title: Validation of the Lung Subtyping Panel in Multiple Fresh-Frozen and Formalin-Fixed, Paraffin-Embedded Lung Tumor Gene Expression Data Sets.
abstract: Context .- A histologic classification of lung cancer subtypes is essential in guiding therapeutic management. Objective .- To complement morphology-based classification of lung tumors, a previously developed lung subtyping panel (LSP) of 57 genes was tested using multiple public fresh-frozen gene-expression data sets and a prospectively collected set of formalin-fixed, paraffin-embedded lung tumor samples. Design .- The LSP gene-expression signature was evaluated in multiple lung cancer gene-expression data sets totaling 2177 patients collected from 4 platforms: Illumina RNAseq (San Diego, California), Agilent (Santa Clara, California) and Affymetrix (Santa Clara) microarrays, and quantitative reverse transcription-polymerase chain reaction. Gene centroids were calculated for each of 3 genomic-defined subtypes: adenocarcinoma, squamous cell carcinoma, and neuroendocrine, the latter of which encompassed both small cell carcinoma and carcinoid. Classification by LSP into 3 subtypes was evaluated in both fresh-frozen and formalin-fixed, paraffin-embedded tumor samples, and agreement with the original morphology-based diagnosis was determined. Results .- The LSP-based classifications demonstrated overall agreement with the original clinical diagnosis ranging from 78% (251 of 322) to 91% (492 of 538 and 869 of 951) in the fresh-frozen public data sets and 84% (65 of 77) in the formalin-fixed, paraffin-embedded data set. The LSP performance was independent of tissue-preservation method and gene-expression platform. Secondary, blinded pathology review of formalin-fixed, paraffin-embedded samples demonstrated concordance of 82% (63 of 77) with the original morphology diagnosis. Conclusions .- The LSP gene-expression signature is a reproducible and objective method for classifying lung tumors and demonstrates good concordance with morphology-based classification across multiple data sets. The LSP panel can supplement morphologic assessment of lung cancers, particularly when classification by standard methods is challenging.
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Hawazin
authors.initials: H
authors.lastname: Faruki
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Mayhew
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Scott
authors.initials: S
authors.lastname: Parker
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Lauren
authors.initials: L
authors.lastname: Kam-Morgan
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Marcia
authors.initials: M
authors.lastname: Eisenberg
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Bruce
authors.initials: B
authors.lastname: Horten
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: From the Clinical Development Department, GeneCentric Diagnostics, Durham, North Carolina (Drs Faruki, Mayhew, and Lai-Goldman); the Lineberger Comprehensive Cancer Center (Mr Fan and Drs Hayes and Perou) and the Department of Genetics (Drs Wilkerson and Perou), University of North Carolina, Chapel Hill; and the Center for Molecular Biology and Pathology, Laboratory Corporation of America Holdings, Research Triangle Park, North Carolina (Mr Parker and Drs Kam-Morgan, Eisenberg, and Horten).
authors.forename: Myla
authors.initials: M
authors.lastname: Lai-Goldman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016612:Paraffin Embedding; D016707:Tissue Fixation / Q000379:methods; D055815:Young Adult