title: A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors.
abstract: A diagnosis of neuroendocrine carcinoma is often morphologically straight-forward; however, the tumor site of origin may remain elusive in a metastatic presentation. Neuroendocrine tumor subtyping has important implications for staging and patient management. In this study, the novel use and performance of a 92-gene molecular cancer classifier for determination of the site of tumor origin are described in a series of 75 neuroendocrine tumors (44 metastatic, 31 primary; gastrointestinal (n=12), pulmonary (n=22), Merkel cell (n=10), pancreatic (n=10), pheochromocytoma (n=10), and medullary thyroid carcinoma (n=11)). Formalin-fixed, paraffin-embedded samples passing multicenter pathologist adjudication were blinded and tested by a 92-gene molecular assay that predicts tumor type/subtype based upon relative quantitative PCR expression measurements for 87 tumor-related and 5 reference genes. The 92-gene assay demonstrated 99% (74/75; 95% confidence interval (CI) 0.93-0.99) accuracy for classification of neuroendocrine carcinomas and correctly subtyped the tumor site of origin in 95% (71/75; 95% CI 0.87-0.98) of cases. Analysis of gene expression subsignatures within the 92-gene assay panel showed 4 genes with promising discriminatory value for tumor typing and 15 genes for tumor subtyping. The 92-gene classifier demonstrated excellent accuracy for classifying and determining the site of origin in tumors with neuroendocrine differentiation. These results show promise for use of this test to aid in classifying neuroendocrine tumors of indeterminate primary site, particularly in the metastatic setting.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kerr
authors.affiliation: bioTheranostics, Inc., San Diego, CA, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Schnabel
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Sullivan
authors.affiliation: bioTheranostics, Inc., San Diego, CA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: bioTheranostics, Inc., San Diego, CA, USA.
authors.forename: Vivian J
authors.initials: VJ
authors.lastname: Huang
authors.affiliation: bioTheranostics, Inc., San Diego, CA, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Elena F
authors.initials: EF
authors.lastname: Brachtel
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009382:Neoplasms, Unknown Primary / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D018358:Neuroendocrine Tumors / Q000145:classification / Q000235:genetics* / Q000556:secondary*; D010641:Phenotype; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D014481:United States
chemical_list: D014408:Biomarkers, Tumor