Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation

Cell. Volume 173 Issue 2: p338-354.e15, 5 April 2018 10.1016/j.cell.2018.03.034

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression machine learning algorithm (OCLR) to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune system cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.

Data in the GDC

• GDC Manifests
  • Open-Access Data - Download Manifest (16 Files)

Supplemental Data

• MAF Files
  • Mutation - mc3.v0.2.8.PUBLIC.maf.gz
• Associated Data Files
  • RNA expression - EBPlusPlusAdjustPANCAN_IlluminaHiSeq_RNASeqV2.geneExp.tsv
  • DNA methylation - jhu-usc.edu_PANCAN_HumanMethylation450.betaValue_whitelisted.tsv
  • Clinical Data - clinical_PANCAN_patient_with_followup.tsv
  • Survival data - TCGA-CDR-SupplementalTableS1.xlsx
  • Samples to be used - merged_sample_quality_annotations.tsv
  • miRNA - pancanMiRs_EBadjOnProtocolPlatformWithoutRepsWithUnCorrectMiRs_08_04_16.csv
  • RPPA - TCGA-RPPA-pancan-clean.txt
  • CIBERSORT - TCGA.Kallisto.cibersort.relative.tsv
  • Pathologic - Merged_EPC_reviews.tsv
  • Purity/Ploidy - Purity_Ploidy_All_Samples_9_28_16.tsv
• Supplementary Data Files
  • DNA Methylation - DNAmethylation and RNAexpression Stemness Signatures.xlsx
  • Patient Enrichment Analysis Results (mRNAsi) - PSEA_mRNAsi.xlsx
  • Patient Enrichment Analysis Results (mDNAsi) - PSEA_mDNAsi.xlsx
  • Patient Enrichment Analysis Results (mRNAsi) - PSEA_EREG-mRNAsi.xlsx
  • Patient Enrichment Analysis Results (T-Test Results) - T.test results for continuous variables.xlsx
• Stemness Index Workflow and PanCanStemness Web Portal are available here

Additional Resources

• Broad Institute FireCloud (link is external) The Broad Institute
• cBioPortal for Cancer Genomics (link is external) Memorial Sloan-Kettering Cancer Center
• PanCanAtlas Additional Files