Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre

Our plain-English summary of Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre, by K. Marshall, S. Jackson, J. Jones, et al (Lung Cancer, 2020).

The study

• Authors: K. Marshall, S. Jackson, J. Jones, J. Holme, J. Lyons, E. Barrett, P. Taylor, P. Bishop, C. Hodgson, M. Green, N. Telford, M. Evison
• Journal: Lung Cancer
• Published: 2020;150:195-200
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Detection of homozygous deletion of the p16 gene (CDKN2A) by fluorescence in situ hybridization (FISH) has been investigated as an ancillary technique in the diagnosis of malignant mesothelioma.

Method: This retrospective study reviewed the results of all p16 FISH tests performed at a regional mesothelioma centre from February 2012 to November 2019 in cases of possible mesothelioma to examine the diagnostic utility of this test as well as patients characteristics and survival in p16 FISH positive mesothelioma versus p16 FISH negative mesothelioma.

Results: P16 FISH testing was requested in 216 pathological samples in the study period. The test failure rate was 4% (10/216). Median time from request to result was 10 days (IQR 7-13, range 1-30). The sensitivity, specificity, NPV and PPV were 60 %, 100 %, 39 % and 100 % respectively. There were no false positive results and this genetic aberration was only detected in cases of mesothelioma. The prevalence of p16 FISH positive mesothelioma was higher in cytological specimens compared to histological specimens (75 % vs 58 %, p = 0.03) and lower in women compared to men (33 % vs 66 %, p = 0.003). P16 FISH positive mesothelioma was associated with significantly worse survival (median overall survival 285 vs 339 days, p = 0.0018). This remained significant after adjusting for confounding variables (OR 4.4, 95 %CI 1.84-11.14, p = 0.001).

Conclusions: In this study, 60 % of mesotheliomas harbour a homozygous deletion of CDKN2A and can be accurately, reliably and efficiently identified by p16 FISH testing. This test can be embedded within routine practice in mesothelioma pathways to enhance diagnostic accuracy.

Copyright © 2020. Published by Elsevier B.V.

In plain English

This retrospective study at a regional mesothelioma centre in Manchester, UK, reviewed every p16 FISH test requested between February 2012 and November 2019. The test looks for loss of both copies of the CDKN2A gene. It was used on samples where mesothelioma was suspected but could not be confirmed. The study did not examine asbestos exposure. Of 216 samples, 206 (96%) gave a result. The final diagnosis was mesothelioma in 164 samples, benign pleuritis in 39 and primary lung cancer in 3. The test was positive in 99 of the 164 mesothelioma samples (sensitivity 60%). It was never positive in benign pleuritis or lung cancer (specificity 100%). Sensitivity was 75% in fluid samples and 56% in tissue samples. Among patients with mesothelioma, women tested positive less often than men. Median survival was 285 days with a positive test and 339 days with a negative test. The authors concluded that about 60% of mesotheliomas carry this deletion. They noted the retrospective design and wide confidence intervals in the survival analysis.

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: Retrospective review of all p16 FISH tests performed for suspected mesothelioma at one centre (described by the authors as a retrospective service evaluation)
• Who was studied: 216 pathological samples from Manchester University NHS Foundation Trust, a regional mesothelioma centre for North West England, February 2012 to November 2019. All were samples with suspected mesothelioma but no definitive diagnosis. The 206 samples with a successful test came from 205 patients (mean age 71, 82% male).
• Exposure: Asbestos exposure was not studied. The study evaluated a laboratory test (p16 FISH) for homozygous deletion of the CDKN2A gene. A test was reported positive when 20% or more of cells showed the deletion.
• Main results:
  • 206 of 216 samples (96%) were successfully tested. In 3 there were too few mesothelial cells and in 7 the test failed. Median time from request to result was 10 days.
  • Final diagnosis among the 206 tested samples: mesothelioma in 164, primary lung cancer in 3, benign pleuritis in 39.
  • The test was positive in 99 of 164 mesothelioma samples (sensitivity 60%).
  • There were no false positive results (specificity 100%, positive predictive value 100%). The test was negative in all 39 benign pleuritis cases and all 3 lung cancer cases.
  • 65 samples tested negative but were mesothelioma (negative predictive value 39%).
  • Sensitivity was 75% (30 of 40 mesotheliomas) in cytology (fluid) samples and 56% (69 of 124) in histology (tissue) samples. The difference was reported as significant (p = 0.03).
  • The highest proportion of cells with the deletion in any benign pleuritis case was 13%, seen in two cases. Lowering the cut-off to 13.5% would have given sensitivity of 65% with no false positives.
  • Among patients with mesothelioma, females made up 9 of 99 test-positive patients versus 18 of 64 test-negative patients (p = 0.003 in Table 3).
  • Among patients with mesothelioma, there was no statistically significant difference in age, performance status, tumour sub-type or treatment between test-positive and test-negative patients.
  • Median survival was 285 days for patients with p16 FISH positive mesothelioma and 339 days for those with p16 FISH negative mesothelioma (p = 0.0018).
  • A positive test remained a statistically significant predictor of death after adjusting for age, performance status, mesothelioma sub-type and treatment (OR 4.4, 95% CI 1.84 to 11.14; p = 0.001 per the abstract).
• The authors' conclusion: The authors concluded that the deletion seems to occur in about 60% of mesotheliomas. In their view, testing for it offers a significant chance of a diagnosis when there is pathological suspicion but no definitive diagnosis. They described the lower prevalence in females, the higher prevalence in cytology samples and the association with worse survival as findings worthy of further exploration.
• Limitations the authors state:
  • The retrospective design inherently risks bias.
  • Clinicians were not blinded to the test result, which could have influenced the final diagnosis. The authors concluded this influence was unlikely.
  • The optimal cut-off was determined retrospectively and risks overfitting.
  • The confidence intervals for the survival estimate were wide, possibly because of the sample size and low survival rate.
  • The negative predictive value depends on each institution's working practices and on which cases are tested.

Topics

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

Medical terms in this study, explained in our Lexicon: Homozygous Deletion, CDKN2A, Mesothelioma, Fluorescence In Situ Hybridization (FISH), Median Overall Survival, Confounding.

Related studies

• Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats — Y. Okazaki, N. Misawa, et al. (2020)
• Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: a case report — K. Minami, N. Jimbo, et al. (2020)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival — A.M. Krasinskas, D.L. Bartlett, 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)
• Homozygous deletion of p16INK4a and tobacco carcinogen exposure in nonsmall cell lung cancer — K.S. Kraunz, H.H. Nelson, et al. (2006)

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