Background Glioblastoma (GBM) has one of the worst 5-year survival rates of all cancers. While genomic studies of the disease have been performed, alterations in the non-coding regulatory regions of GBM have largely remained unexplored. We apply whole-genome sequencing (WGS) to identify non-coding mutations, with regulatory potential in GBM, under the hypothesis that regions of evolutionary constraint are likely to be functional, and somatic mutations are likely more damaging than in unconstrained regions. Results We validate our GBM cohort, finding similar copy number aberrations and mutated genes based on coding mutations as previous studies. Performing analysis on non-coding constraint mutations and their position relative to nearby genes, we find a significant enrichment of non-coding constraint mutations in the neighborhood of 78 genes that have previously been implicated in GBM. Among them, SEMA3C and DYNC1I1 show the highest frequencies of alterations, with multiple mutations overlapping transcription factor binding sites. We find that a non-coding constraint mutation in the SEMA3C promoter reduces the DNA binding capacity of the region. We also identify 1776 other genes enriched for non-coding constraint mutations with likely regulatory potential, providing additional candidate GBM genes. The mutations in the top four genes, DLX5 , DLX6 , FOXA1 , and ISL1 , are distributed over promoters, UTRs, and multiple transcription factor binding sites. Conclusions These results suggest that non-coding constraint mutations could play an essential role in GBM, underscoring the need to connect non-coding genomic variation to biological function and disease pathology.

中文翻译：

---

胶质母细胞瘤的全基因组测序揭示了已知和新基因中非编码约束突变的富集


背景 胶质母细胞瘤 (GBM) 是所有癌症中 5 ​​年生存率最差的一种。虽然已经对该疾病进行了基因组研究，但 GBM 非编码调控区的改变在很大程度上仍未被探索。我们应用全基因组测序（WGS）来识别非编码突变，在 GBM 中具有调节潜力，假设进化限制区域可能具有功能，并且体细胞突变可能比不受限制区域更具破坏性。结果我们验证了 GBM 队列，发现与之前的研究相似的基于编码突变的拷贝数畸变和突变基因。对非编码约束突变及其相对于附近基因的位置进行分析，我们发现先前与 GBM 相关的 78 个基因附近的非编码约束突变显着富集。其中，SEMA3C 和 DYNC1I1 显示出最高频率的改变，多个突变与转录因子结合位点重叠。我们发现 SEMA3C 启动子中的非编码约束突变降低了该区域的 DNA 结合能力。我们还鉴定了 1776 个富含非编码约束突变的其他基因，这些突变可能具有调节潜力，从而提供了额外的候选 GBM 基因。前四个基因 DLX5 、DLX6 、FOXA1 和 ISL1 中的突变分布在启动子、UTR 和多个转录因子结合位点上。结论 这些结果表明非编码约束突变可能在 GBM 中发挥重要作用，强调将非编码基因组变异与生物功能和疾病病理学联系起来的必要性。