LAUSR

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent childhood hematological malignancy and the leading cause of childhood cancer-related mortality. To date, the molecular pathogenesis of B-ALL has not been completely defined, limiting our ability to develop targeted therapies. Despite great advances in identifying mutations in cancer patients, the functional consequences of noncoding mutations are still difficult to interpret. Transcriptional enhancers are key determinants of tissue-specific gene expression. Several recent studies have reported novel mutations in cancer genome that disrupt enhance function and thus expression of their target genes. However, systematic detection of noncoding mutations that perturb either enhancer sequence or enhancer-promoter (EP) interaction is still challenging. Such analysis can help to identify novel driver mutations and improve our understanding of the disease. Here we introduce a novel algorithm for identifying causal mutations that disrupt enhancer function and target gene expression in B-ALL. The algorithm takes as input whole genome sequencing (WGS) and RNA-Seq data to predict causal noncoding mutations. We apply the algorithm to analyze data from 163 B-ALL patients and identify 332 noncoding mutations that disrupt EP interactions and gene expression. Our analysis recapitulate previously known translocations such as t(14;X) that leads to CRLF2 overexpression, as well as novel causal translocations that leads to deregulation of TMEM106A and MIR663B. Systematic analysis of the identified mutations indicated that SNVs in enhancer region have a higher variant allele frequency (VAF), suggesting enhancer mutations likely occur earlier than coding mutations during oncogenesis. In addition, pathway analysis show that the majority (57%) of mutations perturbing metabolic pathways are noncoding mutations. Further analysis and experimental follow-up of the predicted noncoding mutations may reveal novel insights into the pathogenesis of B-cell ALL. Citation Format: Bing He, Peng Gao, Yang Ding, Chia-Hui Chen, Hannah Kim, Stephen P. Hunger, Sarah K. Tasian, Kai Tan. Systematic analysis of causal noncoding mutations in pediatric B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2280.