title: The MYCN-HMGA2-CDKN2A pathway in non-small cell lung carcinoma--differences in histological subtypes.
abstract: BACKGROUND
  Extensive research has increased our understanding of the molecular alterations needed for non-small cell lung cancer (NSCLC) development. Deregulation of a pathway including MYCN, HMGA2 and CDKN2A, with the participation of DICER1, is of importance in several solid tumours, and may also be of significance in the pathogenesis of NSCLC.
  
  
  METHODS
  Gene expression of MYCN, HMGA2, CDKN2A and DICER1 were investigated with RT-qPCR in surgically resected NSCLC tumour tissue from 175 patients. Expression of the let-7 microRNA family was performed in 78 adenocarcinomas and 16 matching normal lung tissue samples using microarrays. The protein levels of HMGA2 were determined by immunohistochemistry in 156 tumour samples and the protein expression was correlated with gene expression. Associations between clinical data, including time to recurrence, and expression of mRNA, protein and microRNAs were analysed.
  
  
  RESULTS
  Compared to adenocarcinomas, squamous cell carcinomas had a median 5-fold increase in mRNA expression of HMGA2 (p = 0.003). A positive correlation (r = 0.513, p < 0.010) between HMGA2 mRNA expression and HMGA2 protein expression was seen. At the protein level, 90% of the squamous cell carcinomas expressed high levels of the HMGA2 protein compared to 47% of the adenocarcinomas (p < 0.0001). MYCN was positively correlated with HMGA2 (p < 0.010) and DICER1 mRNA expression (p < 0.010), and the expression of the let-7 microRNAs seemed to be correlated with the genes studied. MYCN expression was associated with time to recurrence in multivariate survival analyses (p = 0.020).
  
  
  CONCLUSIONS
  A significant difference in HMGA2 mRNA expression between the histological subtypes of NSCLC was seen with a higher expression in the squamous cell carcinomas. This was also found at the protein level, and we found a good correlation between the mRNA and the protein expression of HMGA2. Moreover, the expression of MYCN, HMGA2, and DICER1 seems to be correlated to each other and the expression of the let7-genes impacted by their expression. MYCN gene expression seems to be of importance in time to recurrence in this patient cohort with resected NSCLC.
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. haeid@rr-research.no.|Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. haeid@rr-research.no.
authors: Hanne A
authors: HA
authors: Eide
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. Ann.Rita.Halvorsen@rr-research.no.
authors: Ann Rita
authors: AR
authors: Halvorsen
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. mamok@rr-research.no.|Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. mamok@rr-research.no.
authors: Maria Moksnes
authors: MM
authors: Bjaanæs
authors: Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran. hosseinpiry@gmail.com.
authors: Hossein
authors: H
authors: Piri
authors: Department of Pathology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. rho@ous-hf.no.
authors: Ruth
authors: R
authors: Holm
authors: Department of Cardiothoracic Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway. ssolberg@ous-hf.no.
authors: Steinar
authors: S
authors: Solberg
authors: Department of Cardiothoracic Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway. lhr@ous-hf.no.
authors: Lars
authors: L
authors: Jørgensen
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. ot.brustugun@gmail.com.|Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. ot.brustugun@gmail.com.
authors: Odd Terje
authors: OT
authors: Brustugun
authors: Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. CKK@ous-hf.no.|Department of Oncology, National Advisory Unit on Late Effects After Cancer Treatment, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. CKK@ous-hf.no.
authors: Cecilie Essholt
authors: CE
authors: Kiserud
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. aslaug.helland@gmail.com.|Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. aslaug.helland@gmail.com.
authors: Åslaug
authors: Å
authors: Helland
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D000071447:N-Myc Proto-Oncogene Protein; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D043244:Ribonuclease III / Q000096:biosynthesis* / Q000235:genetics; D016019:Survival Analysis
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025743:HMGA2 Protein; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases