title: Evaluation of Salivary Transcriptome Markers for the Early Detection of Oral Squamous Cell Cancer in a Prospective Blinded Trial.
abstract: BACKGROUND
  Oral squamous cell cancer (OSCC) is often diagnosed in late stages. Informative biomarkers could play a key role in early diagnosis. Prior case-control studies identified discriminatory salivary mRNA markers for OSCC. The National Cancer Institute (NCI) recommends prospective-specimencollection, retrospective-blinded-evaluation (PRoBE) design study for rigorous biomarker identification and validation.
  
  
  METHODS
  A PRoBE design study enrolled 170 patients with lesions suspicious for OSCC. Saliva was collected before performing oral biopsy. Six pre-specified oral-cancer-associated mRNAs (IL1β, IL8, OAZ1, SAT, S100P, and DUSP1) and five housekeeping mRNAs (MT-ATP6, RPL30, RPL37A, RPL0, and RPS17) were measured by quantitative polymerase chain reaction (PCR) without knowledge of tissue diagnosis. A pre-specified multi-marker panel from prior NCI - Early Detection Research Network (EDRN) studies was evaluated in this new PRoBE dataset. Individual marker cycle thresholds (Ct) from PCR were also compared in cancer versus control, and new discriminatory models were generated.
  
  
  RESULTS
  The EDRN model was validated based on pre-specified statistical analysis plan. Ct values of individual mRNAs reflect an approximately twofold to nearly fourfold increase in concentration in invasive OSCC (P less than 0.01 for all). A new model from this intended-use population with incorporation of housekeeping genes demonstrates a maximal sum of sensitivity and specificity of 150.7% with an area under the receiver operating characteristic (ROC) curve of over 0.85.
  
  
  CONCLUSIONS
  The validation of six pre-specified individual salivary transcriptome markers of OSCC and a pre-specified multi-marker model in a new prospective population supports the robustness of these markers and the multi-marker methodology. New models generated in this intended-use population have the potential to further enhance the decision process for early biopsy. Lesions at very low risk for cancer could be identified noninvasively as could those at significantly increased risk. Further study is necessary to assure effective implementation of this technology into routine clinical practice.
authors.affiliation: Past President, Sharpe Strumia Research Foundation, Bryn Mawr, Pennsylvania; Chief Medical Officer, PeriRx LLC, Broomall, Pennsylvania.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Martin
authors.affiliation: Guest Faculty, University of Maryland Dental School, Baltimore, Maryland; Director of Dental Education, PeriRx LLC, Broomall, Pennsylvania; Diplomate, American Board of Periodontology; Private Practice, Periodontics, Havertown, Pennsylvania.
authors.forename: Neil
authors.initials: N
authors.lastname: Gottehrer
authors.affiliation: Attending Oral Surgeon, St. John Macomb-Oakland Hospital, Warren, Michigan.
authors.forename: Harvey
authors.initials: H
authors.lastname: Zalesin
authors.affiliation: Attending Physician, MI Otolaryngology Surgery Associates, Ypsilanti, Michigan.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Hoff
authors.affiliation: Director of Research, St. John Macomb-Oakland Hospital, Warren, Michigan.
authors.forename: Michael
authors.initials: M
authors.lastname: Shaw
authors.affiliation: Assistant Professor, Michigan State University, Department of Surgery, Lansing, Michigan.
authors.forename: James Hw
authors.initials: JH
authors.lastname: Clarkson
authors.affiliation: Research Coordinator, Michigan State University, Department of Surgery, Lansing, Michigan.
authors.forename: Pam
authors.initials: P
authors.lastname: Haan
authors.affiliation: Clinical Coordinator, University of Michigan, Department of Surgery, Ann Arbor, Michigan.
authors.forename: Mark
authors.initials: M
authors.lastname: Vartanian
authors.affiliation: Research Nurse, Michigan State University, Department of Surgery, Lansing, Michigan.
authors.forename: Terry
authors.initials: T
authors.lastname: McLeod
authors.affiliation: Chief Executive Officer, PeriRx LLC, Broomall, Pennsylvania.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Swanick
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000235:genetics*; D055088:Early Detection of Cancer; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012307:Risk Factors; D012463:Saliva / Q000737:chemistry*; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor