Cell monitors completion of DNA synthesis and DNA damage Metaphase Anaphase

14. Tumor Suppressor Genes  Tumor suppressor genes decrease cell division  Encode proteins that suppress cell division and regulate the cell cycle  These gene products act at control points in the cell cycle, at G1/S or G2/M  Deletion or inactivation of these products cause cells to divide continuously

15. Oncogenes  Oncogenes increase cell division  Proto-oncogenes - Genes that initiate or maintain cell division  May become cancer genes (oncogenes) by mutation  Oncogenes - Genes that induce or continue uncontrolled cell proliferation

16. Proto-Oncogenes To Oncogenes  Oncogenes are permanently switched on proto-oncogenes that cause uncontrolled cell division  A single base change can produce an altered gene product (A,T,C,G)  Mutations can increase the number of copies of a normal gene

17. Retinoblastoma  A malignant tumor of the eye arising in retinoblasts (embryonic retinal cells that disappear at about 2 years of age)  Usually occurs only in children  Mature retinal cells do not transform into tumors  Associated with a deletion in the long arm of chromosome 13  The responsible gene, Rb, is located on chromosome 13

18. Two Types of Retinoblastoma  Familial retinoblastoma  Individuals inherit one mutant copy of RB1 gene  85% to 95% chance of developing the disease  Sporadic retinoblastoma  Mutations of both copies of RB1 gene occur in a single cell  Occurs with a frequency of approximately 1 in 15,000

19. The RB1 Gene  The tumor-suppressing protein pRB (retinoblastoma protein) controls the G1/S transition in the cell cycle  G1/S Transition – cell either enters the next phase of the cycle or enters a nondividing state called G-0.  Without pRB, cell division is uncontrolled

20. Mutant Cancer Genes  Many basic properties of cancer result from the inability of cancer cells to repair damage to DNA  High rates of mutation, chromosomal abnormalities, and genomic instability  DNA repair genes are now recognized as a class of cancer-related genes (along with tumor suppressor genes and proto-oncogenes)

21.  Mutations in BRCA1 and BRCA2 genes can predispose women to breast and ovarian cancer Genetic Predisposition to Cancer BRCA2 BRCA1 13 17

22. BRCA1 and BRCA2 are DNA Repair Genes  BRCA1 protein, found only in the nucleus, is activated when DNA is damaged  Stops DNA replication  Binds to Rap80 protein to identify DNA damage and initiate repair  Mutant forms are unable to repair DNA  Mutations accumulate; cell become cancerous  Male Breast Cancer  Very rare  Approximately 2,000 cases per year  Men who inherit mutant BRCA1 or BRCA2 have an 80-fold elevated risk

23. Colon Cancer: a Genetic Model for Cancer  Cancer is a multistep process that requires a number of specific mutations  Study of colon cancer provides insight into the number and order of steps involved in transforming normal cells into cancer cells  Starts as a benign tumor that later becomes malignant  Six or more mutations required to initiate cancer  There are two pathways to colon cancer related to genetic predispositions 1. Familial adenomatous polyposis (FAP) 2. Hereditary nonpolyposis colon cancer (HNPCC) 

24. A Multi-step Model For Colon Cancer Chromosome 5q12p18q17p Other Alteration MutationDeletion Mutations Gene APCK-RASDCCp53 Normal colon epithelium PolypIntermediate adenoma Late adenoma with villi Colon cancer Metastatic cancer Mutation

25. Colon and Rectal Cancer in the US

26. 1. Familial adenomatous polyposis (FAP)  An autosomal dominant trait resulting in the development of polyps and benign growths in the colon  Polyps often develop into malignant growths and cause cancer of the colon and/or rectum  Small clusters of dividing cells on the lining of colon

27. 2. Hereditary Nonpolyposis Colon Cancer (HNPCC)  An autosomal dominant trait associated with genomic instability of microsatellite DNA sequences and a form of colon cancer  Is caused by DNA repair defects  Microsatellites: DNA sequences, 2 to 9 nucleotides long, that are repeated thousands of times and located on many chromosomes  Clusters are called simple sequence repeats (SSRs) or short tandem repeats (STRs)  Mutations in MSH2 or MLH1 genes destabilize the genome, generating a cascade of mutations in DNA microsatellites

28. HNPCC is due to DNA Repair Defect  Proteins encoded by MSH2 and MLH1 genes repair errors made during DNA replication  When these genes are inactivated by mutation, microsatellite mutation rates increase, promoting mutations in other genes

29. Chromosome Rearrangements and Cancers  Some cancers, such as chronic myelogenous leukemia, are caused by translocation events, creating hybrid genes that activate cell division  Philadelphia chromosome - was first discovered and described in 1960 by Peter Nowell from the University of Pennsylvania School of Medicine and David Hungerford from the Fox Chase Cancer Center's Institute for Cancer Research and was therefore named after the city in which both facilities are located.

30. The Philadelphia Chromosome  Abnormal chromosome produced by translocation between the long arms of chromosomes 9 and 22  Linked to chronic myelogenous leukemia (CML)

31. Translocations and Hybrid Genes  Many proto-oncogenes are located at or close to the breakpoints of chromosomal translocations involved with specific forms of leukemia  In chronic myelogenous leukemia, the C-ABL gene (chromosome 9) is moved next to the BCR gene (chromosome 22)  The hybrid gene encodes an abnormal protein that signals CML cells to divide

32. Translocations Associated with Cancers

33. Genomics, Epigenetics and Cancer  Sequencing cancer genomes has allowed the identification of additional cancer-associated genes

34. VIDEO: Genetically Modified Virus Used to Fight Cancer

35. VIDEO: Genome Research Improving Cancer Understanding

36. Breast Cancer Susceptibility Genes

37. Epigenetics and Cancer  Abnormal DNA methylation is associated with many types of cancers  Epigenetic changes to DNA can alter gene expression and contribute to cancer

38. Epigenetics and Cancer Chromatin Chromosome Epigenetic factors (methyl groups, acetyl groups, phosphate groups) DNA methylation Methyl group can tag DNA and activate or repress genes. Histone tails Methyl group Histone modification The binding of epigenetic factors to histone “tails” alters the extent to which DNA is wrapped around histones and the accessibility of genes in the DNA. DNA Gene Histones are proteins around which DNA can wind for compaction and gene regulation Histone DNA accessible, gene active DNA inaccessible, gene inactive

39. Targeted Therapies  Use drugs that selectively block the activity of specific oncogenes  Gleevec blocks the BCR-Abl oncogene in CML  Herceptin blocks the HER2 receptor on certain breast cancers

40. Targeted Therapies ATPPPP BCR–ABL hybrid protein Signal protein (a) P Signal protein CML

41. Targeted Therapies Gleevec BCR–ABL hybrid protein Signal protein (b) No CML

42. Cancer and the Environment  Many cancers are environmentally induced  Epidemiology  The study of factors that control the presence, absence, or frequency of a disease  Provides statistical correlation between the environment and diseases such as cancer

43. Rate of Melanoma 22.5 20 17.5 15 12.5 10 Rate per 100,000 7.5 KEY 5 Male and female Male 2.5 Female 0 1982 1998 1999 2000 Year of diagnosis 197319741975197619771978197919801981 1997199619951994199319921991199019891988198719861985 1984 1983

44. Cancer and Environmental Factors  Smoking: 85% of lung cancer in men and 75% in women are related to smoking  Sunlight and skin cancer  Some viral infections: HPV and cervical cancer  Radiation  Occupational exposure to some chemicals

45. Types of Skin Cancers Basal-cell carcinoma Squamous-cell carcinoma Malignant melanoma

46. The Genetic Revolution: Cancer Stem Cells  A new cancer model states that some cancers have stem cells  A small population of cells in the tumor whose continuous division drives the growth of the tumor  May offer a new more specific approach to therapy

47. 1. What are the ultimate cause of cancer? 2. What is a somatic cell? 3. What are 5 causes of cancer (On Cancer and Genetics slide)? 4. What is a tumor suppressor gene? 5. What is a proto-oncogene? 6. What are the two types of retinoblastoma? 7. What are the two mutations that predispose women to breast and ovarian cancer? 8. What is familial adenomatous polyposis? 9. What disease is the Philadelphia chromosome linked to? 10. What is epidemiology? 11. What percentage of lung cancer in caused by smoking in men? In women?