Gene Expression Profiling Reveals Distinct Molecular Subtypes of Esophageal Squamous Cell Carcinoma in Asian Populations

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, particularly in Asian populations, and responds poorly to conventional therapy. Sub-classification of ESCCs by molecular analysis is a powerful strategy in extending conventional clinicopathologic classification, improving prognosis and therapy. Here we identified two ESCC molecular subtypes in Chinese population using gene expression profiling data, and further validated the molecular subtypes in two other independent Asian populations (Japanese and Vietnamese). Subtype I ESCCs were enriched in pathways including immune response, while genes over-expressed in subtype II ESCCs were mainly involved in ectoderm development, glycolysis process and cell proliferation. Specifically, we identified potential ESCC subtype-specific diagnostic markers (FOXA1 and EYA2 for subtype I, LAMC2 and KRT14 for subtype II) and further validated them in a fourth Asian cohort. In addition, we propose a few subtype-specific therapeutic targets for ESCC, which may guide future ESCC clinical treatment when further validated. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 81602362 to XG; No. 61571414 to AL), the program for Science and Technology Development in Henan Province (No.162102310391 to XG), the program for Young Key Teacher of Henan Province (No. 2016GGJS-214 to XG), the supporting grants of Henan University (No. 2015YBZR048 to XG; No. B2015151 to XG), the program for Innovative Talents of Science and Technology in Henan Province (No. 18HASTIT048 to XG), and Yellow River Scholar Program (No. H2016012 to XG). The funding bodies were not involved in the study design, data collection, analysis and interpretation of data, or in writing of this manuscript. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: A tissue Arrayer (Beecher, MTA-1) was used to construct the ESCC tissue microarray (TMA) comprising of 166 primary ESCC cases collected from Linzhou Cancer Hospital, Henan, China, between 2010 and 2011, as an independent cohort, which were obtained with Institutional review board approval and a waiver of consent due to the archival nature of the specimens.