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

Our plain-English summary of p16INK4A inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos, by P. Andujar, J. Wang, A. Descatha, et al (Lung Cancer, 2010).

The study

• Authors: P. Andujar, J. Wang, A. Descatha, F. Galateau-Sallé, I. Abd-Alsamad, M.A. Billon-Galland, H. Blons, B. Clin, C. Danel, B. Housset, P. Laurent-Puig, F. Le Pimpec-Barthes, M. Letourneux, I. Monnet, J.F. Régnard, A. Renier, J. Zucman-Rossi, J.C. Pairon, M.C. Jaurand
• Journal: Lung Cancer
• Published: 2010;67(1):23-30
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This French laboratory study examined how a tumor-suppressor gene, P16/CDKN2A, was switched off in tumors from 75 patients operated on for non-small-cell lung cancer at four hospitals between 1994 and 1999. Thirty-four were classed as asbestos-exposed: a questionnaire showed definite occupational exposure for over 10 years, their lung tissue held over 1000 asbestos bodies per gram of dry tissue, or both. The other 41 were classed as unexposed. The article does not name fiber types. Loss of the gene's protein, and gene changes overall, were not significantly different between the groups. The type of change did differ. Deletion of one or both gene copies was found in 17 exposed cases (50.0%) and 10 unexposed cases (24.4%), a significant difference after adjusting for age and smoking. A chemical silencing called promoter hypermethylation was found in 8 exposed (23.5%) and 20 unexposed (48.8%) cases. It was significantly more frequent in smokers of over 40 pack-years than in smokers below 40 pack-years. The authors concluded that deletions were more frequent in asbestos-exposed cases, suggesting a possible link with asbestos fibers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (molecular) comparison of tumor tissue from consecutive surgically treated lung cancer patients, asbestos-exposed versus unexposed
• Who was studied: 75 patients with primary non-small-cell lung cancer (34 asbestos-exposed, 41 unexposed) who had surgery at four hospitals in Créteil, Paris, Caen and Plessis-Robinson, France, from January 1994 through June 1999
• Exposure: Occupational asbestos exposure, defined as definite occupational exposure for more than 10 years on a face-to-face questionnaire and/or more than 1000 asbestos bodies per gram of dry lung tissue. Median asbestos body counts were 1446 (range 0 to 21200) in the exposed group and 58 (range 0 to 484) in the unexposed group. Fiber types were not named.
• Main results:
  • Lack of p16INK4A protein expression was found in 24 (70.6%) asbestos-exposed and 27 (65.8%) unexposed cases. The difference was not statistically significant.
  • P16/CDKN2A gene alterations of any kind were found in 79.4% of asbestos-exposed and 68.3% of unexposed cases. The difference was not statistically significant.
  • Promoter hypermethylation was found in 8 asbestos-exposed patients (23.5%) and 20 unexposed cases (48.8%), P = 0.0244
  • After adjustment for age and cumulative tobacco use, and excluding six never smokers, hypermethylation was found in 8 (24.2%) asbestos-exposed and 18 (48.7%) unexposed cases. The difference remained statistically significant (P = 0.0079; odds ratio 4.43, 95% confidence interval 1.48 to 13.31).
  • Heavy smokers (more than 40 pack-years) had significantly more promoter hypermethylation than smokers of less than 40 pack-years, with never smokers excluded (P = 0.0295; odds ratio 3.37, 95% confidence interval 1.13 to 10.06, after adjustment for age and asbestos exposure)
  • After adjustment for age and cumulative tobacco use, homozygous deletion and loss of heterozygosity were significantly more frequent in asbestos-exposed cases (n = 17, 50.0%) than in unexposed cases (n = 10, 24.4%) (P = 0.0172; odds ratio 3.58, 95% confidence interval 1.25 to 10.23)
  • FISH was done on 19 samples (13 exposed, 6 unexposed). It found homozygous deletions in 2 exposed and 2 unexposed subjects, and loss of heterozygosity in 11 exposed and 4 unexposed subjects.
  • Deletion was not significantly different between heavy smokers and other subjects (P = 0.0754; odds ratio 2.59, 95% confidence interval 0.91 to 7.40)
  • Five point mutations (6.7%) were found: two in asbestos-exposed cases and three in unexposed cases, all in former or current smokers
• The authors' conclusion: The authors concluded that, although the overall frequency of P16/CDKN2A alterations was similar in the two groups, deletions were significantly more frequent in asbestos-exposed cases. Because this pattern is also found in mesothelioma, they suggested a possible relationship with an effect of asbestos fibers.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, CDKN2A, Tumor Suppressor Gene, Homozygous Deletion, Asbestos Exposure, Habit, Asbestos Bodies, Malignant Mesothelioma.

Related studies

• Homozygous deletion of p16INK4a and tobacco carcinogen exposure in nonsmall cell lung cancer — K.S. Kraunz, H.H. Nelson, et al. (2006)
• Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma — P. Andujar, J.C. Pairon, et al. (2013)
• Loss of heterozygosity of chromosome 3p21 is associated with mutant TP53 and better patient survival in non-small-cell lung cancer — C.J. Marsit, M. Hasegawa, et al. (2004)
• Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer — D.H. Kim, H.H. Nelson, et al. (2001)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)

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