title: Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.
abstract: OBJECTIVE
  The molecular epidemiology of most EGFR and KRAS mutations in lung cancer remains unclear.
  
  
  METHODS
  We genotyped 3,026 lung adenocarcinomas for the major EGFR (exon 19 deletions and L858R) and KRAS (G12, G13) mutations and examined correlations with demographic, clinical, and smoking history data.
  
  
  RESULTS
  EGFR mutations were found in 43% of never smokers and in 11% of smokers. KRAS mutations occurred in 34% of smokers and in 6% of never smokers. In patients with smoking histories up to 10 pack-years, EGFR predominated over KRAS. Among former smokers with lung cancer, multivariate analysis showed that, independent of pack-years, increasing smoking-free years raise the likelihood of EGFR mutation. Never smokers were more likely than smokers to have KRAS G > A transition mutation (mostly G12D; 58% vs. 20%, P = 0.0001). KRAS G12C, the most common G > T transversion mutation in smokers, was more frequent in women (P = 0.007) and these women were younger than men with the same mutation (median 65 vs. 69, P = 0.0008) and had smoked less.
  
  
  CONCLUSIONS
  The distinct types of KRAS mutations in smokers versus never smokers suggest that most KRAS-mutant lung cancers in never smokers are not due to second-hand smoke exposure. The higher frequency of KRAS G12C in women, their younger age, and lesser smoking history together support a heightened susceptibility to tobacco carcinogens.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Dogan
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Ang
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Johnson
authors.forename: Sandra P
authors.initials: SP
authors.lastname: D'Angelo
authors.forename: Paul K
authors.initials: PK
authors.lastname: Paik
authors.forename: Edyta B
authors.initials: EB
authors.lastname: Brzostowski
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D020125:Mutation, Missense; D049451:Nomograms; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects*; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins