Genomic Profiles to Identify the Key Events in Metastasis for Esophageal Squamous Cell Carcinoma

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is a deadly cancer with high incidence in Asia. Metastasis is the major cause leading to the treatment failure in advanced ESCC. However, little is known about the key genetic events contributing to ESCC metastasis. We aim to blueprint the genomic profiles of metastatic ESCC, identify the critical genetic events and use these genetic alterations as the biomarkers for predicting patient clinical outcomes. Methods: We performed the whole-exome (WES) and/or whole-genome (WGS) sequencing for the primary ESCC, synchronous LN metastases, and non-neoplastic mucosa in 24 ESCC cases. The single nucleotide variants (SNVs), copy number variations (CNVs) and structural variants (SVs) were identified using our in-house bioinformatics pipelines. The SNVs and breakpoints for the SVs were validated by Sanger sequencing. The CNVs were validated by qPCR. Results: In WES, tumor mutation load and signatures are similar between primary and synchronous LN metastases. Several genetic alterations were frequently detected in the metastatic ESCC, including point mutations at TP53, KMT2D, ZNF750 and IRF5, and 6p22 and 11q23.3 deletions of histone clusters. Analysis for 629 primary ESCC indicated that the cases with LN metastasis more often carried ZNF750 mutations than those without metastasis (14% versus 3.4%, P =1.78×10-5). Survival analysis revealed that the cases harbouring the 6p22 or 11q23.3 deletion had shorter overall survival than those without deletion in these two regions. Among 11 cases analysed with matched samples, chromosome 6p22 deletions were recurrently found in three synchronous nodal metastases, but absent in the primary tumors. The detailed analysis of WGS data for SVs is ongoing. In the metastatic ESCC, a median of 51 SVs are private compared to the matched primary ESCC. Conclusions: The key genetic events including ZNF750 mutations and deletion of histone clusters were associated with ESCC LN metastasis, and thus, have the potential to be used as the biomarkers for ESCC metastasis. Acknowledgements: The study is funded by Theme-Based Research Scheme grant T12-701/17-R and CRF grant C7031-15G to MLL