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Identifying OxPhos dependent tumors across different cancer types
Daniel Gusenleitner Adviser: Stefano Monti
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DLBCL - Oxphos Subtype Monti, Savage, Kutok, et al. Blood, 2005
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OxPhos samples respond to targeted treatment
PPARγ antagonists Caro et al., Cancer Cell, 2012
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Developing a biomarker for CCC
Trainings dataset Validation on CCC biomarker BCR HR OxPhos signatures
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Oxidative Phosphorylation
Vander Heiden et al, Science, 2009
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Goal Identification of OxPhos samples across different cancer types
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Outline Evidence for OxPhos – NonOxPhos stratification in other tumor types Most genes of DLBCL OxPhos signature are also present in solid tumors, but we found additional concordant genes No evidence of association with genomic instability (mutations and/or SCNAs) Strong candidates of OxPhos/Non-OxPhos cell-lines
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OxPhos subtype in Melanoma
p-value: PGC1a OxPhos Signature OxPhos metagene GSEA results
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Datasets TCGA Breast Curtis CCLE LUAD: lung adenocarcinoma
LUSC: lung squamous cell carcinoma BRCA: breast invasive carcinoma HNSC: head and neck squamous carcinoma Breast Curtis CCLE
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Outline Evidence for OxPhos – NonOxPhos stratification in other tumor types Most genes of DLBCL OxPhos signature are also present in solid tumors, but we found additional concordant genes No evidence of association with genomic instability (mutations and/or SCNAs) Strong candidates of OxPhos/Non-OxPhos cell-lines
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Clustering is not always the best way to define a subtype
OxPhos signature DLBCL samples
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Differences in background expression levels make classification infeasible
Additional DLBCL OxPhos meta gene expression DLBCL Lung Cancer
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Assign ‘intuition’ Adaptive linear regression …
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ASSIGN is able to score the activation of a signature
.. and to identify the genes that are the main drivers of the signature
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ASSIGN is able to adjust for differing backgrounds
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In BRCA OxPhos is activated in comparison to BCR …
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… but a stratification in a heatmap is hard to quantify
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Unlike active signatures, the weights for random signatures are exponentially distributed
scaled gene weights random signatures OxPhos signature
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Gene weights for inactive signatures cannot be distinguished from weights of random signatures
scaled gene weights OxPhos signature BCR signature p-value: 3.28E-06 p-value: p-values based on whether the signature follows an exponential distribution
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OxPhos appears to be active in all TCGA datasets
Signature Dataset p-value OxPhos BRCA HNSC 1.30E-05 LUAD 3.28E-06 LUSC 8.84E-06 BCR
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OxPhos score
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We can find the OxPhos signal in all cancer datasets we looked at
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Expansion of the OxPhos signature
CCC OxPhos signature: Derived from DLBCL samples robust (>>FC) high minimum expression Represented on U133A General OxPhos signature 108 BIOCARTA MITOCHONDRIA PATHWAY KEGG OXIDATIVE PHOSPHORYLATION REACTOME ELECTRON TRANSPORT CHAIN REACTOME RESPIRATORY ELECTRON TRANSPORT OXIDOREDUCTASE ACTIVITY ACTING ON NADH OR NADPH REACTOME TCA CYCLE AND RESPIRATORY ELECTRON TRANSPORT 232 287
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Expanded OxPhos signature in LUAD
General OxPhos genes DLBCL OxPhos signature
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Continuous GSEA to find gene-sets that correlate with ASSIGN score
Expression Set Correlation with ASSIGN score DLBCL derived OxPhos signature
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ASSIGN score GSEA - up FDR Gene Set Avg. Rank Curtis discov.
DLBCL 2010 TCGA BRCA TCGA HNSC TCGA LUAD TCGA LUSC KEGG OXIDATIVE PHOSPHORYLATION 5.8 0.005 NA 0.013 0.007 0.002 0.001 REACTOME METABOLISM OF PROTEINS 8.2 0.122 0.028 0.003 REACTOME TRANSLATION 9.2 0.1 0.024 SRP DEPENDENT COTRANSLATIONAL PROTEIN TARGETING TO MEMBRANE 9.7 0.079 0.022 0.004 0.006 MITOCHONDRIAL PROTEIN IMPORT 14 0.073 0.008 REACTOME METABOLISM OF MRNA 16 0.3 0.019 REACTOME METABOLISM OF RNA 19.3 0.32 REACTOME CYCLIN E ASSOCIATED EVENTS DURING G1 S TRANSITION 22.7 0.057 0.033 0.01 REACTOME SCFSKP2 MEDIATED DEGRADATION OF P27 P21 23.2 0.071 0.025 0.009 KEGG RIBOSOME 23.3 0.023 0.011 FDR
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ASSIGN score GSEA - down
Gene Set Avg. Rank Curtis dis DLBCL 2010 TCGA BRCA TCGA HNSC TCGA LUAD TCGA LUSC REACTOME NRAGE SIGNALS DEATH THROUGH JNK 30.5 0.03 0.091 0.174 0.022 0.019 0.048 KEGG PHOSPHATIDYLINOSITOL SIGNALING SYSTEM 0.067 0.086 0.172 0.04 0.025 0.058 KEGG DORSO VENTRAL AXIS FORMATION 38.3 0.031 0.09 0.181 0.033 0.028 0.035 PID RHOA REG PATHWAY 41 0.029 0.088 0.243 0.024 0.026 PID FAK PATHWAY 0.045 0.163 0.046 0.059 ST INTEGRIN SIGNALING PATHWAY 41.2 0.097 0.168 0.023 0.05 0.038 BIOCARTA PAR1 PATHWAY 41.8 0.066 0.1 0.133 REACTOME SIGNALING BY RHO GTPASES 42.2 0.156 0.186 0.041 REACTOME BMAL1 CLOCK NPAS2 ACTIVATES CIRCADIAN EXPRESSION 45.2 0.096 0.118 0.027 0.056 PID KITPATHWAY 47.5 0.195 0.18 0.072 FDR
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GSEA with generalized list
OxPhos general up OxPhos general down
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Outline Evidence for OxPhos – NonOxPhos stratification in other tumor types Most genes of DLBCL OxPhos signature are also present in solid tumors, but we found additional concordant genes No evidence of association with genomic instability (mutations and/or SCNAs) Strong candidates of OxPhos/Non-OxPhos cell-lines
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There is a good concordance between all TCGA sets
Signatures’ overlap
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Good concordance between OxPhos signature and TCGA sets
Lymphoma- derived signature
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There are additional genes in the solid tumors
2010
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Outline Evidence for OxPhos – NonOxPhos stratification in other tumor types Most genes of DLBCL OxPhos signature are also present in solid tumors, but we found additional concordant genes No evidence of association with genomic instability (mutations and/or SCNAs) Strong candidates of OxPhos/Non-OxPhos cell-lines
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Looking for link to genomic instability - GISTIC
KS - test DEL 1 pVal 1 DEL 2 pVal 2 … … … ASSIGN score Significant CNVs (>0.99 confidence) DEL N pVal N CNV profile AMP 1 pVal 1 AMP 2 pVal 2 … … … AMP N pVal N TCGA samples
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The only significantly enriched deletion peak is enriched in the intermediate cases
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No evidence of link to genomic instability - GISTIC
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Looking for link to genomic instability - MutSigCV
KS - test Gene 1 pVal 1 Gene 2 pVal 2 Gene 3 pVal 3 ASSIGN score Significant Mutations (<0.25 FDR) … … … Mut profile Gene X pVal X Gene Y pVal Y Gene Z pVal Z TCGA samples
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There is only one enriched mutation across all TCGA datasets
TBL1XR1
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No evidence of link to genomic instability - MutSigCV
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Outline Evidence for OxPhos – NonOxPhos stratification in other tumor types Most genes of DLBCL OxPhos signature are also present in solid tumors, but we found additional concordant genes No evidence of association with genomic instability (mutations and/or SCNAs) Strong candidates of OxPhos/Non-OxPhos cell-lines
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Testing “OxPhosness” in cell-lines
CCLE - pVal Predictions Lung 5.53E-06 Lung adeno 0.0073 Lung small cell 0.0154 Lung squamous 0.0553 Breast 5.08E-05 HNCC 5.67E-05 Melanoma 0.001
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Lung Adenocarcinoma Cell-lines
CCLE_score CCLE_prob NCI-H1355 0.175 1 HCC-2279 0.193 NCI-H1651 0.209 NCI-H1573 0.216 NCI-H2023 0.232 SK-LU-1 0.236 MOR/CPR 0.262 NCI-H1703 0.269 NCI-H2087 0.271 Calu-3 HCC-44 LXF-289 NCI-H1373 NCI-H2009 NCI-H2085 NCI-H322 NCI-H3255 NCI-H854 RERF-LC-Ad1 RERF-LC-Ad2 Lung Adenocarcinoma Cell-lines
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Breast Cancer Cell-lines
CCLE_score CCLE_prob EVSA-T 0.985 1 SK-BR-3 0.885 YMB-1 0.879 AU565 0.878 ZR-75-1 0.837 HCC2218 0.83 EFM-192A 0.784 MDA-MB-453 0.777 MCF7 0.773 CAL-148 0.758 HDQ-P1 0.027 HCC1143 0.001 Hs 742.T HCC1806 Hs 606.T Hs-578-T 0.0005 Hs 274.T Hs 739.T Hs 281.T Hs 343.T Breast Cancer Cell-lines
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HNCC Cell-lines Cellline CCLE_score CCLE_prob FADU 0.937 1 SNU-1214
0.911 SNU-46 0.831 HSC-3 0.787 PE/CA-PJ34 (clone C12) 0.728 SNU-1041 0.715 BICR 18 0.708 YD-15 0.689 CAL-27 0.679 BICR 16 0.673 SNU-1066 0.165 BICR 22 BHY BICR 56 SCC-9 SNU-1076 HNCC Cell-lines
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Future Work Functional validation of the top and bottom cell-lines
Association with TCGA methylation data
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Conclusion Evidence for OxPhos – NonOxPhos stratification in other tumor types Most genes of DLBCL OxPhos signature are also present in solid tumors, but we found additional concordant genes No evidence of association with genomic instability (mutations and/or SCNAs) Strong candidates of OxPhos/Non-OxPhos cell-lines
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Acknowledgements Stefano Monti Ying Shen Liye Zhang Francesca Mulas Yuxiang Tan Evan Johnson Marc Lenburg Luis Carvalho Björn Chapuy Nika Danial Margaret Shipp
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