Homozygous deletion of p16INK4a and tobacco carcinogen exposure in nonsmall cell lung cancer

Our plain-English summary of Homozygous deletion of p16INK4a and tobacco carcinogen exposure in nonsmall cell lung cancer, by K.S. Kraunz, H.H. Nelson, M. Lemos, et al (International Journal of Cancer, 2006).

The study

• Authors: K.S. Kraunz, H.H. Nelson, M. Lemos, J.J. Godleski, J.K. Wiencke, K.T. Kelsey
• Journal: International Journal of Cancer
• Published: 2006;118(6):1364-9
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Inactivation of p16(INK4a) in the Rb pathway is among the most common somatic alterations observed in nonsmall cell lung cancers (NSCLCs). While epigenetic inactivation of the p16(INK4a) gene promoter has been shown to be associated with increased tobacco carcinogen exposure, little investigation of any similar association of homozygous deletion or mutation of p16(INK4a) and tobacco use has been completed. In 177 consecutive NSCLCs, we examined the determinants of p16(INK4a) homozygous deletion and mutation, including the pattern of tobacco smoking and asbestos exposure. We observed that p16(INK4a) homozygous deletion occurred at a higher frequency in never smokers as compared to former and current smokers (p = 0.01). This observation suggested that tumors from these patients might be more prone to DNA deletion events; consistent with this, epigenetic silencing of the DNA double-strand break repair genes FancF and BRCA1 was also associated with homozygous deletion of p16(INK4a)(p = 0.002 and p = 0.06, respectively). Finally, mutation of p16(INK4a) was rare and only occurred in patients who were smokers. Hence, the character of somatic alteration in the Rb pathway (deletion, mutation or methylation silencing) in NSCLC is associated with the pattern of tobacco exposure, suggesting that susceptibility to lung cancer is, at least in part, mediated by the biological mechanism that selects for the character of the induced somatic lesion.

In plain English

This study examined 177 consecutive non-small cell lung cancers removed at Massachusetts General Hospital from November 1992 to January 1996. Smoking history and occupational asbestos exposure came from an interviewer-administered questionnaire. The authors tested tumors for loss of both copies (homozygous deletion) of the p16INK4a gene and for mutations in it. Deletion was found in 34% (59/177). It was more frequent in never smokers than in former and current smokers; compared with current smokers, never smokers had an adjusted odds ratio of 2.6 (95% CI 1.1–6.2). In squamous cell carcinomas, deletion was also associated with methylation of the DNA repair gene FancF (p = 0.002). Among adenocarcinomas, deletion was more frequent in asbestos-exposed than unexposed patients (odds ratio 3.2, 95% CI 0.8–13.2). The authors noted the small sample size limited this analysis. Mutations were rare, 2% (4/172). These occurred only in ever smokers who had smoked longer than the median of 39 years, not a statistically significant pattern. The authors concluded that deletion likely reflects an intrinsic sensitivity. Radon, arsenic and environmental tobacco smoke were not measured.

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: case series: laboratory analysis of tumor DNA and protein, combined with questionnaire data on smoking and asbestos exposure
• Who was studied: 177 consecutive primary non-small cell lung cancers from patients who had surgery at Massachusetts General Hospital, November 1992 to January 1996
• Exposure: tobacco smoking (smoking status, years smoked, packs per day) and occupational exposure to asbestos, from an interviewer-administered questionnaire; no fiber types reported
• Main results:
  • Homozygous deletion of p16INK4a was found in 34% of tumors (59/177)
  • Deletion was more frequent in never smokers than in former and current smokers; in Table II, never smokers compared with current smokers (the reference group) had OR 2.6 (95% CI 1.1–6.2), adjusted for age, gender and histology
  • In adenocarcinomas, deletion was more frequent in never smokers than in current smokers (OR 2.7, 95% CI 1.1–6.5)
  • In squamous cell carcinomas (no never smokers), deletion was more frequent in former than in current smokers (OR 1.9, 95% CI 1.0–3.5)
  • There was no clear association of deletion with number of years smoked
  • In squamous cell carcinomas, deletion was associated with FancF methylation (p = 0.002)
  • A borderline significant association was found between deletion and BRCA1 methylation (p = 0.06; shown in adenocarcinomas in Figure 2)
  • In adenocarcinomas, deletion was more frequent in asbestos-exposed than unexposed patients (OR 3.2, 95% CI 0.8–13.2)
  • p16INK4a mutation was found in 2% of tumors (4/172)
  • Mutations occurred only in ever smokers who smoked longer than the median of 39 years; not statistically significant
• The authors' conclusion: The authors concluded that deletion of p16INK4a likely occurs as a result of an intrinsic sensitivity, and that the type of alteration is linked to the pattern of exposure
• Limitations the authors state:
  • The asbestos analysis was limited by small sample size
  • The BRCA1 analysis was limited by small numbers
  • Other lung cancer risk factors were not measured
  • Protein staining was limited by the number of slides available (126 tumors stained)

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: Homozygous Deletion, Lung Cancer, Asbestos Exposure.

Related studies

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• 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)
• Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma — M. Hamasaki, S. Matsumoto, et al. (2016)
• Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre — K. Marshall, S. Jackson, et al. (2020)
• Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats — Y. Okazaki, N. Misawa, et al. (2020)

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