Nones Katia, Waddell Nicola, Wayte Nicci, Patch Ann-Marie, Bailey Peter, Newell Felicity, Holmes Oliver, Fink J Lynn, Quinn Michael C J, Tang Yue Hang, Lampe Guy, Quek Kelly, Loffler Kelly A, Manning Suzanne, Idrisoglu Senel, Miller David, Xu Qinying, Waddell Nick, Wilson Peter J, Bruxner Timothy J C, Christ Angelika N, Harliwong Ivon, Nourse Craig, Nourbakhsh Ehsan, Anderson Matthew, Kazakoff Stephen, Leonard Conrad, Wood Scott, Simpson Peter T, Reid Lynne E, Krause Lutz, Hussey Damian J, Watson David I, Lord Reginald V, Nancarrow Derek, Phillips Wayne A, Gotley David, Smithers B Mark, Whiteman David C, Hayward Nicholas K, Campbell Peter J, Pearson John V, Grimmond Sean M, Barbour Andrew P
Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
Nat Commun. 2014 Oct 29;5:5224. doi: 10.1038/ncomms6224.
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.
在西方国家，食管腺癌（EAC）的发病率正在迅速上升。更好地了解EAC是改善早期检测和治疗结果的努力的基础。虽然迄今为止大规模的EAC外显子测序研究发现了反复出现的功能丧失突变，但致癌驱动事件的研究较少。在这里，我们结合全基因组测序（WGS）和单核苷酸多态性阵列分析，表明基因组灾难在EAC中很常见，近三分之一（32%，n = 40/123）经历了染色体碎裂事件。对22例EAC病例的WGS显示，灾难可能通过染色体碎裂衍生的双微体染色体形成（MYC和MDM2）或断裂-融合-桥接（KRAS、MDM2和RFC3）导致癌基因扩增。在具有局部复杂重排的EAC中，端粒缩短更为明显。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BRCA2突变驱动。这些发现表明，基因组灾难在EAC的恶性转化中起重要作用。
