title: Somatic copy number alterations detected by ultra-deep targeted sequencing predict prognosis in oral cavity squamous cell carcinoma.
abstract: BACKGROUND
  Ultra-deep targeted sequencing (UDT-Seq) has advanced our knowledge on the incidence and functional significance of somatic mutations. However, the utility of UDT-Seq in detecting copy number alterations (CNAs) remains unclear. With the goal of improving molecular prognostication and identifying new therapeutic targets, we designed this study to assess whether UDT-Seq may be useful for detecting CNA in oral cavity squamous cell carcinoma (OSCC).
  
  
  METHODS
  We sequenced a panel of clinically actionable cancer mutations in 310 formalin-fixed paraffin-embedded OSCC specimens. A linear model was developed to overcome uneven coverage across target regions and multiple samples. The 5-year rates of secondary primary tumors, local recurrence, neck recurrence, distant metastases, and survival served as the outcome measures. We confirmed the prognostic significance of the CNA signatures in an independent sample of 105 primary OSCC specimens.
  
  
  RESULTS
  The CNA burden across 10 targeted genes was found to predict prognosis in two independent cohorts. FGFR1 and PIK3CAamplifications were associated with prognosis independent of clinical risk factors. Genes exhibiting CNA were clustered in the proteoglycan metabolism, the FOXO signaling, and the PI3K-AKT signaling pathways, for which targeted drugs are already available or currently under development.
  
  
  CONCLUSIONS
  UDT-Seq is clinically useful to identify CNA, which significantly improve the prognostic information provided by traditional clinicopathological risk factors in OSCC patients.
authors.affiliation: Departments of Resource Center for Clinical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.
authors.forename: Chien-Hua
authors.initials: CH
authors.lastname: Peng
authors.affiliation: Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.|Head and Neck Oncology Group, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.
authors.forename: Chun-Ta
authors.initials: CT
authors.lastname: Liao
authors.affiliation: Institute of Statistics, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.
authors.forename: Ka-Pou
authors.initials: KP
authors.lastname: Ng
authors.affiliation: Institute of Statistics, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.
authors.forename: An-Shun
authors.initials: AS
authors.lastname: Tai
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.
authors.forename: Shih-Chi
authors.initials: SC
authors.lastname: Peng
authors.affiliation: Institute of Statistics, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.
authors.forename: Jen-Pao
authors.initials: JP
authors.lastname: Yeh
authors.affiliation: Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan, R.O.C.
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Medical Biotechnology and Laboratory Science, Research Center for Emerging Viral Infections, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.|Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.
authors.forename: Kuo-Chien
authors.initials: KC
authors.lastname: Tsao
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.affiliation: Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Hsieh
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D016009:Chi-Square Distribution; D056915:DNA Copy Number Variations; D018450:Disease Progression; D018572:Disease-Free Survival; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D009062:Mouth Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor
keywords: biomarker; clinically actionable genes; copy number alteration; oral cavity squamous cell carcinoma; ultradeep-targeted sequencing