title: Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes.
abstract: The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127×. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant-based filter were employed to call somatic gene-copy number variations. Significantly mutated genes were identified with Oncodrive FM and the Youn and Simon's method. Candidate driver genes were nominated based on Gene Set Enrichment Analysis. The observed mutational spectrum was similar to that reported by the TCGA project. In addition to confirming known genes of OSCC (TP53, CDKNA2, CASP8, PIK3CA, HRAS, FAT1, TP63, CCND1 and FADD) the analysis identified several candidate novel driver events including mutations of NOTCH3, CSMD3, CRB1, CLTCL1, OSMR and TRPM2, amplification of the proto-oncogenes FOSL1, RELA, TRAF6, MDM2, FRS2 and BAG1, and deletion of the recently described tumor suppressor SMARCC1. Analysis also revealed significantly altered pathways not previously implicated in OSCC including Oncostatin-M signalling pathway, AP-1 and C-MYB transcription networks and endocytosis. There was a trend for higher number of mutations, amplifications and driver events in samples with history of shammah exposure particularly those that tested EBV positive, suggesting an interaction between tobacco exposure and EBV. The work provides further evidence for the genetic heterogeneity of oral cancer and suggests shammah-associated OSCC is characterized by extensive amplification of oncogenes.
authors.affiliation: Department of Preventive Dentistry, College of Dentistry, Jazan University, Jazan, Kingdom of Saudi Arabia.
authors.forename: Nezar Noor
authors.initials: NN
authors.lastname: Al-Hebshi
authors.affiliation: Department of Oncology and Pharmacogenomics, Beijing Genome Institute (BGI), Shenzhen, Republic of China.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Sana'a University, Yemen.
authors.forename: Akram Thabet
authors.initials: AT
authors.lastname: Nasher
authors.affiliation: Substance Abuse Research Center (SARC), Jazan University, Jazan, Kingdom of Saudi Arabia.
authors.forename: Maged
authors.initials: M
authors.lastname: El-Setouhy
authors.affiliation: Substance Abuse Research Center (SARC), Jazan University, Jazan, Kingdom of Saudi Arabia.
authors.forename: Rashad
authors.initials: R
authors.lastname: Alsanosi
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Blancato
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Loffredo
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology* / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000453:epidemiology* / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D009857:Oncogenes; D015398:Signal Transduction; D014030:Tobacco, Smokeless / Q000009:adverse effects*
chemical_list: D015415:Biomarkers
keywords: carcinoma; exome; genetics; head and neck neoplasms; high-throughput nucleotide sequencing; mouth; shammah; smokeless; squamous cell; tobacco