title: A three-microRNA signature predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma.
abstract: OBJECTIVE
  To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC).
  
  
  METHODS
  The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis.
  
  
  RESULTS
  A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power.
  
  
  CONCLUSIONS
  The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence.
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Motonobu
authors.initials: M
authors.lastname: Saito
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Kouya
authors.initials: K
authors.lastname: Shiraishi
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Schetter
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ogata-Kawata
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Tsuchiya
authors.affiliation: Department of Medical Oncology, Japanese Red Cross Medical Center, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kunitoh
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.affiliation: Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kumamoto
authors.affiliation: Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Takenoshita
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Cancer Genome Biology, Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. tkkohno@ncc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000032:analysis*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017671:Platinum Compounds / Q000627:therapeutic use*; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C574604:MIRN1290 microRNA, human; C544965:MIRN135 microRNA, human; C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D017671:Platinum Compounds