Loss of function of p16 gene and prognosis of pulmonary adenocarcinoma.
BACKGROUND
Stepwise progression of peripheral-type lung adenocarcinoma was characterized morphologically and was related to prognosis. Expression of the tumor suppressor gene p16 in pulmonary adenocarcinoma decreased, mainly as a result of aberrant methylation of the CpG islands of the promoter region.


METHODS
Aberrant methylation status of the p16 promoter region, the expression of its product, and loss of heterozygosity (LOH) on 9p21 were examined in surgically resected lung specimens from 57 patients (28 males and 29 females) with peripheral-type lung adenocarcinoma measuring </= 2 cm in diameter.


RESULTS
Aberrant methylation of the p16 promoter region, negative p16 protein expression, and LOH of the 9p21 region were detected in 40.4%, 50.9%, and 40.4% of tumor samples, respectively. The alterations of the p16 gene were associated with poor prognosis, and in particular the prognosis of patients with aberrant p16 methylation was significantly worse than that of patients without aberrant methylation. These alterations also were associated with morphologic classification into bronchioloalveolar carcinoma (BAC) and non-BAC adenocarcinoma. Both aberrant methylation and LOH of 9p21 were associated with negative protein expression, but the former was correlated more closely with loss of function than was the latter. Cases with both alterations were completely negative for expression of the p16 gene product.


CONCLUSIONS
Aberrant methylation of the promoter region of the p16 gene and loss of expression of its product were in accord with the multistep progression of peripheral-type lung adenocarcinoma, and these alterations were associated closely with poor prognosis of the disease.
Tanaka
Ryota
R
Department of Surgery II, Institute of Medical Sciences, Kyorin University, Tokyo, Japan.
Wang
Daye
D
Morishita
Yukio
Y
Inadome
Yukinori
Y
Minami
Yuko
Y
Iijima
Tatsuo
T
Fukai
Shimao
S
Goya
Tomoyuki
T
Noguchi
Masayuki
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D002899:Chromosomes, Human, Pair 9; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012307:Risk Factors