Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Nucleic Acids Res. 2024 Sep 9;52(16):e77. doi: 10.1093/nar/gkae646.
Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm 'HYENA' to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.
体细胞结构变异（SVs）可在基因组中重排 DNA 含量、改变调控元件并改变基因组结构。当 SV 将远端增强子转移到原癌基因时，就会发生增强子劫持。然而，大多数增强子劫持研究仅集中在蛋白编码基因上。在这里，我们开发了一种名为“HYENA”的计算算法，该算法可根据肿瘤全基因组和转录组测序数据，识别由增强子劫持激活的候选癌基因（包括蛋白编码和非编码基因）。HYENA 通过基于排名的回归模型检测与体细胞 SV 相关的基因表达上调的基因。我们系统地分析了 25 种成人肿瘤中的 1146 个肿瘤，总共鉴定出 108 个候选癌基因，包括许多非编码基因。在 10%的胰腺癌中，通过改变三维基因组结构，各种类型的 SV 激活了长非编码 RNA TOB1-AS1。我们发现，TOB1-AS1 的高表达可以促进细胞侵袭和转移。我们的研究强调了非编码区域的遗传改变对肿瘤发生和肿瘤进展的贡献。
