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The Cancer Genome Atlas Update

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Presentation by Scott Woodman, MD, PhD. Presented at the 2018 Eyes on a Cure: Patient & Caregiver Symposium, hosted by the Melanoma Research Foundation's CURE OM initiative. 

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The Cancer Genome Atlas Update

  1. 1. A Comprehensive and Integrated Analysis of Uveal Melanoma 7th Annual Eyes on a Cure: Ocular Melanoma Patient and Caregiver Symposium Scott E. Woodman, M.D. Ph.D. Associate Professor Melanoma Medical Oncology Systems Biology University of Texas MD Anderson Cancer Center April 21, 2018
  2. 2. The Cancer Genome Atlas (TCGA) • Launched in 2006 as a pilot, expanded in 2009, ended in 2017 • NIH-funded program to perform a comprehensive and integrated analysis of key genomic/molecular features of many cancers • A ‘marker paper’ in each project to provide fundamental insights • Make the data publicly available to the research community • Serves as a model for the power of teamwork in science. U.K., France, Netherlands, Canada, U.S. • Uveal melanoma chosen as one of 10 rare cancers included
  3. 3. Comprehensive and Integrated Analysis of Features Kim Roy: “Knowledge is power!” Scott Woodman: “There is not a Principle Investigator (PI) of the Mars rover mission(s)”
  4. 4. https://www.123rf.com/photo_52129452 C G A T DNA: • genes = 20,000; specific sequence of A, C, T and G’s; 1% of genome • genome = sequence of 3,200,000,000 A, C, T and G’s; on chromosomes • chromosomes = 23 chromosomes (mother) and 23 chromosomes (father), thus 46 chromosomes total Biology in 60 sec: Features ~ 20,000 23 pairs
  5. 5. Biology in 60 sec: Feature – Methylation turns genes on or off http://missinglink.ucsf.edu/lm/genes_and_genomes/methylation.html ON OFF
  6. 6. Biology in 60 sec: more Features Central Dogma Newer Understanding mRNA (~ 20,000) miRNA (~ 3,000) lncRNA (~ 13,000) DNA Protein
  7. 7. Disomy 3, Monosomy 3 and BAP1 in Uveal Melanoma Background: Chromosome has a “p” smaller and “q” larger part 23 chromosomes from mother 23 chromosomes from father thus 46 chromosomes total
  8. 8. Monosomy 3 in Uveal Melanoma Loss of one chromosome 3 = Monosomy 3 Disomy 3 Monosomy 3 Chromosome 3 pq
  9. 9. Monosomy 3 and BAP1 in Uveal Melanoma Disomy 3 Monosomy 3 Chromosome 3 pq BAP1 mutationX Harbour JW et al, Science, 2010 BAP1 gene mutation in the remaining chromosome 3 of monosomy 3 Somatic copy number alteration (SCNA) Gene mutation
  10. 10. Molecular Features Discussed So Far • Genes • Mutated (change function, e.g., BAP1 mutation) • Methylated (change expression) • Chromosomes • Parts lost or gained, e.g., monosomy 3) • RNA • miRNA • lncRNA • mRNA  protein
  11. 11. TCGA: The Pipeline for Comprehensive Characterization Tissue Sample Pathology QC DNA & RNA Isolation, QC Sequencing Expression, CNA & LOH, Epigenetics Data Storage at DCC & CGHub Comprehensive Characterization of a Cancer Genome GDAC Integrative Analysis ~90d Whole Genome seq ~45d Methylation ~60d miRNA seq ~105d mRNA seq ~120d Exome seq ~180d ~12-24 months 3 months – 2 years Molecular Features: Clinical/Pathological Features:
  12. 12. Uveal Melanoma TCGA 80 primary uveal melanoma Comprehensive/Features Integrated “Soldiers”
  13. 13. Automated Clustering of Samples Based on SCNA Features Samples p q Chromosome p q . . . . Modified from Figure 1A, Cancer Cell, 2017
  14. 14. Copy number cluster Monosomy 3Disomy 3 6p Comprehensive Unsupervised Clustering Analysis: D3 and M3 Samples Separate into Two Subclusters 1p 3p 6q 8q 8p Modified from Figure 1A, Cancer Cell, 2017 3q 3p 8q 8p 3q
  15. 15. SCNA DNA methylation BAP1 alteration (DNA-seq) BAP1 alteration (RNA-seq) Chr 3 Copy Number Integration of SCNA Clustering Shows 1:1 Overlap with BAP1 Alterations and a DNA Methylation Profile Modified from Figure 2, Cancer Cell, 2017Monosomy 3 Samples Genes
  16. 16. Summary of Thus Far • Monosomy 3 tumors have a 1:1 overlap with BAP1 alterations • Monosomy 3 tumors have a 1:1 overlap with a specific DNA methylation profile • Monosomy 3 and Disomy 3 tumors each separate into two subgroups
  17. 17. CYSLTR2 (4%) YAP TAZ p38 JNK PIP2 Trio Rho Rac PLCB4 (1%) RAF MEK ERK IP3 DAG RAS PKC RasGRP3 All Uveal Melanoma Have Mutant: CYSLTR2 or GNAQ or GNA11 or PLCB4 Cell proliferation/survival Van Raamsdonk CD et al: Nature 2009 Van Raamsdonk CD et al: N Engl J Med 2010 Moore AR et al: Cell Rep 2018 GNAQ (45%) GNA11 (45%)
  18. 18. Monosomy 3Disomy 3 GNA11, GNAQ, CYSLTR2 and PLCB4 Mutations are “Mutually Exclusive” Copy number clusters GNA11 mutations GNAQ mutations CYSLTR2 mutations PLCB4 mutations Modified from: Figure 1A, Cancer Cell, 2017 CYSLTR2 PLCB4GNAQ GNA11
  19. 19. SF3B1 EIF1AX BAP1 (20% of Disomy 3) spicing factor (20% of Disomy 3) translational initiator (85% of Monosomy 3) de-mono-ubiquitinator Mutually Exclusive Mutations of Other Genes in Uveal Melanoma: Mutually Exclusive Daniels AB et al: Invest Ophthalmol Vis Sci 2012 Harbour JW et al: Nature Genetics 2013 Moore AR et al: Nature Genetics 2016
  20. 20. Monosomy 3Disomy 3 Comprehensive and Integrated Nature of Mutated Genes in UM Copy number clusters Chr 8q copy number DNA methylation clusters mRNA clusters lncRNA clusters miRNA clusters GNA11 mutations GNAQ mutations CYSLTR2 mutations PLCB4 mutations EIF1AX mutations SF3B1 mutations SRSF2 mutations BAP1 alteration (DNA-seq) BAP1 alteration (RNA-seq) EIF1AX, SF3B1 and BAP1 mutations align with specific SCNA and DNA methylation clusters
  21. 21. Furhter Summary • GNA11, GNAQ, CYSLTR2 and PLCB4 show a mutually exclusive mutation pattern • EIF1AX, SF3B1, and BAP1 show a mutually exclusive mutation pattern • Discovered novel SRSF2 gene mutations in UM (like SF3B1) • EIF1AX mutations align with specific SCNA and DNA methylation states • SF3B1 mutations align with specific SCNA and DNA methylation states • No ultraviolet light mutation signature in UM
  22. 22. Transcript Expression Pattern in UM mRNA lncRNA miRNA Modified from Figure 3 and S3, Cancer Cell, 2017 1 4 2 3 2 3 1 4 3 4 2 1
  23. 23. Summary of Transcriptome Expression Landscape • Our unsupervised clustering, based on the gene expression of different RNA species (mRNA, lncRNA and miRNA) separated high- and low-risk tumors each into two further subtypes, for a total of four groups • Cluster 1 and 2 tumors highly overlapped with Disomy 3 tumors, but had distinct expression profiles • Cluster 3 and 4 tumors highly overlapped with Monosomy 3 tumors, but had distinct expression profiles • Cluster 4 tumors showed evidence of greater immune infiltration compared to all other clusters
  24. 24. Modified from Figure 7, Cancer Cell, 2017 Clinical Outcomes of Two Subtypes of High-Risk Monosomy 3 Cohort
  25. 25. Immune Gene Expression in Monosomy 3 vs. Disomy 3 Uveal Melanoma Modified from Figure 4, Cancer Cell, 2017
  26. 26. * *Leukocyte fraction was estimated from DNA methylation data using an approach: Carter et al, Nat Biotechnol, 2012 Low risk Low risk 1 4 2 3 The 4 mRNA Clusters Separate the Two Risk Groups, Defined by the 12-gene Panel, Each Into Two Distinct Subsets mRNA cluster High risk High risk
  27. 27. Overall Model of Uveal Melanoma From Figure 7B, Cancer Cell, 2017
  28. 28. Takehome Messages From UM TCGA Cancer Cell, 2017 • Advocacy Matters! • Comprehensive, Integrated Investigations Require a Highly Functional and Skilled Team Approach • The Comprehensive Approach has Pretty Much Identified All Gene Mutations or Chromosomal Aberrations in UM • UM is a Cancer Whose Features (Gene Mutations, Chromosomal Aberrations, DNA Methylation, RNA Subtype Profiles) are Highly Overlapping • High Risk UM May Subdivide Into Two Groups with Different Characteristics
  29. 29. Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, Hess JM, Uzunangelov V, Walter V, Danilova L, Lichtenberg TM, Kucherlapati M, Kimes PK, Tang M, Penson A, Babur O, Akbani R, Bristow CA, Hoadley KA, Iype L, Chang MT; TCGA Research Network, Cherniack AD, Benz C, Mills GB, Verhaak RGW, Griewank KG, Felau I, Zenklusen JC, Gershenwald JE, Schoenfield L, Lazar AJ, Abdel-Rahman MH, Roman-Roman S, Stern MH, Cebulla CM, Williams MD, Jager MJ, Coupland SE, Esmaeli B, Kandoth C, Woodman SE. Collaborators (170) Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor- prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes. 2017 Aug 14;32(2):204-220.e15.
  30. 30. Special thanks to.. Cyriak Kandoth Juliann Shih, Ewan A. Gibb, Christina Yau, Luda Danilova, Rehan Akbani, Colleen M. Cebulla, Mohamed H. Abdel-Rahman, Tara M. Lichtenberg, Martine J. Jager, Sara Coupland, Ina Flau -- and many many other talented and dedicated team members and collaborators… -- and the MRF CURE OM!!!! A. Gordon Robertson Bita EsmaeliJunna Oba

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