K-ras oncogene activation in atypical alveolar hyperplasias of the human lung.
Atypical alveolar hyperplasia (AAH) is a potential precursor lesion from which lung adenocarcinomas arise and may be a good target for studying the early events of lung tumorigenesis. A common genetic alteration in lung adenocarcinomas is mutational activation of K-ras. To determine the timing of K-ras activation, we evaluated formalin-fixed and paraffin-embedded tissue samples of 41 AAHs and their paired lung neoplasms from 28 patients for codon 12 point mutations of the K-ras oncogene. K-ras codon 12 mutations were detected using PCR followed by allele-specific oligonucleotide hybridization. Mutations were found in 16 (39%) of the 41 AAHs, 8 (42%) of the 18 adenocarcinomas, and none (0%) of the 5 lung neoplasms that were not adenocarcinomas. Of the 18 patients with both an AAH and a synchronous lung adenocarcinoma, 6 had K-ras mutation in the adenocarcinoma but not in the AAH, 6 had mutations in the AAH but not in the adenocarcinoma, 4 did not harbor mutations in either the AAH or the adenocarcinoma, and 2 had mutations in both their AAH and their synchronous adenocarcinoma. In just 1 of the 18 patients was the same K-ras mutation present in the AAHs and adenocarcinoma of the patient. The detection of independent activating point mutations in a cancer-causing gene points to the neoplastic nature of AAH and suggests that glandular neoplasms of the lung arise from a background of field cancerization.
Westra
W H
WH
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6971, USA.
Baas
I O
IO
Hruban
R H
RH
Askin
F B
FB
Wilson
K
K
Offerhaus
G J
GJ
Slebos
R J
RJ
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D006965:Hyperplasia; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D018631:ras Proteins