Cis- regulatory mutations with driver hallmarks in major cancers

Zhongshan Cheng; Michael Vermeulen; Micheal Rollins-Green; Brian DeVeale; Tomas Babak

doi:10.1016/j.isci.2021.102144

Cis- regulatory mutations with driver hallmarks in major cancers

iScience. 2021 Feb 4;24(3):102144. doi: 10.1016/j.isci.2021.102144. eCollection 2021 Mar 19.

Authors

Zhongshan Cheng¹, Michael Vermeulen¹, Micheal Rollins-Green¹, Brian DeVeale², Tomas Babak¹

Affiliations

¹ Department of Biology, Queen's University, Kingston, ON K7L 3N6, Canada.
² The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.

Abstract

Despite the recent availability of complete genome sequences of tumors from thousands of patients, isolating disease-causing (driver) non-coding mutations from the plethora of somatic variants remains challenging, and only a handful of validated examples exist. By integrating whole-genome sequencing, genetic data, and allele-specific gene expression from TCGA, we identified 320 somatic non-coding mutations that affect gene expression in cis (FDR<0.25). These mutations cluster into 47 cis-regulatory elements that modulate expression of their subject genes through diverse molecular mechanisms. We further show that these mutations have hallmark features of non-coding drivers; namely, that they preferentially disrupt transcription factor binding motifs, are associated with a selective advantage, increased oncogene expression and decreased tumor suppressor expression.

Keywords: Cancer Systems Biology; Genetics; Genomics.