An Overview of Cancer Genetics

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Audio and slides for this presentation are available on YouTube: http://youtu.be/e_KVYJX2GTs

Have you ever wondered about your genetic predisposition to cancer? How cancer evolves in families? Or how cancer cells differ from normal cells in your body? Join Judy Garber, MD, MPH, director of the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute, as she explores the basics of cancer genetics, DNA mutations, genetic screening, management, and more.

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An Overview of Cancer Genetics

  1. Cancer Genetics Judy E. Garber, MD MPHDirector, Cancer Genetics and Prevention Dana-Farber Cancer Institute
  2. Cancer is a Genetic DiseaseNormal cells and Cancer cells contain the same 30,000 genes what distinguishes them is which of the genes are turned on and off Normal Cancer Which genes are activated in cancer?
  3. Chromosomes, DNA, and Genes Gene Nucleus Cell Chromosomes ProteinAdapted from Understanding Gene Testing, NIH, 1995
  4. The DNA Double Helix Sugarphosphate Base pairbackbone Bases Adenine (A) Cytosine (C) Thymine (T) Guanine (G)
  5. Normal Male Karyotype p Centromere q Chromosome 5
  6. Genetic Code A codon is made of 3 base pairs 64 codons total1 codon (AUG) encodes 61 codons encode 3 codons stop methionine and starts 20 amino acids proteintranslation of all proteins (redundant code) translation A U G G C A U A A Met Ala
  7. Disease-Associated Mutations Alter Protein Function Functional protein Nonfunctional or missing protein
  8. Autosomal Dominant Inheritance Each child has 50% chance of inheriting the mutation No “skipped generations” Equally transmitted by men and women Unaffected Affected
  9. The Two-Hit HypothesisFirst hit First hit in Second hit germline (tumor)
  10. Tumor Suppressor Genes Normal genes (prevent cancer) 1st mutation (susceptible carrier) 2nd mutation or loss (leads to cancer)
  11. Oncogenes Normal genes (regulate cell growth) 1st mutation (leads to accelerated cell division)1 mutation sufficient for role in cancer development
  12. Normal (male) chromosomes andBRCA1-deficient cancer cells withgross chromosomal abnormalities
  13. More Subtle PedigreesPR 60 CO 61? 55* OV 59 BR 32 BR 34 *TAH/BSO at 40
  14. Genetic Testing 2012• Genetic testing requires a DNA sample from blood, saliva or other tissue• Testing costs are usually covered by health insurance, at least partially• Laws to prevent discrimination in health insurance exist (GINA)• Testing is often offered at the time of cancer diagnosis, because the information can affect management decisions• Autonomy and Access are still important
  15. +
  16. Once the mutation isfound in one personin the family after fullprice testing, the restof the family can betested to see whetherthey do or do NOTshare the mutation.The “single site”testing is usuallyabout $500.
  17. BR/OV Cancer Risk Management Options for BRCA Mutation CarriersSurveillance (does not  risk)• Mammogram, MRI, Exam, +/- US• (TransVaginal Ultrasound, CA125)Chemoprevention• Tamoxifen/ Raloxifene? Exemestane? Other?• Birth Control Pills  Ov ca riskProphylactic Surgery• 90% Bilateral mastectomy• Removal ovaries & fallopian tubes: 90% Ov ca risk; if done premenopausal, ~50%  BrCa risk
  18. I’M OUT OFESTROGENAND I AMNOT HAPPYABOUT IT
  19. Risk of Colorectal Cancer (CRC)General population 5% Personal history ofcolorectal neoplasia 15%–20% Inflammatory 15%–40% bowel disease HNPCC mutation 70%–80% FAP >95% 0 20 40 60 80 100 Lifetime risk (%)
  20. Hereditary Non-Polyposis ColorectalCancer (HNPCC, Lynch Syndrome) • Colon, Uterine and other cancers • In HNPCC, the tumor CO 45 UT 38 tissue stored in a CO 40 pathology department _ + can be studied for evidence that theCO 28 Cecum 35 syndrome is present, soST 32 even a deceased relative can be informative 4
  21. A Li - F raum eni S yndrom e K indred C R C , 72 Lung, 48 80 O S , 14 Laryn x, 56 B reast, 26 B reast, 22, 27 S T S , 33* S tom ach, 32 B reast, 32 ACC, 5 O S , 14 S T S , 26** tum or in R T field of prior m alig na ncy
  22. FDG-PET/CT Screening in LFS Results Fused PET/CT CT
  23. Survival of TP53 Mutation Carriers inSurveillance and Non-Surveillance Groups Villani A et al. Lancet Oncol 2011;12:559-567
  24. Decisions Potentially Influenced byBRCA1/2 Status in Breast Cancer Patients• Management of newly diagnosed patients – Primary Therapy: Surgical Options – Chemotherapy – Hormonal therapy• Management of breast cancer survivors – Additional primary breast cancer risk – Ovarian cancer risk – Treatment of metastatic disease• Implications for Relatives
  25. Breast Cancer Subtypes are Associated with Different Germline Mutations ER+ PR+/HER2- BRCA2, TP53 ER+ or ER-/HER2+ TP53 ER-, PR-, HER2- BRCA1
  26. Kaplan-Meier estimates of recurrence-free survival and overall survival after neoadjuvant T-FAC by :BRCA status Path CR TNBC Arun B et al. J Clin Oncol 2011;29:3739-3746
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  28. Expanded Commercial Cancer Genetic Testing is Here
  29. TP53 Germline Deletion in Patient With t-AMLBR 37 +OV 39R-OV 42AML 42 3 Link DC et al. JAMA 2011;305:1568-1576
  30. Pharmacogenetics:Predicting Efficacy and Toxicity
  31. =Breast Cancer
  32. A Paradigm Shift – The Genomic View of CancerFrom Anatomy… From KIT Germline (Imatinib) • Lung Tumor Blood Genomic Genomic • Breast Profiling EGFR Profiling (Erlotinib) •Prostate HER2 (Trastuzumab) • Colon BRAF (PLX4032) • Brain PIK3CA (BEZ235)
  33. Potential Findings from Sequencing DNA from Tumor & Blood of DFCI Cancer Patients in PCMP• Tumor genome: treatment targets, predictors of response• Personal genome: • Variation in drug metabolizing genes that affect dose or choice of agent • Mutations in genes that confer  risk of the patient’s cancer and related cancers (e.g, BRCA, HNPCC), important to patient and family • Mutations in genes associated with Non-Cancer conditions that could be more important to relatives (e.g., long QT; Fragile X)
  34. Learn more about the DFCI Gene Display.Gene Display in the Yawkey Center for Cancer Care
  35. Audience Q&AWhat about people who are adopted and don’t know anything about their family history?
  36. Audience Q&AWhat is does the insurance industry think about preventative surgeries?
  37. Audience Q&A For insurance purposes, do you have to build a caseto justify preventative surgery based on genetic testing?
  38. Resources and Additional Information • Check out the Cancer Genetics and Prevention Program at Dana-Farber. • Watch Dr. Judy Garber discuss her work as the director of Cancer Genetics and Prevention Program. • View more resources available through DFCI for patients and families dealing with cancer. To schedule an appointment at DFCI, click here.

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