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Department of Otolaryngology, Division of Head and Neck Cancer Research [M. S-C., L. W., J. J., D. S.], and Departments of Oncology Biostatistics [S. P.], Pathology [W. H. W.], and Surgery [S. C. Y], Johns Hopkins University School of Medicine, Baltimore, Maryland 21206-2198; Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 [S. A. A.]; and Medical Oncology Department, Hospital Universitari Germans Trias I Pujol, Badalona, 08916 Barcelona, Spain [R. R., M .M.]
The etiology of lung tumors arising in nonsmokers remains unclear.
Although mutations in the K-ras and p53
genes have been reported to be significantly higher in
smoking-related lung carcinomas, in the present study we performed a
more comprehensive analysis in search of additional genetic changes
between lung adenocarcinoma from tobacco- and non-tobacco-exposed
patients. We selected a matched cohort of 18 lifetime nonsmoking and 27
smoking patients diagnosed with primary adenocarcinoma of the lung and
searched for chromosomal alterations in each tumor by testing normal
and tumor tissue with 54 highly polymorphic microsatellite markers
located on 28 different chromosomal arms. Allelic losses or gains at
chromosomal arms 3p (37 versus 6%), 6q (46
versus 12%), 9p (65 versus 22%), 16p
(28 versus 0%), 17p (45
versus 11%), and 19p (58 versus 16%)
were present significantly more often in adenocarcinomas from smokers
than from nonsmokers. Chromosomal arms showing allelic imbalance in
lung tumors from nonsmokers were rare but occurred more often at 19q
(22%), 12p (22%), and 9p (22%). The FAL (fractional allelic loss or
gain) is defined as the percentage of chromosomal arm losses/gains
among the total informative chromosomal arms. Tumors from smokers
harbored higher levels of FAL (13 (48%) of 27 showed FAL 
0.3) compared with the lung tumors from the nonsmoker patients
(2 (11%) of 18 showed FAL 0.3;
P = 0.02; odds ratio,
0.13; 95% confidence interval, 0.01–0.79). Our data
demonstrate that widespread chromosomal abnormalities are frequent in
lung adenocarcinoma from smokers, whereas these abnormalities are
infrequent in such tumors arising in nonsmokers. These observations
support the notion that lung cancers in nonsmokers arise through
genetic alterations distinct from the common events observed in tumors
from smokers.
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