Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma.
OBJECTIVE
KRAS mutations are found in approximately 25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib.


METHODS
We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas.


RESULTS
KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G-->A) rather than the transversion mutations known to be smoking-related (G-->T or G-->C; P < 0.0001).


CONCLUSIONS
Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.
Riely
Gregory J
GJ
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. rielyg@mskcc.org
Kris
Mark G
MG
Rosenbaum
Daniel
D
Marks
Jenifer
J
Li
Allan
A
Chitale
Dhananjay A
DA
Nafa
Khedoudja
K
Riedel
Elyn R
ER
Hsu
Meier
M
Pao
William
W
Miller
Vincent A
VA
Ladanyi
Marc
M
D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012907:Smoking; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
Cancer. 2001 Sep 15;92(6):1525-30
11745231
J Clin Oncol. 2007 Feb 10;25(5):561-70
17290066
Int J Cancer. 2006 Dec 1;119(11):2586-91
16988931
PLoS Med. 2005 Jan;2(1):e17
15696205
J Natl Cancer Inst. 1999 Dec 1;91(23):2032-8
10580029
J Clin Oncol. 2006 Apr 10;24(11):1700-4
16505411
J Natl Cancer Inst. 1999 Jul 21;91(14):1194-210
10413421
N Engl J Med. 2004 May 20;350(21):2129-39
15118073
J Clin Oncol. 2007 Nov 20;25(33):5240-7
18024870
N Engl J Med. 2005 Jun 23;352(25):2589-97
15972865
Int J Cancer. 1994 Nov 15;59(4):494-504
7960219
N Engl J Med. 1990 Aug 30;323(9):561-5
2199829
Carcinogenesis. 2001 Mar;22(3):367-74
11238174
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
15329413
J Clin Oncol. 1999 Feb;17(2):668-75
10080613
Lung Cancer. 1995 Apr;12 Suppl 1:S59-70
7551935
Science. 2004 Jun 4;304(5676):1497-500
15118125
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
N Engl J Med. 1987 Oct 8;317(15):929-35
3041218
Cancer Res. 2004 Dec 15;64(24):8919-23
15604253
J Clin Oncol. 2007 Jun 1;25(16):2248-55
17538169
Nat Rev Cancer. 2007 Oct;7(10):778-90
17882278
Cancer. 2006 May 15;106(10):2200-7
16598760