Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, PR China.
Department of Oncology, Shanghai Medical College, Fudan University, Dongan Road, Shanghai, PR China.
J Pathol. 2020 Nov;252(3):263-273. doi: 10.1002/path.5516. Epub 2020 Oct 2.
Rates of gastroesophageal junction adenocarcinomas (GEJAs) have shown an alarming increase; however, the genetic background of GEJA and its Siewert classification have yet to be uncovered. Here, 60 paired tumor and normal DNA samples from GEJA patients were analyzed by whole-exome sequencing. Among them, 13 were Siewert type I, 14 were type II, and 33 were type III. A predominance of C/G>T/A substitutions was discovered in GEJA, followed by C/G>A/T substitutions. Notably, Siewert type I and type II/III display distinct sets of driver genes, mutational spectrum, and recurrently disrupted pathways. Siewert type I showed similarity to esophageal adenocarcinomas (EACs) and the chromosomal instability subtype of stomach adenocarcinomas, while Siewert type II/III showed similarity to the genomic stable subtype of stomach adenocarcinoma. We also found that mutation of FBXW7, a driver gene of GEJA, was enriched in Siewert type I. Our data identify differences between GEJA and stomach/EACs at the genomic level and provide evidence for differential treatment based on Siewert classification of GEJA. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
胃食管结合部腺癌（GEJA）的发病率呈惊人增长趋势，但 GEJA 的遗传背景及其 Siewert 分类尚未被揭示。本研究中，我们对 60 对 GEJA 患者的肿瘤和正常 DNA 样本进行了全外显子组测序分析。其中，13 例为 Siewert Ⅰ型，14 例为 Siewert Ⅱ型，33 例为 Siewert Ⅲ型。研究发现，GEJA 中存在 C/G>T/A 取代为主，其次是 C/G>A/T 取代。值得注意的是，Siewert Ⅰ型和Ⅱ/Ⅲ型显示出不同的驱动基因、突变谱和反复被破坏的通路。Siewert Ⅰ型与食管腺癌（EAC）和胃腺癌的染色体不稳定亚型相似，而 Siewert Ⅱ/Ⅲ型与胃腺癌的基因组稳定亚型相似。我们还发现，GEJA 的驱动基因 FBXW7 的突变在 Siewert Ⅰ型中富集。我们的数据在基因组水平上识别出了 GEJA 与胃/EAC 的差异，并为基于 GEJA 的 Siewert 分类的差异化治疗提供了证据。
