Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Commun Biol. 2022 Apr 8;5(1):335. doi: 10.1038/s42003-022-03238-7.
Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.
食管腺癌 (OAC) 为大规模重排提供了一个理想的案例研究。我们对 383 例病例进行了全基因组短读测序，其中 214 例有匹配的全转录组，观察到结构变异 (SV)，以缺失、串联重复和染色体间连接为主，这些可以被鉴定为 LINE-1 移动元件 (ME) 插入。类似于断裂-融合-桥循环或染色体外环状 DNA 的复杂重排簇占影响已知致癌基因的复杂 SV 的 22%。计算影响已知驱动基因的 SV 事件，大大增加了这些驱动基因的复发率。在排除脆性位点后，我们在 SV 破坏的基因组区域中鉴定出 51 个候选新的驱动基因，包括 ETV5、KAT6B 和 CLTC。RUNX1 是最常被改变的基因（24%），许多缺失使 runt 结构域失活，但保留了阅读框，提示改变了蛋白质产物。这些发现强调了在 OAC 中识别 SV 事件的重要性，这对靶向治疗具有重要意义。
