title: Sequential binary gene ratio tests define a novel molecular diagnostic strategy for malignant pleural mesothelioma.
abstract: OBJECTIVE
  To develop a standardized approach for molecular diagnostics, we used the gene expression ratio bioinformatic technique to design a molecular signature to diagnose malignant pleural mesothelioma (MPM) from among other potentially confounding diagnoses and differentiate the epithelioid from the sarcomatoid histologic subtype of MPM. In addition, we searched for pathways relevant in MPM in comparison with other related cancers to identify unique molecular features in MPM.
  
  
  METHODS
  We conducted microarray analysis on 113 specimens including MPMs and a spectrum of tumors and benign tissues comprising the differential diagnosis of MPM. We generated a sequential combination of binary gene expression ratio tests able to discriminate MPM from other thoracic malignancies. We compared this method with other bioinformatic tools and validated this signature in an independent set of 170 samples. Functional enrichment analysis was conducted to identify differentially expressed probes.
  
  
  RESULTS
  A sequential combination of gene expression ratio tests was the best molecular approach to distinguish MPM from all the other samples. Bioinformatic and molecular validations showed that the sequential gene ratio tests were able to identify the MPM samples with high sensitivity and specificity. In addition, the gene ratio technique was able to differentiate the epithelioid from the sarcomatoid type of MPM. Novel genes and pathways specifically activated in MPM were identified.
  
  
  CONCLUSIONS
  New clinically relevant molecular tests have been generated using a small number of genes to accurately distinguish MPMs from other thoracic samples, supporting our hypothesis that the gene expression ratio approach could be a useful tool in the differential diagnosis of cancers.
authors.affiliation: The Thoracic Surgery Oncology Laboratory, and International Mesothelioma Program, Division of Thoracic Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Assunta
authors.initials: A
authors.lastname: De Rienzo
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Coleman
authors.forename: Peter E
authors.initials: PE
authors.lastname: Sugarbaker
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Yaoyu E
authors.initials: YE
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Roderick V
authors.initials: RV
authors.lastname: Jensen
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D003937:Diagnosis, Differential; D020869:Gene Expression Profiling; D006801:Humans; D008654:Mesothelioma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D025202:Molecular Diagnostic Techniques; D020411:Oligonucleotide Array Sequence Analysis; D010997:Pleural Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor