title: A Sensitive NanoString-Based Assay to Score STK11 (LKB1) Pathway Disruption in Lung Adenocarcinoma.
abstract: Serine/threonine kinase 11 gene (STK11), better known as liver kinase β1, is a tumor suppressor that is commonly mutated in lung adenocarcinoma (LUAD). Previous work has shown that mutational inactivation of the STK11 pathway may serve as a predictive biomarker for cancer treatments, including phenformin and cyclooxygenase-2 inhibition. Although immunohistochemical (IHC) staining and diagnostic sequencing are used to measure STK11 pathway disruption, there are serious limitations to these methods, thus emphasizing the importance of validating a clinically useful assay.
  
  
  
  An initial STK11 mutation mRNA signature was generated using cell line data and refined using three large, independent patient databases. The signature was validated as a classifier using The Cancer Genome Atlas (TCGA) LUAD cohort as well as a 442-patient LUAD cohort developed at Moffitt. Finally, the signature was adapted to a NanoString-based format and validated using RNA samples isolated from formalin-fixed, paraffin-embedded tissue blocks corresponding to a cohort of 150 patients with LUAD. For comparison, STK11 IHC staining was also performed.
  
  
  
  The STK11 signature was found to correlate with null mutations identified by exon sequencing in multiple cohorts using both microarray and NanoString formats. Although there was a statistically significant correlation between reduced STK11 protein expression by IHC staining and mutation status, the NanoString-based assay showed superior overall performance, with a -0.1588 improvement in area under the curve in receiver-operator characteristic curve analysis (p < 0.012).
  
  
  
  The described NanoString-based STK11 assay is a sensitive biomarker to study emerging therapeutic modalities in clinical trials.
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Brienne E
authors.initials: BE
authors.lastname: Engel
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Welsh
authors.affiliation: Molecular Genomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Yoder
authors.affiliation: Pathology Services M2Gen, Tampa, Florida.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Brantley
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Cao
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Kaye
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schabath
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address: Douglas.Cress@moffitt.org.
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics; D001681:Biological Assay / Q000379:methods*; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics; D009154:Mutation; D036103:Nanotechnology; D009367:Neoplasm Staging; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012372:ROC Curve
chemical_list: D014408:Biomarkers, Tumor; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
keywords: COX-2 inhibition; LKB1; NanoString; STK11; biomarker