Abstract
Transcriptional dysregulation is a key feature of cancer. Transcription factors (TFs) are the main link between signalling pathways and the transcriptional regulatory machinery of the cell, positioning them as key oncogenic inductors and therefore potential targets of therapeutic intervention. We implemented a computational pipeline to infer TF regulatory activities from basal gene expression and applied it to publicly available and newly generated RNA-seq data from a collection of 1,010 cancer cell lines and 9,250 primary tumors. We show that the predicted TF activities recapitulate known mechanisms of transcriptional dysregulation in cancer and dissect mutant-specific effects in driver genes. Importantly, we show the potential for predicted TF activities to be used as markers of sensitivity to the inhibition of their upstream regulators. Furthermore, combining these inferred activities with existing pharmacogenomic markers significantly improves the stratification of sensitive and resistant cell lines for several compounds. Our approach provides a framework to link driver genomic alterations with transcriptional dysregulation that helps to predict drug sensitivity in cancer and to dissect its mechanistic determinants.
List of abbreviations
- ACC
- Adrenocortical carcinoma
- ALL
- Acute myeloid leukemia
- BLCA
- Bladder carcinoma
- BRCA
- Breast carcinoma
- CCLE
- Cancer Cell Lines Encyclopedia
- CESC
- Cervical squamous carcinoma
- ChIP
- Chromatin immunoprecipitation
- ChIP-X
- Chromatin immunoprecipitation coupled with high-throughput technique
- CNA
- Copy number alteration
- COREAD
- (COAD/READ) Colon adenocarcinoma/Rectal adenocarcinoma
- CTFR
- Consensus transcription factor regulon
- DLBC
- Difuse B cell lymphoma
- EMT
- Epithelial-mesenchymal transition
- FDR
- False discovery rate
- FET
- Fisher’s exact test
- GBM
- Glioblastoma multiforme
- GDSC
- Genomics of Drug Sensitivity in Cancer
- HNSC
- Head and neck squamous cell carcinoma
- KICH
- Kidney chromophome
- KIRC
- Kidney renal clear cell carcinoma
- KIRP
- Kidney renal papillary carcinoma
- LAML
- Acute myeloid leukemia
- LGG
- Lower grade glioma
- LIHC
- Liver hepatocarcinoma
- LUAD
- Lung adenocarcinoma
- LUSC
- Lung squamous cell carcinoma
- MB
- Medulloblastoma
- MM
- Myeloma
- NSCLC
- Non-Small cell lung carcinoma
- OV
- Serous ovarian adenocarcinoma
- PRAD
- Prostate adenocarcinoma
- SKCM
- Skin carcinoma
- STAD
- Stomach adenocarcinoma
- TCGA
- The Cancer Genome Atlas
- TF
- Transcription factor
- TFBS
- Transcription factor binding site
- THCA
- Thyroid carcinoma
- UCEC
- Uterine corpus endometrioid carcinoma
- WES
- Whole exome sequencing