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. Subclassification 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 overexpressed 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.

Analysis of Differentially Expressed Genes in a Chinese Cohort of Esophageal Squamous Cell Carcinoma

“…Upregulated and down-regulated genes were identified, suggesting the power and sensitivity of an RNA-seq based approach. We propose this data provides important clues for understanding the molecular mechanisms of ESCC pathogenesis [4,10,14].…”

“…Nevertheless, another distinct classifier called ESCC4 that is also associated with worse survival has distinct changes including chromosomal instability and a high frequency of loss of heterozygosity. Whether or not these molecular classifications will stand-up in the long term remains to be determined since there is remarkable molecular heterogeneity in ESCCs both within and between geographical populations [10].…”

“…The pathogenesis of ESCC still remains unclear with genetic and environmental factors thought to both contribute [4]. The wide geographic and cultural variations in the incidence of ESCC emphasize the environmental association, for example, smoking and alcohol abuse appear as major contributors to ESCC burden in Western populations along with dietary habits, while in China, salty, hot and fumigated foods and drinks have been reported to contribute to high ESCC prevalence [9,10]. The epidemiological evidence is supported by animal…”

Biological Significance of Tumor Heterogeneity in Esophageal Squamous Cell Carcinoma

“…In another study, ESCC specimens from 360 East Asian individuals were divided into four molecular subtypes associated with distinct clinical metrics [25]. Most recently, a new research work has categorized Asian ESCCs into two subtypes, with subtype I overexpressing genes in immune response process and subtype II linked to ectoderm development, cell proliferation, and glycolysis process [26]. Additionally, Tanaka et al [27] reported the presence of an immune-reactive subtype of ESCC patients with cytotoxic T-lymphocyte signatures activated by chemoradiotherapy.…”

<p>OSacc: Gene Expression-Based Survival Analysis Web Tool For Adrenocortical Carcinoma</p>

“…Due to the limited treatment options for patients with locally advanced ACC and high risk of relapse even after major operative resection, identifying new prognostic biomarkers and therapeutic targets to improve the therapies for ACC patients is very important 2–4. In recent decades, clinical bio-samples have been extensively analyzed by gene microarray or RNA-Seq technologies 5,6. Although numerous public transcriptomic datasets with clinical information are available, it is very difficult for researchers or clinicians without bioinformatics training to quickly assess the prognostic value of putative biomarkers.…”