Alterations of the p16(INK4) locus in human malignant mesothelial tumors

Our plain-English summary of Alterations of the p16(INK4) locus in human malignant mesothelial tumors, by T. Hirao, R. Bueno, C.J. Chen, et al (Carcinogenesis, 2002).

The study

• Authors: T. Hirao, R. Bueno, C.J. Chen, G.J. Gordon, E. Heilig, K.T. Kelsey
• Journal: Carcinogenesis
• Published: 2002;23(7):1127-30
• Cited by: 97 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The INK4 locus has two promoters and encodes two unique proteins that share exons in different reading frames, p16(INK4a) and p14(ARF). The p16(INK4a) protein, by inhibiting cyclin-dependent kinase, down regulates Rb-E2F and leads to cell cycle arrest in the G1 phase. The p14(ARF) protein interacts with the MDM2 protein, neutralizing MDM2-mediated degradation of p53. Since p53/Rb genes are not altered in malignant mesothelioma, additional components of these pathways, such as p16(INK4a) and p14(ARF), are candidates for inactivation. In this study, we have examined p16(INK4a) and p14(ARF) alterations (gene deletion, mutation and promoter methylation) in 45 primary malignant mesothelioma specimens. Fourteen patients (31%) had altered p16; four tumors had a methylated promoter region (8.8%), 10 tumors showed p16 to be deleted (22.2%), and one tumor had a point mutation (2%). We did not find any instances of methylation in the p14(ARF) 5'-CpG island. Patients whose tumors had p16 deletion were significantly younger than those with methylation, and, in the patients whose lungs were studied for the prevalence of asbestos fibers, those with any p16 alteration had lower fiber counts than those with no p16 alteration. Hence, p16 gene alteration is relatively common in malignant mesothelioma, while p14(ARF) is rarely, if ever, methylated. Our data suggest that deletion of p16 occurs in a relatively susceptible subset of the population.

In plain English

This laboratory study examined surgically removed tumors from 45 malignant mesothelioma patients at Brigham and Women’s Hospital for changes in the p16 and p14 genes. Asbestos exposure was judged from medical and occupational history or lung fiber counts; 28 patients were classed as heavily exposed. Fourteen of 45 patients (31%) had an altered p16 gene. Ten tumors had a deletion, 4 had methylation (a chemical change that can silence a gene) and 1 had a point mutation. One tumor was listed with both deletion and methylation. No p14 methylation was found. Patients with p16 deletion were significantly younger (mean 50.8 years) than those with methylation (mean 60.3 years). Among patients with lung fiber counts, those with p16 deletion or methylation had lower counts than those without that change. However, the authors reported no significant association between asbestos exposure level and p16 alteration. Patients with deletion had smoked fewer pack-years, which the authors considered most likely due to confounding. The authors concluded that p16 alteration is relatively common in mesothelioma, and suggested that deletion occurs in a relatively susceptible subset of the population.

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 study of genetic changes (gene deletion, point mutation, promoter methylation and gene activity) in surgically removed tumor specimens
• Who was studied: 45 malignant mesothelioma tumor specimens from patients who had surgery at Brigham and Women’s Hospital, Boston: 34 men and 11 women. Study dates are not given.
• Exposure: Asbestos exposure was assessed from medical and occupational history, or by counting asbestos fibers in tissue (34 cases). Exposure was called heavy if fiber counts were above 200 and light if non-occupational. 28 patients (62%) had a known history of heavy exposure. Fiber types are not named. Tobacco smoking was also recorded: 32 patients (71%) were smokers.
• Main results:
  • 14 of the 45 patients (31%) had an altered p16 gene.
  • Among the 45 tumors, 4 had p16 methylation (8.8%), 10 had p16 deleted (22.2%) and 1 had a point mutation (2%).
  • The article's Table II lists one tumor (a 57-year-old man) with both deletion and methylation. This is why the categories add up to more than 14.
  • No methylation was found in the promoter region of the p14 gene.
  • Patients whose tumors had p16 deletion were significantly younger (mean 50.8 years, n = 10) than those whose tumors had p16 methylation (mean 60.3 years, n = 4). The reported P value was 0.04; the comparison sign was lost in scanning.
  • p16 deletion was found in 7 of 28 heavily exposed patients (25%) and in 3 of 16 patients with light or unknown exposure (19%).
  • Among patients whose lungs were studied for asbestos fibers, fiber counts were lower in those with p16 alterations than in those without (units not stated in the table). With p16 deletion: median 642 (mean 1323.6). Without deletion: median 2919 (mean 5139.9). With p16 methylation: median 425 (mean 425.0). Without methylation: median 2594 (mean 4603.67). Fiber count information was missing for some cases in each group.
  • Overall, the authors observed no significant association between level of asbestos exposure and p16 alteration. They described only a suggestion that alteration occurred in patients with lighter exposure.
  • Mean pack-years smoked was 32.8 in patients without p16 deletion and 10.1 in patients with deletion. The text gives P 0.01 for this; the Table IV footnote gives 0.006. Medians were 26.0 and 5.0 pack-years, and that difference was also reported as significant (P 0.04).
  • Of the 4 patients with p16 methylation, half had a known heavy asbestos exposure history and all were smokers.
• The authors' conclusion: The authors concluded that p16 alteration is relatively common in malignant mesothelioma, while p14 is rarely, if ever, methylated. They suggested that p16 deletion occurs in a relatively susceptible subset of the population.
• Limitations the authors state:
  • The authors state that relative asbestos exposure is difficult to evaluate accurately, whether by questionnaire or by fiber counting.
  • Surgical samples contain normal tissue, which makes gene deletions harder to detect.
  • Only a small number of tumors had p16 methylation.
  • The authors considered the link between p16 deletion and smoking most likely to reflect confounding by another factor rather than a causal association.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma.

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