p16INK4A inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos.
Epidemiological studies have shown that asbestos fibers constitute the major occupational risk factor and that asbestos acts synergistically with tobacco smoking to induce lung cancer. Although some somatic gene alterations in lung cancer have been linked to tobacco smoke, few data are available on the role of asbestos fibers. P16/CDKN2A is an important tumor suppressor gene that is frequently altered in lung cancer via promoter 5'-CpG island hypermethylation and homozygous deletion, and rarely via point mutation. Many studies suggest that tobacco smoking produces P16/CDKN2A promoter hypermethylation in lung cancer, but the status of this gene in relation to asbestos exposure has yet to be determined. The purpose of this study was to investigate the mechanism of P16/CDKN2A alterations in lung cancer in asbestos-exposed patients. P16/CDKN2A gene status was studied in 75 human non-small-cell lung cancer (NSCLC) cases with well-defined smoking habits, and detailed assessment of asbestos exposure, based on occupational questionnaire and determination of asbestos bodies in lung tissue. The results of this study confirm published data on the effect of tobacco smoke on P16/CDKN2A gene alterations, characterized by significantly higher P16/CDKN2A promoter hypermethylation in heavy smokers (more than 40 pack-years (P-Y)) than in smokers of less than 40 P-Y. These results also demonstrate a higher incidence of loss of heterozygosity and homozygous deletion in asbestos-exposed cases, after adjustment for age and cumulative tobacco consumption, than in unexposed cases (P=0.0062). This study suggests that P16/CDKN2A gene inactivation in asbestos-exposed NSCLC cases mainly occurs via deletion, a feature also found in malignant mesothelioma, a tumor independent of tobacco smoking but associated with asbestos exposure, suggesting a possible relationship with an effect of asbestos fibers.
Andujar
Pascal
P
Hôpital Intercommunal de Créteil, Service de Pneumologie et de Pathologie Professionnelle, Créteil F-94010, France.
Wang
Jinhui
J
Descatha
Alexis
A
Galateau-Sallé
Françoise
F
Abd-Alsamad
Issam
I
Billon-Galland
Marie-Annick
MA
Blons
Hélène
H
Clin
Bénédicte
B
Danel
Claire
C
Housset
Bruno
B
Laurent-Puig
Pierre
P
Le Pimpec-Barthes
Françoise
F
Letourneux
Marc
M
Monnet
Isabelle
I
Régnard
Jean-François
JF
Renier
Annie
A
Zucman-Rossi
Jessica
J
Pairon
Jean-Claude
JC
Jaurand
Marie-Claude
MC
D000368:Aged; D001194:Asbestos / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012907:Smoking
D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D001194:Asbestos