CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

Our plain-English summary of CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival, by A.M. Krasinskas, D.L. Bartlett, K. Cieply, et al (Modern Pathology, 2010).

The study

• Authors: A.M. Krasinskas, D.L. Bartlett, K. Cieply, S. Dacic
• Journal: Modern Pathology
• Published: 2010;23(4):531-8
• Cited by: 94 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases. MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of CDKN2A deleted cases. This study examines the genetic alterations in peritoneal mesotheliomas, which may have a different pathogenesis than their pleural counterparts. Twenty-six cases of peritoneal mesotheliomas in a triplicate tissue microarray were studied. Dual-color fluorescence in situ hybridization was performed with CDKN2A and MTAP locus-specific probes. Nine of 26 (35%) peritoneal mesotheliomas had homozygous deletion of CDKN2A; MTAP was co-deleted in every case. All cases with CDKN2A deletions had loss of p16 protein expression; five cases had loss of p16 protein without evidence of CDKN2A deletions. All patients with CDKN2A deletions were men (P, NS) and were significantly older (mean, 63 years) than the patients with no deletions (mean, 52 years) (P=0.033, t-test). An association with asbestos exposure could not be proved in this study. Similar to pleural mesotheliomas, patients with CDKN2A deletions and loss of p16 protein expression had worse overall and disease-specific survival (P=0.010 and 0.006, respectively; Kaplan-Meier log rank). Detection of CDKN2A-MTAP co-deletion in peritoneal mesotheliomas, coupled with a p16 immunohistochemical stain as an inexpensive screening tool, can help identify those patients who may have an unfavorable outcome after aggressive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and those who may respond to targeted therapy of the MTAP pathway.

In plain English

This study examined archived tumor tissue from 26 patients with malignant peritoneal mesothelioma (mesothelioma of the abdominal lining). All had cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) at the University of Pittsburgh Medical Center between 2001 and 2007. The researchers tested the tumors for deletions of two neighboring genes, CDKN2A and MTAP, and for p16 protein loss. Nine of 26 tumors (35%) had CDKN2A deletions; MTAP was deleted in the same nine. All nine were men, a difference that was not statistically significant. The text reports they were older on average than those without deletions (63 versus 52 years), though Table 1 shows the reverse (51 versus 63). Seven patients, all men, had known asbestos exposure. Four of the seven had the deletions, which was not statistically significant. All nine tumors with deletions had lost p16, as had 5 of 17 without deletions. Patients with deletions had worse overall and disease-specific survival. The authors concluded that the deletions strongly predicted survival. They noted that the small cohort and difficulty determining exposure history limited their asbestos assessment.

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 study of archived tumor tissue (tissue microarray) using gene testing by fluorescence in situ hybridization (FISH) and protein staining (immunohistochemistry), with survival analysis
• Who was studied: 26 patients with malignant peritoneal mesothelioma who underwent cytoreductive surgery with HIPEC at the University of Pittsburgh Medical Center from 2001 to 2007 and had archived tissue available. 22 were male. Mean age at surgery was 56 years (range 23 to 76). 25 tumors were epithelioid and 1 was sarcomatoid.
• Exposure: The main factors studied were the tumor gene deletions (CDKN2A, MTAP) and p16 protein loss, not asbestos. Seven patients had a known history of asbestos exposure. No fiber type, product, job or dose is given.
• Main results:
  • Homozygous deletion of CDKN2A was found in 9 of 26 tumors (35%). MTAP was deleted in the same nine tumors, a 100% correlation.
  • According to the text, the 9 patients with deletions were older on average (mean 63 years) than the patients without deletions (mean 52 years), with P = 0.033. Table 1 instead lists a mean age of 51 years for the deletion group and 63 years for the group without deletions. All nine with deletions were male, which was not statistically significant.
  • Asbestos exposure did not correlate with the deletions: 4 of the 7 men with asbestos exposure had CDKN2A-MTAP deletions, which was not statistically significant.
  • 14 tumors (54%) showed loss of p16 protein. All 9 tumors with deletions lost p16, compared with 5 of the 17 tumors without deletions (text gives P = 0.0007).
  • Patients with deletions had worse overall survival (P = 0.010) and worse disease-specific survival (P = 0.006), measured both from surgery and from initial diagnosis. All nine died with disease.
  • Patients with p16 protein loss also had worse overall survival, from diagnosis (P = 0.010) and from surgery (P = 0.044). They had worse disease-specific survival from diagnosis (P = 0.038), with a trend from surgery (P = 0.066).
  • The amount of disease left after surgery did not correlate with overall or disease-specific survival in this study.
• The authors' conclusion: The authors concluded that detecting CDKN2A deletions by FISH is a very strong predictor of survival in peritoneal mesothelioma, and that p16 loss also predicts poor outcome. They suggested p16 staining could be a first-line test, with loss confirmed by FISH. They wrote that there did not appear to be an association between asbestos exposure and CDKN2A deletions.
• Limitations the authors state:
  • The small cohort and the difficulty of determining exposure history in a retrospective study limited the assessment of asbestos exposure.
  • Because there were few women in the cohort, the finding that all deletions occurred in men did not reach statistical significance.
  • The authors did not test for methylation of the CDKN2A gene, which might explain p16 loss without deletion.

Topics

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

Medical terms in this study, explained in our Lexicon: CDKN2A, MTAP, Peritoneal Mesothelioma, Homozygous Deletion, Pleural Mesothelioma, Fluorescence In Situ Hybridization (FISH), Asbestos Exposure, Cytoreductive Surgery.

Related studies

• Correlation of methylthioadenosine phosphorylase (MTAP) protein expression with MTAP and CDKN2A copy number in malignant pleural mesothelioma — D.B. Chapel, A.M. Dubuc, et al. (2021)
• Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry — T. Hida, M. Hamasaki, et al. (2017)
• 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)
• MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma — D.B. Chapel, J.J. Schulte, et al. (2020)
• Evaluation of MTAP immunohistochemistry loss of expression in ovarian serous borderline tumors as a potential marker for prognosis and progression — N. Nilforoushan, N.A. Moatamed (2020)
• The value of BRCA-1-associated protein 1 expression and cyclin-dependent kinase inhibitor 2A deletion to distinguish peritoneal malignant mesothelioma from peritoneal location of carcinoma in effusion cytology specimens — W. Althakfi, S. Gazzo, et al. (2020)

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