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Biotweeps Conference 2017

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Biotweeps conference:
RNA sequencing-based cell proliferation analysis across 19 cancers identifies a subset of proliferation-informative cancers with a common survival signature

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Biotweeps Conference 2017

  1. 1. BTCon17 Presenta/on: RNA sequencing-based cell prolifera/on analysis across 19 cancers iden/fies a subset of prolifera/on-informa/ve cancers with a common survival signature BriFany N. Lasseigne, PhD @bnlasse 29 June 2017
  2. 2. 1 #BTCon17 @HudsonAlpha examined RNAseq cell prolif index (PI, value aggregated from prolif-assoc genes) in 19 #TCGA cancers @OncotargetJrnl
  3. 3. KIRP LGG KIRC LIHC PAAD ACC MESO LUAD BRCA GBM SARC STAD HNSC LAML ESCA OV BLCA LUSC CESC Proliferative Index (Counts/Million) 0 20 40 60 80 100 0 20 40 60 80 Breast Lung Pancreas Esophagus Stomach Liver Kidney (KIRC) Bladder Cervix Kidney (KIRP) Tumor Adjacent Normal Healthy (GTEx) A B Proliferative Index (Counts/Million) Basal-like Her-2 Enriched Luminal A Luminal B Normal-like rho=-0.65 Basal−like Luminal A Normal−like 10 20 30 40 50 60 ProliferativeIndex Her2-Enriched Luminal B 0.8 ber C D E F −100 −50 0 50 −100050100−50 PC1 (9.25%) PC2(6.72%) 5 4 3 2 1 (A) Tumor proliferative index (PI) distributions across The Cancer Genome Atlas (TCGA) cancers. (B) PI values in healthy G e n o t y p e - T i s s u e E x p r e s s i o n ( G T E x ) samples (blue), TCGA tumor-adjacent normal tissue (red) and TCGA tumor tissue (green). (C) Heatmap of principal c o m p o n e n t - t u m o r P I c o r r e l a t i o n s a c r o s s cancers. Counts/Million) 60 80 100 0 20 40 60 80 Proliferative Index (Counts/Million) Basal-like Her-2 Enriched Luminal A Luminal B Normal-like rho=-0.65 al A Normal−likeLuminal B AC C 0.00.20.40.60.8 PrincipalComponentNumber SpearmanCorrelation(rho) BLCABRCACESCESCAG BMHNSCKIRCKIRPLAM LLG G LIHCLUADLUSCM ESOO V PAADSARCSTAD D F −100 −50 0 50 −100050100−50 PC1 (9.25%) PC2(6.72%) 0 50 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1C
  4. 4. 2 #BTCon17 PI signif assoc w/ pa/ent survival, tumor stage, nodal invasion in 7/19 cancers, which we defined “prolif-inform. cancers”(PICs)
  5. 5. ESCA STAD OV LUSC GBM LAML LIHC SARC BLCA CESC HNSC BRCA ACC MESO KIRP LUAD PAAD LGG KIRC OV STAD LAML GBM HNSC ESCA LUSC BLCA SARC BRCA CESC LIHC LUAD PAAD MESO KIRP LGG ACC KIRC Cox PH p−value (−log10) 0 5 10 15 20 10 20 30 40 50 0 5 10 15 20 Median PI (Counts/Million) −log10Coxp−value M Stage (% M1) 0 1284 0 604020 N Stage (% N1) T Stage (% > T2) Mean Age (Years) Race (% White) Gender (% Male) -Log10 PI Cox p-value Scaled -log10 Cox p-value TopCrossCancerSurvivalGenes 0 604020 80 0 4020 80 0 60 8020 40 0 60 8020 40 0 15 205 10 -1 2 30 1 No Data Available A B C * BonferonniAdjustedp=0.05 Rho = -0.751 KIRC ACC LGG KIRP PAAD MESO LIHC LUAD BRCA SARC GBM BLCA LUSC CESC HNSC ESCA LAML STAD (A) Tumor proliferative index (PI) Cox regression negative log p-values plotted by cancer with the first seven cancers showing significant association with patient outcome. (B) Tumor PI survival associations (Cox regression negative log p-values) are anti-correlated with the median tumor PI of each cancer. (C) Heatmap of negative log Cox regression p-values of genes significant (p < 0.05, n = 84) in at least 9 of 19 cancers identifies proliferative- informative cancers (PICs) (right). PICsNon-PICs
  6. 6. 3 #BTCon17 Non-PICs had rela/vely unique, non-prolif survival-assoc genes favoring cell metabolism, angiogenesis, immune-related terms, etc
  7. 7. small molecule metabolic process cellular response to camptothecin cellular localization free ubiquitin chain polymerization coenzyme metabolic process cofactor metabolic process metabolic process primary metabolic process antigen processing and presentation of peptide or polysaccharide antigen via MHC class II cell cycle process cell proliferation cellular component organization or biogenesis cellular process cellular response to DNA damage stimulus chromosome localization chromosome organization chromosome segregation DNA replication microtubule−based process nitrogen compound metabolism organic substance metabolism regulation of cell division reproductive process single organism reproductive process single−organism process ACC DNA cytosine deamination lipoprotein metabolism negative regulation of transposition BLCA BRCA anatomical structure formation involved in morphogenesis angiogenesis cell morphogenesis involved in differentiation ovulation positive regulation of monocyte chemotactic protein−1 production primary follicle stage substrate−dependent cerebral cortex tangential migration positive regulation of cell adhesion chromatin assembly extracellular matrix organization regulation of tight junction assembly immune response inflammatory response leukocyte migration lipopolysaccharide−mediated signaling pathway positive regulation of antigen receptor−mediated signaling pathway regulation of vascular endothelial growth factor receptor signaling pathway response to oxygen levels response to oxygen−containing compound response to stress taxis cellular protein metabolic process DNA cytosine deamination macromolecule modification peptidyl−proline hydroxylation protein hydroxylation oxidation−reduction process acetyl−CoA metabolism angiogenesis biological adhesion cell activation cell adhesion cellular component movement extracellular matrix organization immune response immune system process nitrogen cycle metabolism positive regulation of vitamin D biosynthesis protein hydroxylation single−organism metabolism single−organism process CESC dendritic spine maintenance inorganic cation import into cell protein initiator methionine removal regulation of lateral mesodermal cell fate specification response to ketone GBM histone H3−K79 methylation immune system process multi−organism metabolism regulation of leukocyte cell−cell adhesion HNSC amino−acid betaine metabolism antigen processing and presentation of peptide or polysaccharide antigen via MHC class II cell division cellular component organization or biogenesis cellular process cellular response to DNA damage stimulus microtubule−based process mitotic cell cycle process nuclear division protein localization to chromosome, centromeric region protein ubiquitination regulation of chromosome segregation single−organism process KIRC catabolic process peptidyl−proline hydroxylation anatomical structure development cell cycle process cell proliferation cellular component movement cellular component organization or biogenesis cellular process cellular response to DNA damage stimulus chromosome segregation collagen metabolism developmental process establishment of chromosome localization macromolecule metabolism microtubule−based process organelle fission protein hydroxylation regulation of cell division reproductive process single organism reproductive process single−organism process KIRP arachidonic acid metabolic process fatty−acyl−CoA catabolic process positive regulation of lipid metabolic process protein polyubiquitination sterol metabolic process antigen processing and presentation biological regulation cell cycle detection of chemical stimulus involved in sensory perception of taste fatty acid derivative metabolism immune system process mesoderm development negative regulation of leukocyte proliferation sterol metabolism LAML macromolecule metabolic process calcium ion transmembrane import into mitochondrion anterior/posterior pattern specification cell cycle process cellular component organization or biogenesis cellular process chromosome organization chromosome segregation developmental process dimethylallyl diphosphate biosynthesis microtubule−based process negative regulation of viral process single−organism cellular localization single−organism process LGG protein stabilization regulation of establishment of protein localization to chromosome connective tissue development extracellular matrix disassembly L−ornithine transmembrane transport protein stabilization pyruvate metabolism response to oxidative stress spermine metabolism LIHC cell cycle single−organism cellular processanaphase−promoting complex−dependent proteasomal ubiquitin−dependent protein catabolic process nicotinamide nucleotide metabolic process nucleotide phosphorylation spermine metabolic process antigen processing and presentation binding of sperm to zona pellucida cell division cell proliferation cellular component organization or biogenesis cellular process coenzyme A transmembrane transport heterotypic cell−cell adhesion intermediate filament−based process microtubule−based process mitotic cell cycle process nuclear division regulation of chromosome segregation response to inorganic substance single−organism carbohydrate catabolism single−organism process LUAD glycerolipid catabolic process epithelial fluid transport lipid transport anatomical structure development extracellular matrix organization immune system process negative regulation of endothelial cell apoptotic process platelet degranulationprotein activation cascade response to stimulus single−multicellular organism process LUSC alpha−amino acid metabolic process DNA metabolic process DNA replication ethanol oxidation negative regulation of biological process negative regulation of cellular process protein K6−linked ubiquitination purine nucleoside bisphosphate catabolic process pyrimidine deoxyribonucleoside metabolic process regulation of molecular function regulation of phosphorus metabolic process signal transduction in response to DNA damage regulation of smooth muscle cell migration cellular response to radiation actin filament−based process angiogenesis cell cycle process cell proliferation cellular component movement cellular component organization or biogenesis chromosome organization chromosome segregation DNA replication establishment of chromosome localization microtubule−based process regulation of chromosome segregation single−organism process wound healing MESO amino sugar metabolism binding of sperm to zona pellucida cell communication membrane biogenesis positive regulation of glucose transport response to insulin−like growth factor stimulus signaling single organism signaling telencephalon regionalization OV actin filament−based process antigen processing and presentation of exogenous peptide antigen biological regulation cell cycle process cell differentiation involved in embryonic placenta development cell proliferation cell−substrate adhesion cellular component movement cellular component organization or biogenesis chromosome segregation DNA replication microtubule−based process nuclear division organelle localization regulation of chromosome segregation response to organic cyclic compound viral process PAAD cell differentiation trigeminal ganglion development cellular aromatic compound metabolic process heterocycle metabolic process immune response response to cytokine metabolic process biological_process immune system process multi−organism process negative regulation of multi−organism process nitrogen compound metabolism nuclear inner membrane organization organic cyclic compound metabolism organic substance metabolism single−organism process SARC cellular response to light stimulus negative regulation of retinoic acid receptor signaling pathway positive regulation of translational initiation in response to starvation negative regulation of RNA export from nucleus sodium−independent organic anion transportdetection of chemical stimulus involved in sensory perception of smell multicellular organismal process response to stimulus sodium−independent organic anion transport STAD catabolic process cobalt ion transport mRNA metabolic process ncRNA metabolic process metabolic process primary metabolic process peptide biosynthetic process snRNA transcription from RNA polymerase II promoter antigen receptor−mediated signaling pathway cell cycle cellular component organization or biogenesis cellular metabolism cellular process epithelium migration immune system process interspecies interaction between organisms intracellular transport localization macromolecule catabolism macromolecule metabolism nitrogen compound metabolism organic substance metabolism snRNA transcription Proliferation Informative Non-proliferation Informative angiotensin maturation demethylation methylation ESCA Cell Proliferation/Divison Associated Process Gene ontology enrichment analysis on survival-associated genes in each cancer. Adrenocortical Carcinoma Kidney Renal Clear Cell Carcinoma Kidney Renal Papillary Cell Carcinoma Pancreatic Adenocarcinoma Brain Lower Grade Glioma Lung Adenocarcinoma Mesothelioma Bladder Urothelial Carcnioma Breast Invasive Carcinoma Cervical Squamous Cell & Endocervical Adenocarcinoma Ovarian Serous Cystadenocarcinoma Glioblastoma multiforme Head and Neck Squamous Cell Carcinoma Acute Myeloid Leukemia Sarcoma Liver Hepatocellular Carcinoma Lung Squamous Cell Carcinoma Stomach Adenocarcinoma Esophageal Carcinoma Proliferative -Informative Cancers Non- Proliferative Informative Cancers
  8. 8. 4 #BTCon17 with #MachineLearning we generated cross-cancer survival models (AUC=0.651)-PICs-only model had improved performance (AUC=0.856)
  9. 9. Full Patient Cohort (n=6,312) Shortest Survivors (n=342) Longest Survivors (n=342) Training Cohort (n=479) Testing Cohort (n=205) Dichotomize 18 shortest and 18 longest surviving patients for each cancer Randomly split into training (70%) and testing cohorts (30%) Feature selection in training cohort Model evaluation in Testing Cohort AUC Frequency 0.5 0.6 0.7 0.8 0.9 0 2 4 6 8 10 12 Observed PIC AUC 1 2 3 4 5 0.5 Number of PICs in Permutation AUC A DC 12 0.6 0.7 0.8 rho=0.569 False positive rateTruepositiverate 0.0 0.2 0.4 0.6 0.8 1.0 0.00.20.40.60.81.0 All Cancers (AUC:0.651) PICs (AUC:0.856) Non PICs (AUC: 0.634 All Cancers (AUC: 0.651) PICs (AUC: 0.856) Non PICs (AUC: 0.634) B (A) Workflow for cross- cancer survival model generation. (B) Receiver operating characteristic (ROC) curve for multivariate Cox regression with LASSO for variable selection on all 19 cancers (blue), PICs only (green) and non- PICs only (orange). (C) Histogram showing the distribution of ROC area under the curve (AUC) values for survival models generated on 100 randomly sampled s e t s o f c a n c e r s equivalent in number to the PICs. (D) The ROC curve AUC values are directly proportional to the n u m b e r o f P I C s included in random sample sets
  10. 10. 5 #BTCon17 strong corr b/w tumor PI & # soma/c muta/ons across/within #cancer & #breastcancer subtype; poten/al RELN role in breastcancer
  11. 11. 2 3 4 5 6 10 20 30 40 50 60 Log10 Somatic Mutation Number ProliferativeIndex Basal-like Her2-Enriched Luminal A Luminal B Normal-like Unknown 0 20 40 60 80 ProliferativeIndex RELN Mutant RELN Wild Type All Tumors Basal-Like HER2-Enriched Luminal A Luminal B 0 1000 3000 5000 0.00.40.8 PercentSurvival Days RELN Low Expresser or PAM RELN High Expresser A C D p=0.08 2000 4000 6000 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Expected P−value (−log10 scale) ObservedP−value(−log10scale) TP53 RB1 PIK3CA B (A) Tumor proliferative index (PI) is correlated with TCGA breast cancer somatic mutation burden. (B) Q-Q plot of p- values derived from gene mutation burden-PI associations. (C) TCGA breast tumors containing non-synonymous mutations in RELN have higher PI compared to wild-type. (D) Kaplan-Meier survival plot shows reduced expression or protein-altering mutations in RELN are markers of poor prognosis in patients with basal breast cancer.
  12. 12. 6 #BTCon17 Thx for checking out our @HudsonAlpha #genomics w/ #MachineLearning #opendata #publicdata; see #CRAN #Rpackage Prolifera/veIndex
  13. 13. Publication in Oncotarget, 2017: http://www.impactjournals.com/oncotarget/index.php? journal=oncotarget&page=article&op=view&path%5B%5D=16961 Institute website: http://hudsonalpha.org/ Lab website: http://hudsonalpha.org/faculty/richard-myers http://hudsonalpha.org/faculty/sara-cooper

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