title: Frequency and clinicopathologic correlates of KRAS amplification in non-small cell lung carcinoma.
abstract: BACKGROUND
  Characterization of the non-small cell lung cancer (NSCLC) genome has suggested that KRAS amplification is one of the commonest molecular abnormalities in NSCLC. However, the prevalence and clinicopathologic significance of KRAS amplification, and its relationship with KRAS activating mutations have not been well-defined. The purpose of this study was to establish the prevalence of KRAS amplification in two separate, large NSCLC cohorts, to define the clinicopathologic features of KRAS-amplified NSCLC in a single uniformly treated cohort, and to investigate the interplay between KRAS amplification and KRAS mutation.
  
  
  METHODS
  Fluorescence in situ hybridization was utilized to detect KRAS amplification on tissue microarrays constructed from a Swiss cohort of 538 NSCLCs and a series of 402 patients with NSCLC treated in a single institution in New York. DNA sequencing to detect KRAS codon 12 activating mutations was performed on a subset of tumors. Amplification and mutation status were compared with patient baseline characteristics, tumor characteristics, and overall- and disease-free survival.
  
  
  RESULTS
  The prevalence of KRAS amplification was 13.7% in the Swiss cohort and 15.1% in the New York cohort. Among adenocarcinomas, KRAS amplification was associated with larger (mean size 2.8±1.8 cm vs. 2.1±1.3 cm, p=0.003), less well-differentiated tumors (18% vs. 42%, p=0.004) that were more likely to be invasive (95% vs. 77%, p=0.004) and to exhibit angiolymphatic invasion (24% vs. 12%, p=0.04). These differences were statistically significant within the subset of adenocarcinomas harboring activating KRAS mutations, suggesting a synergistic relationship between amplification and mutation. No significant association between KRAS amplification and nodal metastasis or survival was seen.
  
  
  CONCLUSIONS
  KRAS amplification is a common molecular alteration in NSCLC, characterizing ∼15% of tumors. This alteration is associated with indicators of local aggressiveness, and may act synergistically with KRAS mutations to promote tumor progression.
authors.affiliation: Cardiothoracic Surgery, New York Hospital/Weill Cornell Medical Center, New York, NY, USA. ptrckwgnr@gmail.com
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Wagner
authors.forename: Ann-Cathrin
authors.initials: AC
authors.lastname: Stiedl
authors.forename: Theresia
authors.initials: T
authors.lastname: Wilbertz
authors.forename: Karen
authors.initials: K
authors.lastname: Petersen
authors.forename: Veit
authors.initials: V
authors.lastname: Scheble
authors.forename: Roopika
authors.initials: R
authors.lastname: Menon
authors.forename: Markus
authors.initials: M
authors.lastname: Reischl
authors.forename: Ralf
authors.initials: R
authors.lastname: Mikut
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D044382:Population Groups / Q000706:statistics & numerical data; D015995:Prevalence; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000032:analysis; D016019:Survival Analysis; D013557:Switzerland; D014481:United States; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins