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Gene 210 Cancer Genomics

Gene 210 Cancer Genomics. April 29, 2014. Key events in investigating the cancer genome. M R Stratton Science 2011;331:1553-1558. Flow chart of the genome analysis for a cancer patient. O Kilpivaara , and L A Aaltonen Science 2013;339:1559-1562. Today’s Plan.

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Gene 210 Cancer Genomics

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  1. Gene 210Cancer Genomics April 29, 2014

  2. Key events in investigating the cancer genome M R Stratton Science 2011;331:1553-1558

  3. Flow chart of the genome analysis for a cancer patient O Kilpivaara, and L A Aaltonen Science 2013;339:1559-1562

  4. Today’s Plan • Genetics of common cancers (rare variants and common variants) • Colorectal cancer • Prostate cancer • Lung cancer • Melanoma • Breast cancer • BRCA1 and BRCA2 genes • Robin Starr • **Break** • Linking somatic genetic alterations in cancer to targeted therapeutics • Class exercise

  5. Colorectal Cancer • 3rd most common form of cancer in developed world (excluding skin cancers) • Life time risk of developing colorectal cancer is ~5%

  6. Colorectal Cancer Most colorectal cancers usually begin as a non-cancerous polyp on the inner lining of the colon or rectum ~95% of colorectal cancers are adenocarcinomas

  7. Inherited colorectal cancer syndromes 5-10% of colorectal cancers are caused by inherited gene mutations Familial adenomatouspolyposis (FAP) Caused by mutations in the APCgene ~1% of all colorectal cancer cases due to FAP Hereditary non-polyposis colon cancer (HNPCC; Lynch syndrome) Caused by mutations in DNA damage repair genes HNPCC, also known as Lynch syndrome, accounts for about 3-5% of all colorectal cancers

  8. Familial adenomatouspolyposis (FAP) • Individuals with FAP usually develop hundreds or thousands of polyps in their colon and rectum • Cancer usually develops in 1 or more polyps as early as age 20 • By age 40, most people with this disorder will develop cancer • Surgery to remove colon is a preventive treatment for FAP individuals

  9. Hereditary non-polyposis colon cancer • Not as many polyps as FAP individuals • ~80% lifetime risk of developing colorectal cancer • Mutations in MLH1, MSH2, MSH6, and PMS2, which encode proteins involved in DNA repair Expression of hMSH2 causes a dominant mutator phenotype in E. coli (Fishelet al., Cell 1993)

  10. 14 common variants associated with increased risk of colorectal cancer Houlston et al., Nat Genet 2010 Lubbe et al., Hum Mol Genet 2011

  11. Prostate Cancer • Most common cancer in men • 1 in 6 lifetime risk • Large genetic component (42%)

  12. Multiple prostate cancer risk variants on 8q24 Witte Nat Genet 2007

  13. 12 common variants associated with increased risk of prostate cancer Estes et al., Nat Genet 2009 Takata et al., Nat Genet 2010

  14. Lung Cancer • #1 cause of cancer deaths in United States • ~90% of lung cancer caused by smoking • Heritability of lung cancer 8-14%

  15. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 Thorgeirsson et al., Nature 2008 Amos et al., Nat Genet 2008 Hung et al., Nature 2008

  16. Melanoma (Skin Cancer) • Only accounts for <5% of skin cancers but responsible for most skin cancer deaths • Heritability of melanoma 18-21%

  17. Common variants that confer risk for melanoma Melanocortin-1 receptor: G-protein-coupled receptor expressed in melanocytes. Variants in MC1R associated with red hair and fair skin Hayward Oncogene 2003

  18. Breast Cancer • 2nd most common cancer in women (next to skin cancer) • 2nd leading cause of cancer deaths in women • Heritability of lung cancer 27-40%

  19. Science, 1990 Science, 1994

  20. BRCA1 and BRCA2 • 5-10% of breast cancer is inherited (mostly due to BRCA1/2 mutations) • Also increases risk of ovarian cancer • 23andMe reports 3 known BRCA mutations common in Ashkenzai Jewish population • 185delAG (BRCA1) – increases lifetime risk of breast cancer from 12% to 60% and ovarian cancer from 2% to 40% • 5382insC (BRCA1) – increases lifetime risk of breast cancer from 12% to 60% and ovarian cancer from 2% to 40% • 6174delT (BRCA2) – increases lifetime risk of breast cancer from 12% to 50% and ovarian cancer from 2% to 20% By age 70, 50-60% of women who have a BRCA mutation will develop breast cancer and 20-40% will develop ovarian cancer BRCA1 and BRCA2 encode proteins that repair DNA double-strand breaks

  21. Patenting Genes?

  22. June, 2013 “A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.”

  23. Discussion with Robin Starr

  24. BREAK

  25. Somatic mutations in cancer

  26. Key events in investigating the cancer genome M R Stratton Science 2011;331:1553-1558

  27. Number of somatic mutations in various cancers B Vogelstein et al. Science 2013;339:1546-1558

  28. Flow chart of the genome analysis for a cancer patient O Kilpivaara, and L A Aaltonen Science 2013;339:1559-1562

  29. The Cancer Genome Benefits and applications of cancer genome sequencing? Tumor heterogeneity Design treatments based on tumor sequence Response to therapy

  30. Linking somatic genetic alterations in cancer to targeted therapeutics

  31. Chronic myelogenousleukemia Philadelphia chromosome formed by a translocation t(9;22) Generates the BCR-ABLoncogene Constitutively active c-ABL kinase activity Imatinib (Gleevec) Dramatic therapeutic benefit 6-year survival rates ~90%

  32. BRAF mutations in melanoma Nature 2002 66% of malignant melanomas 80% have same mutation (V600E), which increases kinase activity

  33. BRAF inhibitors

  34. Relapse after 23 weeks of therapy because of therapeutic resistance to PLX4032 MEK1C121S mutation to increases kinase activity and confer robust resistance to both RAF and MEK inhibition

  35. 23 weeks of therapy MEK1C121Smutation to increases kinase activity and confer robust resistance to both RAF and MEK inhibition

  36. Key events in investigating the cancer genome M R Stratton Science 2011;331:1553-1558

  37. DNA copy number arrays DNA methylation Exome sequencing Transcriptome microRNA profiling Proteomics

  38. Class Exercise • You work for a new genome interpretation startup company • Your first customer sends you tumor biopsy DNA samples from 8 cancer patients • You perform genomic analyses on tumor biopsies and generate exome sequence and expression analyses for several major cancer susceptibility genes for each patient (cytogenetic analysis; DNA sequence for BRCA1, BRCA2, EGFR, BRAF; expression analysis for estrogen receptor, HER2, MET) • Use personalized tumor genetic profile to suggest appropriate targeted therapy • Discuss rationale for each therapeutic choice (what is genetic lesion? What defect (e.g. signaling pathway) does this cause? What does the chosen therapy target?)

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