We developed cis-X, a computational method for discovering regulatory noncoding variants in cancer by integrating whole-genome and transcriptome sequencing data from a single cancer sample. cis-X first finds aberrantly cis-activated genes that exhibit allele-specific expression accompanied by an elevated outlier expression. It then searches for causal noncoding variants that may introduce aberrant transcription factor binding motifs or enhancer hijacking by structural variations. Analysis of 13 T-lineage acute lymphoblastic leukemias identified a recurrent intronic variant predicted to cis-activate the TAL1 oncogene, a finding validated in vivo by chromatin immunoprecipitation sequencing of a patient-derived xenograft. Candidate oncogenes include the prolactin receptor PRLR activated by a focal deletion that removes a CTCF-insulated neighborhood boundary. cis-X may be applied to pediatric and adult solid tumors that are aneuploid and heterogeneous. In contrast to existing approaches, which require large sample cohorts, cis-X enables the discovery of regulatory noncoding variants in individual cancer genomes.

我们开发了cis-X，这是一种通过整合单个癌症样本中的全基因组和转录组测序数据来发现癌症中调节性非编码变异的计算方法。cis-X首先发现异常的顺式激活基因，这些基因表现出等位基因特异性表达并伴有异常值的升高。然后，它搜索可能因结构变异而引入异常转录因子结合基序或增强子劫持的因果非编码变异。对13种T系急性淋巴细胞白血病的分析确定了预计会顺式激活TAL1的复发性内含子变异体癌基因，一项通过患者来源异种移植物的染色质免疫沉淀测序在体内验证的发现。候选致癌基因包括通过局部缺失激活的催乳素受体PRLR，该局部缺失去除了CTCF绝缘的邻域边界。cis-X可用于非整倍体和异质性的儿童和成人实体瘤。与需要大量样本的现有方法相反，cis-X可以在单个癌症基因组中发现调节性非编码变异。