Novel candidate genes may be possible predisposing factors revealed by whole exome sequencing in familial esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma is one of the deadliest of all the cancers. Its metastatic properties portend poor prognosis and high rate of recurrence. A more advanced method to identify new molecular biomarkers predicting disease prognosis can be whole exome sequencing. Here, we report the most effective genetic variants of the Notch signaling pathway in esophageal squamous cell carcinoma susceptibility by whole exome sequencing. We analyzed nine probands in unrelated familial esophageal squamous cell carcinoma pedigrees to identify candidate genes. Genomic DNA was extracted and whole exome sequencing performed to generate information about genetic variants in the coding regions. Bioinformatics software applications were utilized to exploit statistical algorithms to demonstrate protein structure and variants conservation. Polymorphic regions were excluded by false-positive investigations. Gene-gene interactions were analyzed for Notch signaling pathway candidates. We identified novel and damaging variants of the Notch signaling pathway through extensive pathway-oriented filtering and functional predictions, which led to the study of 27 candidate novel mutations in all nine patients. Detection of the trinucleotide repeat containing 6B gene mutation (a slice site alteration) in five of the nine probands, but not in any of the healthy samples, suggested that it may be a susceptibility factor for familial esophageal squamous cell carcinoma. Noticeably, 8 of 27 novel candidate gene mutations (e.g. epidermal growth factor, signal transducer and activator of transcription 3, MET) act in a cascade leading to cell survival and proliferation. Our results suggest that the trinucleotide repeat containing 6B mutation may be a candidate predisposing gene in esophageal squamous cell carcinoma. In addition, some of the Notch signaling pathway genetic mutations may act as key contributors to esophageal squamous cell carcinoma.

In silico evidence of high frequency of miRNA‐related SNPs in Esophageal Squamous Cell Carcinoma

“…Revealing potential germline miR‐TS‐SNP variants in ESCC, we analyzed nearly 3,000 SNPs in 3′‐UTRs in every whole‐exome sequencing (WES) data set. In a previous study, by analyzing exome‐located SNPs in these WES data we reported novel candidate genes as predisposing factors in the familial ESCC group that confirmed them with a segregation study (Forouzanfar et al, ).…”

Cellular and Molecular Biology of Esophageal Cancer

“…Using the new robust sequencing platforms, whole exome sequencing and whole genome sequencing of patients in esophageal carcinoma are possible. In the literature, reports of whole exome sequencing noted mainly in esophageal squamous cell carcinoma and occasionally in esophageal adenocarcinoma [58][59][60][61][62][63][64][65][66][67]. There are many novel mutations and genetic pathways detected which could help us to understand the pathogenesis of this group of cancers with complex genetic alternations ( Table 1).…”