Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.
Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.
复制标题
DOI：
10.1038/ncomms6224
复制
发表时间：
2014-10-29
影响因子：
16.6
通讯作者：
Barbour AP
中科院分区：
文献类型：
--
作者：
Nones K;Waddell N;Wayte N;Patch AM;Bailey P;Newell F;Holmes O;Fink JL;Quinn MCJ;Tang YH;Lampe G;Quek K;Loffler KA;Manning S;Idrisoglu S;Miller D;Xu Q;Waddell N;Wilson PJ;Bruxner TJC;Christ AN;Harliwong I;Nourse C;Nourbakhsh E;Anderson M;Kazakoff S;Leonard C;Wood S;Simpson PT;Reid LE;Krause L;Hussey DJ;Watson DI;Lord RV;Nancarrow D;Phillips WA;Gotley D;Smithers BM;Whiteman DC;Hayward NK;Campbell PJ;Pearson JV;Grimmond SM;Barbour AP
食管腺癌（EAC）的发病率在西方国家迅速增加。更好地了解EAC有助于改善早期发现和治疗结果。虽然迄今为止大规模的EAC外显子组测序工作已经发现了复发性功能丧失突变，但致癌驱动事件的代表性不足。在这里，我们使用全基因组测序（WGS）和单核苷酸多态性阵列分析相结合，以显示基因组灾难是频繁的EAC，几乎三分之一（32%，n = 40/123）经历chromothriptic事件。22例EAC病例的WGS结果显示，突变可能通过染色体畸变引起的双微染色体形成（MYC和MDM 2）或断裂融合桥（KRAS、MDM 2和RFC 3）导致癌基因扩增。端粒缩短是更突出的EAC轴承本地化复杂的重排。突变特征分析也证实EAC中的极端基因组不稳定性可由体细胞BRCA 2突变驱动。这些发现表明，基因组灾难在EAC的恶性转化中具有重要作用。
Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n = 40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.