Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Nat Genet. 2013 May;45(5):478-86. doi: 10.1038/ng.2591. Epub 2013 Mar 24.
The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ~15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.
食管腺癌（EAC）的发病率在过去 30 年中上升了 600%。由于 5 年生存率约为 15%，因此对于 EAC 而言，确定新的治疗靶点非常重要。我们分析了 149 对 EAC 肿瘤-正常配对的全外显子测序的突变谱，其中 15 对也进行了全基因组测序。我们确定了一个由 AA 二核苷酸中高比例的 A>C 颠换定义的突变特征。外显子组数据的统计分析确定了 26 个明显突变的基因。其中，五个（TP53、CDKN2A、SMAD4、ARID1A 和 PIK3CA）先前已被证实与 EAC 有关。新的明显突变基因包括染色质修饰因子和候选贡献者 SPG20、TLR4、ELMO1 和 DOCK2。对 ELMO1 中源自 EAC 的突变的功能分析表明，细胞侵袭性增加。因此，我们认为 RAC1 通路的潜在激活可能是 EAC 肿瘤发生的一个因素。
