RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas.
RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas.
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DOI：
10.1158/0008-5472.can-16-0979
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发表时间：
2016-10-01
期刊：
影响因子：
11.2
通讯作者：
Guda K
中科院分区：
文献类型：
--
作者：
Blum AE;Venkitachalam S;Guo Y;Kieber-Emmons AM;Ravi L;Chandar AK;Iyer PG;Canto MI;Wang JS;Shaheen NJ;Barnholtz-Sloan JS;Markowitz SD;Willis JE;Shyr Y;Chak A;Varadan V;Guda K
Esophageal adenocarcinoma (EAC) is a deadly cancer with increasing incidence in the U.S., but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene-fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pre-treatment EAC and 49 non-malignant biopsy tissues from patients undergoing endoscopy for Barrett’s esophagus. In this cohort, we identified 21 novel candidate EAC-associated fusions occurring in 3.33%-11.67% of EACs. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pre-treatment EAC (N=115) and non-malignant (N=183) biopsy tissues. In particular, we observed RPS6KB1–VMP1 gene fusion as a recurrent event occurring in ~10% of EAC cases. Notably, EAC cases harboring RPS6KB1–VMP1 fusions exhibited significantly poorer overall survival as compared to fusion-negative cases. Mechanistic investigations established that the RPS6KB1–VMP1 transcript coded for a fusion protein which significantly enhanced the growth rate of non-dysplastic Barrett’s esophagus cells. Compared to the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1–VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1–VMP1 as a genetic fusion that promotes EAC by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas.
