May 5 2015 Key events in investigating the cancer genome M R Stratton Science 201133115531558 Flow chart of the genome analysis for a cancer patient O Kilpivaara and L A Aaltonen ID: 1037161
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1. Gene 210Cancer GenomicsMay 5, 2015
2. Key events in investigating the cancer genomeM 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 PlanGenetics of common cancers (rare variants and common variants)Colorectal cancerProstate cancerLung cancerMelanomaBreast cancerBRCA1 and BRCA2 genesRobin Starr**Break**Linking somatic genetic alterations in cancer to targeted therapeuticsClass exercise
5. Colorectal Cancer3rd most common form of cancer in developed world (excluding skin cancers)Life time risk of developing colorectal cancer is ~5%
6. Colorectal CancerMost 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 syndromes5-10% of colorectal cancers are caused by inherited gene mutationsFamilial adenomatous polyposis (FAP)Caused by mutations in the APC gene~1% of all colorectal cancer cases due to FAPHereditary non-polyposis colon cancer (HNPCC; Lynch syndrome)Caused by mutations in DNA damage repair genesHNPCC, also known as Lynch syndrome, accounts for about 3-5% of all colorectal cancers
8. Individuals with FAP usually develop hundreds or thousands of polyps in their colon and rectumCancer usually develops in 1 or more polyps as early as age 20By age 40, most people with this disorder will develop cancer Surgery to remove colon is a preventive treatment for FAP individualsFamilial adenomatous polyposis (FAP)
9. Inherited colorectal cancer syndromes5-10% of colorectal cancers are caused by inherited gene mutationsFamilial adenomatous polyposis (FAP)Caused by mutations in the APC gene~1% of all colorectal cancer cases due to FAPHereditary non-polyposis colon cancer (HNPCC; Lynch syndrome)Caused by mutations in DNA damage repair genesHNPCC, also known as Lynch syndrome, accounts for about 3-5% of all colorectal cancers due to Lynch syndrome
10. Not as many polyps as FAP individuals~80% lifetime risk of developing colorectal cancerMutations in MLH1, MSH2, MSH6, and PMS2, which encode proteins involved in DNA repairHereditary non-polyposis colon cancer Expression of hMSH2 causes a dominant mutator phenotype in E. coli (Fisher et al., Cell 1993)
11. 14 common variants associated with increased risk of colorectal cancerHoulston et al., Nat Genet 2010Lubbe et al., Hum Mol Genet 2011
12. Prostate CancerMost common cancer in men1 in 6 lifetime riskLarge genetic component (42%)
13. Multiple prostate cancer risk variants on 8q24Witte Nat Genet 2007
14. 12 common variants associated with increased risk of prostate cancerEstes et al., Nat Genet 2009Takata et al., Nat Genet 2010
15. Lung Cancer#1 cause of cancer deaths in United States~90% of lung cancer caused by smokingHeritability of lung cancer 8-14%
16. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25Thorgeirsson et al., Nature 2008Amos et al., Nat Genet 2008Hung et al., Nature 2008
17. Melanoma (Skin Cancer)Only accounts for <5% of skin cancers but responsible for most skin cancer deathsHeritability of lung cancer 18-21%
18. Common variants that confer risk for melanomaHayward Oncogene 2003Melanocortin-1 receptor: G-protein-coupled receptor expressed in melanocytes. Variants in MC1R associated with red hair and fair skin
19. Breast Cancer2nd most common cancer in women (next to skin cancer)2nd leading cause of cancer deaths in womenHeritability of lung cancer 27-40%
20. Science, 1990Science, 1994
21. BRCA1 and BRCA25-10% of breast cancer is inherited (mostly due to BRCA1/2 mutations)Also increases risk of ovarian cancer23andMe reports 3 known BRCA mutations common in Ashkenzai Jewish population185delAG (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 cancerBRCA1 and BRCA2 encode proteins that repair DNA double-strand breaks
22. Patenting Genes?
23. Discussion with Robin Starr
24. BREAK
25. Somatic mutations in cancer
26. Key events in investigating the cancer genomeM R Stratton Science 2011;331:1553-1558
27. B Vogelstein et al. Science 2013;339:1546-1558Number of somatic mutations in various cancers
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 GenomeBenefits and applications of cancer genome sequencing?Tumor heterogeneityDesign treatments based on tumor sequenceResponse to therapy
30. Linking somatic genetic alterations in cancer to targeted therapeutics
31. Chronic myelogenous leukemiaPhiladelphia chromosome formed by a translocation t(9;22)Generates the BCR-ABL oncogeneConstitutively active c-ABL kinase activityImatinib (Gleevec)Dramatic therapeutic benefit6-year survival rates ~90%
32. BRAF mutations in melanomaNature 200266% of malignant melanomas80% have same mutation (V600E), which increases kinase activity
33. BRAF inhibitors
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36. Key events in investigating the cancer genomeM R Stratton Science 2011;331:1553-1558
37. DNA copy number arraysDNA methylationExome sequencingTranscriptomemicroRNA profilingProteomics
38. Class ExerciseYou work for a new genome interpretation startup companyYour 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 therapyDiscuss rationale for each therapeutic choice (what is genetic lesion? What defect (e.g. signaling pathway) does this cause? What does the chosen therapy target?)