Whole-exome sequencing to identify HOMEZ mutation as a prognostic marker in esophageal squamous cell carcinoma treated with concurrent chemoradiotherapy.

Abstract

e15523 Background: The outcomes of inoperable esophageal squamous carcinoma (ESCC) patients treated with concurrent chemoradiotherapy remain poor. The discovery of novel biomarkers for predicting prognosis could allow for more accurate risk stratification and identification of high-risk patients. Although previous studies have elucidated some genomic alterations could be predictors of survival in these patients, none has focused on comprehensive genetic analysis using high-throughput platforms. Methods: Whole-exome sequencing was done in 96 inoperable ESCC patients treated with concurrent chemoradiotherapy from our phase Ⅲ clinical trial (NCT00686114). The prognostic marker was developed using a Random Survival Forest supervised classification methods based on log-rank splitting rules. The independence of the marker in survival prediction was evaluated by multivariable Cox regression analysis. The marker was further validated for the prognostic utility in an independent cohort (n = 150). The biological function of the genomic alteration was predicted by GO annotations. Results: A HOMEZ mutation (chr14:23744800_ACATCAT/ACAT) was detected in 54.1% of patients with ESCC received concurrent chemoradiotherapy. We identified the mutation was significantly associated with overall survival (hazard ratio [HR] 1.842; 95% confidence interval [CI] 1.080-3.142; P = 0.025) and loco-regional free survival (HR 3.008; 95% CI 1.302-6.947; P = 0.010). Multivariable Cox regression analysis showed that the mutation was also an independent prognostic factors for patients with ESCC (mutation type vs. wild type, overall survival: HR 2.161; 95% CI 1.241-3.764; p = 0·007; loco-regional free survival: HR 3.576; 95% CI 1.509-8.473; p = 0.004). GO annotations showed that HOMEZ tended to be frequently related to transcription factor activity, sequence-specific DNA binding and transcription corepressor activity. Conclusions: HOMEZ mutation is a novel independent prognostic factor for inoperable ESCC patients treated with concurrent chemoradiotherapy, and may be a potential therapeutic target.