Ne. Mills et al., DETECTION OF K-RAS ONCOGENE MUTATIONS IN BRONCHOALVEOLAR LAVAGE FLUIDFOR LUNG-CANCER DIAGNOSIS, Journal of the National Cancer Institute, 87(14), 1995, pp. 1056-1060
Background: Lung cancer is the leading cause of cancer deaths in the U
nited States, A long-standing goal of cancer researchers has been to d
evelop tests that would facilitate earlier diagnosis and treatment of
lung cancer and thereby decrease mortality from this disease, Because
cancer results from the accumulation of a variety of genetic events (e
.g., mutations, rearrangements, and deletions) in genes controlling ce
ll growth and differentiation, these changes might serve as diagnostic
ally useful molecular markers, Activation of the K-ras oncogene by poi
nt mutations in codon 12, which occurs in many cases of lung adenocarc
inoma, may serve as one such clinically useful molecular marker, For d
etection of K-ras point mutations in bronchoalveolar lavage fluid, in
which small numbers of malignant cells are mixed with a population of
predominantly genetically normal cells, the sensitivity of commonly us
ed assays for ras mutations risks false-negative results, Purpose: By
applying a highly sensitive assay, we investigated whether detection o
f K-ras codon 12 mutations in samples of bronchoalveolar lavage fluid
could be clinically useful in diagnosing lung cancer, Methods: We deve
loped a highly sensitive assay for detecting K-ras codon 12 mutations
based on an enriched polymerase chain reaction (PCR) technique, This t
echnique was applied to 87 specimens of bronchoalveolar lavage fluid s
pecimens that were obtained from 86 patients, and associated tumor bio
psy specimens obtained from 35 of these patients who underwent diagnos
tic bronchoscopy for clinically suspected lung cancer, Lavage fluid sp
ecimens were also obtained from nine patients undergoing nondiagnostic
bronchoscopy, Statistical comparisons mere performed by using the two
-tailed Fisher's exact test, Results: Of 52 patients with confirmed lu
ng cancer, samples of bronchoalveolar lavage fluid from 16 patients co
ntained K-ras codon 12 mutations, including 14 (56%) of 25 patients wi
th lung adenocarcinomas, one (33%) of three with bronchoalveolar carci
nomas, one (20%) of five with large-cell carcinomas, and none of the 1
4 with squamous cell carcinomas, Mutations were detected in four addit
ional cases in which cancer was suspected but had patients all yielded
the identical K-ras codon 12 genotype found in the corresponding samp
les of bronchoalveolar lavage fluid, No mutation was found in any samp
le from 30 patients with diagnoses other than non-small-cell lung canc
er, Thus, for those cases in which tissue was available and tested, th
e sensitivity and specificity of detecting K-ras mutations in bronchoa
lveolar lavage fluid for diagnosing Kras mutation-positive lung cancer
were both 100%, For nine patients, K-ras mutations were detected in b
ronchoalveolar lavage fluid obtained during otherwise nondiagnostic br
onchoscopies, Conclusions: Our data demonstrate that sensitive detecti
on of K-ras codon 12 mutations can serve as an important adjunct to cy
tology in the diagnosis of lung cancer, Implications: Detection of the
se mutations could lead to earlier cancer diagnosis and less need for
invasive diagnostic procedures.