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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
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
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)”
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
Biology in 60 sec: Feature –
Methylation turns genes on or off
http://missinglink.ucsf.edu/lm/genes_and_genomes/methylation.html
ON
OFF
Biology in 60 sec:
more Features
Central Dogma Newer Understanding
mRNA (~ 20,000)
miRNA (~ 3,000)
lncRNA (~ 13,000)
DNA
Protein
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
Monosomy 3 in Uveal Melanoma
Loss of one chromosome 3 = Monosomy 3
Disomy 3
Monosomy 3
Chromosome 3
pq
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
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
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:
Uveal Melanoma TCGA
80 primary uveal melanoma
Comprehensive/Features
Integrated
“Soldiers”
Automated Clustering of Samples Based on
SCNA Features
Samples
p
q
Chromosome
p
q
.
.
.
.
Modified from Figure 1A, Cancer Cell, 2017
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
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
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
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%)
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
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
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
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
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
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
Modified from Figure 7, Cancer Cell, 2017
Clinical Outcomes of Two Subtypes of
High-Risk Monosomy 3 Cohort
Immune Gene Expression in Monosomy 3
vs. Disomy 3 Uveal Melanoma
Modified from Figure 4, Cancer Cell, 2017
* *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
Overall Model of Uveal Melanoma
From Figure 7B, Cancer Cell, 2017
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
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.
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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Comprehensive Analysis of Genomic and Molecular Features in Uveal Melanoma

  • 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. 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. 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. 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. Biology in 60 sec: Feature – Methylation turns genes on or off http://missinglink.ucsf.edu/lm/genes_and_genomes/methylation.html ON OFF
  • 6. Biology in 60 sec: more Features Central Dogma Newer Understanding mRNA (~ 20,000) miRNA (~ 3,000) lncRNA (~ 13,000) DNA Protein
  • 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. Monosomy 3 in Uveal Melanoma Loss of one chromosome 3 = Monosomy 3 Disomy 3 Monosomy 3 Chromosome 3 pq
  • 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. 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. 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. Uveal Melanoma TCGA 80 primary uveal melanoma Comprehensive/Features Integrated “Soldiers”
  • 13. Automated Clustering of Samples Based on SCNA Features Samples p q Chromosome p q . . . . Modified from Figure 1A, Cancer Cell, 2017
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Modified from Figure 7, Cancer Cell, 2017 Clinical Outcomes of Two Subtypes of High-Risk Monosomy 3 Cohort
  • 25. Immune Gene Expression in Monosomy 3 vs. Disomy 3 Uveal Melanoma Modified from Figure 4, Cancer Cell, 2017
  • 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. Overall Model of Uveal Melanoma From Figure 7B, Cancer Cell, 2017
  • 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. 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. 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