title: Unique microRNAs in lung adenocarcinoma groups according to major TKI sensitive EGFR mutation status.
abstract: BACKGROUND
  Lung cancer is the leading cause of cancer mortality, despite development of therapeutic strategies. Altered expression of microRNAs(miRNAs) in human malignancies have been well recognized as diagnostic and prognostic indicators, including lung cancer. This study aims to delineate the clinicopathologic significance of three unique miRNAs in adenocarcinoma according to major sensitive EGFR mutation status.
  
  
  METHODS
  One-hundred and three formalin-fixed paraffin-embedded (FFPE) tissues were collected from lung adenocarcinoma patients who underwent surgery and epidermal growth factor receptor (EGFR) mutation study. The samples were divided into three groups which include EGFR mutation in exons 19 and 21 and wild type. Some representative cases from each group were profiled using commercial miRNA microarray plates. Three significant miRNAs were selected and they were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), using collective cases of FFPE samples.
  
  
  RESULTS
  We identified three microRNAs (miR-34c, miR-183, and miR-210) which showed significantly altered expression in all groups of lung adenocarcinoma by microarray study. Compared to normal control lung tissue, down-regulation of miR-34c and up-regulation of miR-183 and miR-210 were identified in caner groups (p < 0.05 for each). We validated the expression of three miRNAs by qRT-PCR. Expression levels of miR-34c, miR-183, and miR-210 were significantly different between normal control group and cancer groups (p = 0.034, <0.000, and 0.036, respectively). Moreover, expression level of miR-183 was significantly higher in EGFR mutation groups than wild type group (p = 0.028). Higher expression levels of three miRNAs were positively related to poor tumor differentiation. Increased expression of miR-183 was positively associated with lymphovascular invasion (p = 0.037). Aberrant expression of miR-210 was independently associated with T stage (p = 0.019), and TNM stage (p = 0.007). However, there was noted a limited statistical significance. In EGFR exon 19 mutation group, miR-34c high expression group showed poor overall survival than low expression one by univariate Kaplan-Meier method. (p = 0.035).
  
  
  CONCLUSIONS
  Here, we show that miR-34c may act as a potential tumor suppressor gene and miR-183 and miR-210 have a potential oncogenic role in pulmonary adenocarcinoma. This study also suggests different miRNA expression between EGFR mutation group and wild type group. Consequently, further studies of the biology of miRNAs may lead to diagnostic and prognostic biomarkers in pulmonary adenocarcinoma.
authors.affiliation: Department of Pathology, Dong-A University Hospital, Busan, Republic of Korea. viowindy@hanmail.net.
authors.forename: Min Gyoung
authors.initials: MG
authors.lastname: Pak
authors.affiliation: Department of Pathology and Medical Research Institute, Pusan National Univeristy Hospital, 1-10 Ami-dong, Seo-gu, Busan, 602-739, Republic of Korea. cnlee@pusan.ac.kr.
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Medical Research Institute, Pusan National Univeristy Hospital, 1-10 Ami-dong, Seo-gu, Busan, 602-739, Republic of Korea. Janus-77@hanmail.net.
authors.forename: Woo-Jeong
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, School of Medicine, Pusan National University, Yangsan, Republic of Korea. donghshin@chollian.net.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea. msroh@dau.ac.kr.
authors.forename: Mee-Sook
authors.initials: MS
authors.lastname: Roh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; C533449:MIRN183 microRNA, human; C543800:MIRN210 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors