p16INK4A inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos

被引：41

作者：

Andujar, Pascal ^{[2
,3
,4
]}

Wang, Jinhui ^{[5
]}

Descatha, Alexis ^{[6
,7
,8
]}

Galateau-Salle, Francoise ^{[9
,10
]}

Abd-Alsamad, Issam ^{[11
]}

Billon-Galland, Marie-Annick ^{[12
]}

Blons, Helene ^{[13
,14
]}

Clin, Benedicte ^{[9
,15
]}

Danel, Claire ^{[16
,17
]}

Housset, Bruno ^{[2
,3
,4
]}

Laurent-Puig, Pierre ^{[13
,14
]}

Le Pimpec-Barthes, Francoise ^{[1
,18
]}

Letourneux, Marc ^{[9
,15
]}

Monnet, Isabelle ^{[2
]}

Regnard, Jean-Francois ^{[19
]}

Renier, Annie ^{[1
,17
]}

Zucman-Rossi, Jessica ^{[1
,17
]}

Pairon, Jean-Claude ^{[2
,3
,4
]}

Jaurand, Marie-Claude ^{[1
,17
]}

机构：

[1] Fdn Jean Dausset CEPH, INSERM, IFR105, U674, F-75010 Paris, France

[2] Hop Intercommunal Creteil, Serv Pneumol & Pathol Profess, F-94010 Creteil, France

[3] INSERM, Equipe 4, U955, F-94010 Creteil, France

[4] Univ Paris 12, Fac Med, F-94010 Creteil, France

[5] INSERM, E0337, F-94010 Creteil, France

[6] Hop Poincare, GHU Ouest, Unite Pathol Profess Environm & Insert, AP HP, F-92380 Garches, France

[7] INSERM, U687, F-94807 Villejuif, France

[8] Univ Versailles St Quentin Yvelines, Fac Med, F-78280 Paris, Guyancourt, France

[9] INSERM, ERI 3, F-14000 Caen, France

[10] CHU Caen, Serv Anatomopathol, F-14033 Caen, France

[11] Hop Intercommunal Creteil, Serv Anatomopathol, F-94010 Creteil, France

[12] Lab Etud Particules Inhalees, F-75013 Paris, France

[13] INSERM, UMR S775, F-75006 Paris, France

[14] Univ Paris 05, F-75005 Paris, France

[15] CHU Caen, Serv Med Travail & Pathol Profess, F-14033 Caen, France

[16] Hop Europeen Georges Pompidou, GHU Ouest, Serv Anatomopathol, AP HP, F-75015 Paris, France

[17] Univ Paris 07, F-75005 Paris, France

[18] Hop Europeen Georges Pompidou, GHU Ouest, Serv Chirurg Thorac, AP HP, F-75015 Paris, France

[19] Ctr Chirurg Marie Lannelongue, Dept Chirurg Thorac & Vasc, F-92350 Le Plessis Robinson, France

来源：

LUNG CANCER | 2010年 / 67卷 / 01期

关键词：

Lung cancer; Asbestos; Occupation; Tobacco smoking; P16/CDKN2A; INK4A; Deletion; Hypermethylation; ABERRANT PROMOTER METHYLATION; HUMAN-MALIGNANT MESOTHELIOMA; TUMOR-SUPPRESSOR; TOBACCO-SMOKE; PLEURAL MESOTHELIOMAS; HOMOZYGOUS DELETION; GERMLINE MUTATIONS; CLINICAL-FEATURES; FORMER SMOKERS; CPG ISLANDS;

D O I：

10.1016/j.lungcan.2009.03.018

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

引用

页码：23 / 30

页数：8

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[1] A mouse model recapitulating molecular features of human mesothelioma [J].