Exome Sequencing of Esophageal Adenocarcinoma

The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. When coupled to the five-year survival rate of only 15% for this disease, identification of new therapeutic targets for EAC is of great importance. Here, we analyze the mutational spectra identified from the whole genome sequencing of 16 EACs and complete exome sequencing of 149 EAC tumors and matched germline samples. We identify a novel mutation signature marked by high prevalence of A to C transversions at AA*(N) trinucleotides. Notably, the development of EAC is preceded by pathologic intestinal metaplasia of the lower esophagus, Barrett's esophagus, itself a response to injury from gastric-esophageal reflux disease (GERD). Thus, we hypothesize to represent these AA*(N) mutations to a novel signature of GERD-induced mutagenesis. Analysis of the exome data identified 26 genes subject to statistically significant recurrent mutation. Of these 26 genes, only TP53, CDKN2A, SMAD4, and PIK3CA had been previously implicated in EAC. Novel mutations include those targeting chromatin modifying factors and novel candidate contributors to EAC: SPG20, TLR4, ELMO1 and DOCK2. Of these, ELMO1 and DOCK2 are notably direct dimerization partners that act to activate Rac1 to enhance cellular invasiveness, thus generating new hypotheses about the potential for the Rac1 pathway to be a novel target for therapy of EAC. "Reprinted from 'Unraveling the mutational complexity of esophageal adenocarcinoma', with permission from Nature Genetics."]]>

食管腺癌（esophageal adenocarcinoma, EAC）的发病率在过去30年间已攀升600%。结合该疾病仅15%的五年生存率，识别食管腺癌全新治疗靶点具有极为重要的临床意义。

本研究对16例食管腺癌的全基因组测序（whole genome sequencing）结果，以及149例食管腺癌肿瘤及其配对生殖系样本（matched germline samples）的全外显子组测序（complete exome sequencing）数据开展分析。我们鉴定出一种全新的突变特征（mutation signature）：在AA*(N)三核苷酸位点上，A到C的颠换（A to C transversions）发生率显著升高。

值得注意的是，食管腺癌的发生常先伴随食管下段的病理性肠上皮化生——巴雷特食管（Barrett's esophagus），而巴雷特食管本身是胃食管反流病（gastroesophageal reflux disease, GERD）造成损伤后的病理性应答反应。据此，我们推测上述AA*(N)位点突变可作为胃食管反流病诱导诱变的全新特征。

对外显子组测序数据的分析共鉴定出26个存在统计学显著性复发性突变的基因。在这26个基因中，仅TP53、CDKN2A、SMAD4及PIK3CA此前已被证实与食管腺癌相关。本次新发现的突变靶点涵盖染色质修饰因子（chromatin modifying factors）以及其他潜在食管腺癌致病候选基因：SPG20、TLR4、ELMO1与DOCK2。其中，ELMO1与DOCK2是直接的二聚化伴侣蛋白，可通过激活Rac1通路增强细胞侵袭能力，这为“Rac1通路有望成为食管腺癌全新治疗靶点”提供了全新的研究假说。

本文改编自《Unraveling the mutational complexity of esophageal adenocarcinoma》，已获《Nature Genetics》授权转载。