title: Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas.
abstract: BACKGROUND
  c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas.
  
  
  METHODS
  In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ⩾3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ⩾2.
  
  
  RESULTS
  We observed c-MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08-2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06-3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24-17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15-18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11-4.10 for DFS).
  
  
  CONCLUSIONS
  c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death.
authors.affiliation: 1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Kyungpook National University College of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 700-842, Korea.
authors.forename: A N
authors.initials: AN
authors.lastname: Seo
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Yang
authors.affiliation: 1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.affiliation: 1] Department of Thoracic Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Thoracic Surgery, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Jheon
authors.affiliation: 1] Department of Thoracic Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Thoracic Surgery, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.affiliation: 1] Department of Internal medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Internal medicine, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: C T
authors.initials: CT
authors.lastname: Lee
authors.affiliation: 1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.affiliation: 1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Yun
authors.affiliation: 1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Chung
authors.affiliation: 1] Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi 463-707, Korea [2] Department of Pathology, Seoul National University College of Medicine, 28 Yeongon-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Paik
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012372:ROC Curve; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; C489427:MYC protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins