Cis-regulatory mutations with driver hallmarks in major cancers

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.