Whole-Exome Sequencing Reveals A Novel Damaging Mutation un Seprase un A Family With Esophageal Squamous CellCarcinoma

Fibroblast activation protein (FAP) is a serine protease gene that fame as a potential cancer therapytarget and is a type uu transmembrane protein with the bulk extracellular domain, including thecatalytic reign and highly expressed in activated fibroblastic cells in tumors, arthritis and fibrosis.The present study is sought to identify rare germline mutations in familial esophageal squamouscell carcinoma by next-generation sequencing (NGS).The coding regions of our proband wascaptured by Sure Select target enrichment system. The reads are mapped against UCSC hg19 humanreference genome. The dbSNP 135 & 1000G were used for population allele frequencies. Thehomology modeling of the novel mutation (A459D) discovered in FAP gene was performed by usingthe online Swiss-Prot server for automated modeling and the resulted structure has been modifiedand analyzed by using bioinformatics software to thoroughly study the structural deficienciescaused by the novel mutation. A rare, novel, human mutation C1367A encoding Ala459 Asp(accession number: KT988039), occurring in the blade of the β propeller domain, was identified in 2sisters with Esophageal Squamous Cell Carcinoma (ESCC). Also thirty-five percent of the mutationswe identified were novel, indicating that screening methods, which none of them found in 70 controlsubjects. Moreover, structural studies of the novel mutation in FAP gene disclosed abnormalities inthe structure of the mutant protein which supports its malfunctioning behavior. This study is thefirst to fully analyzed germline mutations of Apoptosis genes in familial ESCC patients. We prefer toanalyze our data with pathway-oriented method for analyzing broad of data. Additionally,structural analyses of the novel mutant protein uncovered changes in the energy level and stereochemical properties of the FAP gene that unfortunately altered the mutant protein’sfunctionalities.