PT - JOURNAL ARTICLE AU - Halit Ongen AU - Olivier Delaneau AU - Michael W. Stevens AU - Cedric Howald AU - Emmanouil T. Dermitzakis TI - Hundreds of Putative Non-Coding Cis-Regulatory Drivers in Chronic Lymphocytic Leukaemia and Skin Cancer AID - 10.1101/174219 DP - 2017 Jan 01 TA - bioRxiv PG - 174219 4099 - http://biorxiv.org/content/early/2017/08/09/174219.short 4100 - http://biorxiv.org/content/early/2017/08/09/174219.full AB - Perturbations of the coding genome and their role in cancer development have been studied extensively. However the non‐coding genome’s contribution is poorly understood (Khurana et al., 2016), due to not only the difficulty of defining the non‐coding regulatory regions and the genes they regulate, but also the limited power arising from the regulatory regions’ small size. In this study, we try to resolve this issue by defining modules of coordinated non‐coding regulatory regions of genes (cis regulatory domains or CRDs) using the correlation between histone modifications, assayed by ChIP‐seq, in immortalized B‐cells (317 samples) and skin fibroblasts (78 samples). We search for CRDs that accumulate an excess of somatic mutations in chronic lymphocytic leukaemia (CLL) and skin cancer, which affect these cell types. At 5% FDR, we find 149 CRDs with significant excess somatic of mutations in CLL, 92 of which regulate 163 genes, and in skin cancer, 465 significant CRDs 142 of which regulate 187 genes. The genes these CRDs regulate include ones involved in tumorigenesis, and are enriched in pathways already implicated in the respective cancers, like the B‐cell receptor signalling pathway in CLL and the Ras/Ref/MAPK signalling pathway in skin cancer. We discover that the somatic mutations in the significant CRDs of CLL are hitting bases more likely to be functional than the mutations in non‐significant CRDs, and in both cancers there is a significant deviation from the standard mutational signatures observed in the significant CRDs vs. their null sequences. Both results indicate selection acting on these CRDs during tumorigenesis. Finally, we find that the transcription factor biding sites that are disturbed by the somatic mutations in significant CRDs are enriched for factors known to be involved in cancer development. In conclusion, we are describing a new powerful approach to discover non‐coding regulatory somatic mutations likely driving tumorigenesis in CLL and skin cancer, and our approach could be applied to other cancers to find this class of underexplored drivers.