Dissecting the sources of gene expression variation in a pan-cancer analysis identifies novel regulatory mutations
Open Access
- 17 April 2018
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 46 (9), 4370-4381
- https://doi.org/10.1093/nar/gky271
Abstract
Although the catalog of cancer-associated mutations in protein-coding regions is nearly complete for all major cancer types, an assessment of regulatory changes in cancer genomes and their clinical significance remain largely preliminary. Adopting bottom-up approach, we quantify the effects of different sources of gene expression variation in a cohort of 3899 samples from 10 cancer types. We find that copy number alterations, epigenetic changes, transcription factors and microRNAs collectively explain, on average, only 31–38% and 18–26% expression variation for cancer-associated and other genes, respectively, and that among these factors copy number alteration has the highest effect. We show that the genes with systematic, large expression variation that could not be attributed to these factors are enriched for pathways related to cancer hallmarks. Integrating whole genome sequencing data and focusing on genes with systematic expression variation we identify novel, recurrent regulatory mutations affecting known cancer genes such as NKX2-1 and GRIN2D in multiple cancer types. Nonetheless, at a genome-wide scale proportions of gene expression variation attributed to recurrent point mutations appear to be modest so far, especially when compared to that attributed to copy number changes – a pattern different from that observed for other complex diseases and traits. We suspect that, owing to plasticity and redundancy in biological pathways, regulatory alterations show complex combinatorial patterns, modulating gene expression in cancer genomes at a finer scale.Keywords
This publication has 46 references indexed in Scilit:
- The Cancer Genome Atlas Pan-Cancer analysis projectNature Genetics, 2013
- Annotation of functional variation in personal genomes using RegulomeDBGenome Research, 2012
- PARADIGM-SHIFT predicts the function of mutations in multiple cancers using pathway impact analysisBioinformatics, 2012
- The mutational landscape of lethal castration-resistant prostate cancerNature, 2012
- An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in GlioblastomaCell, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- The genomic complexity of primary human prostate cancerNature, 2011
- International network of cancer genome projectsNature, 2010
- Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast CancerJAMA, 2006
- The Human Genome Browser at UCSCGenome Research, 2002