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Hereditary Cancers

Hereditary Cancers. Sidra Ahsan June 14, 2012. Objectives. After this presentation you should understand: 1 . Some basic genetics and genomics concepts 2. How cancer occurs at the cellular level 3. How genetics may play a role in the development of cancer in your family

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Hereditary Cancers

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  1. Hereditary Cancers Sidra Ahsan June 14, 2012

  2. Objectives After this presentation you should understand: 1. Some basic genetics and genomics concepts 2. How cancer occurs at the cellular level 3. How genetics may play a role in the development of cancer in your family 4. How to confront risk with early detection and prevention

  3. Chromosomes and Genes are Inherited SPERM CELL EGG CELL EMBRYO

  4. Chromosomes are like shoes, they come in pairs... Human chromosomes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y

  5. The cell nucleus is like a library... Chromosomes carry the genetic information. The cell nucleus is Chromosomes are like the library. like the bookshelves in the library. Genes are contained on the chromosome. Genes are like the books on the bookshelves. The nucleus contains the chromosomes like the library contains the bookshelves. The DNA is like the letters in the words on the pages of the book.

  6. The Human Machine Total number of cells 1014 Genetic code 6*109 base pairs or 6 GByte (only 3% active or 180 MBytes) Length of chromosome DNA in all cells 1.2*1014m (4.6 light days) Chromosome copy operations (prenatal + 1st year) >40 TBytes/s or 1,000,000 Ultra Wide SCSIs Power consumption (adult) 90-100 Watts (2,000 kilocalories/day) 1.6 pW/cell http://vadim.www.media.mit.edu/MAS862/Project.html

  7. The Human Genome • 3 X 109 base pairs of information • 97% JUNK ! • Codes for ~30,000 Proteins • Proteins are the structural and functional components of the cell. • Mutations in genes cause defective proteins. • Defective proteins can cause a cell to become diseased i.e. Cancer; Myotonic Dystrophy; Huntington’s Disease

  8. Comparative “Genomology” Organism Genome Sizes(Base Pairs) • Escherichia coli (bacterium) genome 4.6 X 106 • Yeast genome (simple eukaryote) 15 X 106 • Smallest human chromosome (Y) 50 X 106 • Largest human chromosome (1) 250 X 106 • Entire human genome (haploid) 3000 X 106

  9. Human Genome Organization 46 Volume Chromosome Encyclopedia

  10. Chromosomes are made of DNA

  11. DNA is copied into RNA and the information translated into proteins

  12. Protein Synthesis occurs on a template of mRNA Ribosome

  13. Gene Expression is Cell-specific • The set of genes transcribed into mRNA and then translated into protein programs the cell type. • Example: Red Blood Cells make hemoglobins and the cellular proteins needed to make it. Corollary: other cells don’t make hemoglobin.

  14. Profiling the RNA of the Genome ALDH1A3 Cyp1B1 KIAA1750 (SET-homologue) COX7A1

  15. DNA is copied into RNA and the information translated into proteins

  16. Comparative “Proteomology” Organism (Genes/Proteins) • Escherichia coli (bacterium) genome 4.3 X 103 • Yeast genome (lower eukaryote) 6.2 X 103 • Smallest human chromosome (Y) 2 X 102 • Largest human chromosome (1) 3 X 103 • Entire human genome (haploid) 3 X 104

  17. Cancer is … A group of more than 100 different diseases characterized by • Abnormal cells • Uncontrolled cell growth (tumors) • Tumors may be benign (non-cancerous) or • Tumors may be malignant (cancerous) and • Tumors may spread away from the primary site of the disease (metastasis)

  18. Cancer Disease Progression 0 5 10 Years of Growth* 1012 Very early breast cancer (undetectable) 10 cm Number of Cells 1010 Clinical Breast Cancer 108 1 cm 105 DCIS 1 mm 104 102 0 5 10 15 20 25 30 35 40 Number of Cell Doublings *Note 90-day doubling time x 40 doublings = 3600 days (approximately 10 years) Harris et al. Breast Diseases, 2nd ed. 1991:165-189.

  19. Cancer is a Multi-Step Genetic Disease Mutations in several genes lead to cancer cells and metastasis Normal cells Gene mutation 1 Gene mutation 2 Divide or die Gene mutation 3 Gene mutation 4 Gene mutation 5 CANCER Metastasis

  20. Gene Alterations in Cancer Oncogenes: One mutation results in activation Tumor Suppressor Genes: Biallelic inactivation necessary for loss of function

  21. Types of Gene Mutations

  22. 1/8 Risk General Population Lifetime Risk of Breast Cancer

  23. Risk Increases as a woman grows older

  24. Categories of Risk Factors • Possible Risk Factors • There is no scientific proof, but the risk factor is being studied to determine whether it is linked to breast cancer. • Identified Risk Factors • There is scientific proof that the risk factor is linked to breast cancer

  25. Possible Risk Factors • High fat/ Low fiber diet • Heavy alcohol use • Hormone use • Prolonged birth control use • Estrogen replacement therapy • Environmental Exposure • Lack of breast feeding

  26. Identified Risk Factors • Family history of breast cancer • Having had breast cancer before • Having first child after age 30 • Starting menstruation before age 12 • Starting menopause after age 50

  27. Most Common Breast Cancer Risk Factors: • Being a woman • Growing older

  28. Identified Breast Cancer Risk Factors

  29. Hereditary Cancers • All cancers have a genetic basis, however most cancers are not hereditary • Only 5-10% of all cancers are hereditary

  30. Inherited Breast Cancer About 5-10% of breast cancer is due to hereditary factors

  31. Inherited Ovarian Cancer Only 10% of all ovarian cancer is due to hereditary factors

  32. BRCA1Chromosome 17 BRCA2Chromosome 13

  33. Breast Cancer Genes BRCA 1 and 2 are Tumor Suppressor Genes

  34. Genes are instructions for making proteins What are Mutations? What Are Genes? Mutations are changes in the genes PROTEIN PROTEIN PRNTEIN PROTEIN 2 working copies in each cell One copy not working

  35. Tumor suppressor genes act like the brakes on a bicycle Bicycle does not hit wall Two working BRCA genes Bicycle does not hit wall One working, one not working

  36. Two copies of the gene, neither working PRNTEIN PRNTEIN

  37. When the bicycle has no brakes Both genes not working, the bicycle crashes

  38. BRCA1 and BRCA2 Mutations Increase the Risk of Other Cancers • Ovarian cancer • Second breast cancer • Male breast cancer • Prostate cancer • Pancreatic cancer

  39. BRCA1/2 • About 2000 genetic mutations associated with BRCA1 and 2 genes • Women who test positive do not necessarily develop breast cancer • Not all mutations carry the same risk • Two most common mutations in BRCA1: 185delAG and 5832ins where 185delAG identified in 15% Ashkenazi Jewish families with breast or ovarian cancer • Germline mutations of BRCA1 or 2 confer similar lifetime risks (80%) for breast cancer (BRCA1) and 70% (BRCA2) for ovarian cancer • BRCA2 mutation carries a lifetime risk of 6% for male breast cancer

  40. BRCA involved in DNA Repair

  41. Inherited Breast and Ovarian Cancer Your family history may hold important clues to your risk of breast and/or ovarian cancer

  42. Hereditary Cancer Family Tree Grandfather Grandmother Father Mother Uncle Aunt A Husband Brother Sister Son Niece Daughter

  43. Features of Families with Hereditary Cancers • Many generations affected • Early age of diagnosis • One individual with 2 or more separate cancers (not a spread of first) • More than one kind of cancer • Can be passed from either mother’s or father’s side of the family • Not all individuals with mutation develop cancer

  44. WRONG Cancer on the Father’s side of the family doesn’t count Ovarian cancer in the family is not a factor in breast cancer risk. The most important risk factor is the number of women with breast cancer. CORRECT Half of all women with a hereditary risk inherited from their father Ovarian Cancer is an important indicator of hereditary risk although it is not always present. Age of onset of breast cancer is more important than the number of women with breast cancer. Misconceptions About Family History

  45. Hereditary Cancer Family Tree

  46. Hereditary versus Sporadic Cancer BR,41 BR,71 BR,47 OV,50 BR,45 BR,75 Hereditary Sporadic

  47. Inherited cancer If you have concerns about your family history... Talk to trained genetic healthcare providers

  48. Genetic Counseling Session: • Gather family and medical history: pedigree • Assess and explain cancer/hereditary risk • Educate patient on genetics and cancer • Explain genetic testing eligibility, pros and cons • Discuss cancer screening and risk reduction strategies • Discuss participation in research studies • Genetic testing for eligible patients

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