Computational and Systems Biology, Agency for Science Technology and Research, Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672, Singapore.
Graduate School of Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore, 117456, Singapore.
Nat Commun. 2018 Apr 18;9(1):1520. doi: 10.1038/s41467-018-03828-2.
Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes to identify recurrently mutated non-coding regions in GC. Applying comprehensive statistical approaches to accurately model background mutational processes, we observe significant enrichment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs). These CBS hotspots remain significant even after controlling for a genome-wide elevated mutation rate at CBSs. In 3 out of 4 tested CBS hotspots, mutations are nominally associated with expression change of neighboring genes. CBS hotspot mutations are enriched in tumors showing chromosomal instability, co-occur with neighboring chromosomal aberrations, and are common in gastric (25%) and colorectal (19%) tumors but rare in other cancer types. Mutational disruption of specific CBSs may thus represent a tissue-specific mechanism of tumorigenesis conserved across gastrointestinal cancers.
大多数癌症类型的非编码基因组区域的组织特异性驱动突变仍然未知。在这里，我们对 212 例胃癌（GC）全基因组进行了无偏分析，以鉴定 GC 中经常发生突变的非编码区域。应用全面的统计方法来准确地模拟背景突变过程，我们观察到在三个胃谱系特异性基因中存在非编码插入缺失（indels）的显著富集。我们进一步鉴定了 34 个突变热点，其中 11 个与 CTCF 结合位点（CBSs）重叠。即使在控制 CBS 上全基因组升高的突变率后，这些 CBS 热点仍然显著。在 4 个测试的 CBS 热点中，有 3 个突变与邻近基因的表达变化有名义上的关联。CBS 热点突变富集在表现出染色体不稳定性的肿瘤中，与邻近的染色体异常共同发生，在胃癌（25%）和结直肠癌（19%）中很常见，但在其他癌症类型中很少见。因此，特定 CBS 的突变破坏可能代表跨胃肠道癌症保守的组织特异性肿瘤发生机制。
