The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

Our plain-English summary of The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma, by A.D. Singhi, A.M. Krasinskas, H.A. Choudry, et al (Modern Pathology, 2016).

The study

• Authors: A.D. Singhi, A.M. Krasinskas, H.A. Choudry, D.L. Bartlett, J.F. Pingpank, H.J. Zeh, A. Luvison, K. Fuhrer, N. Bahary, R.R. Seethala, S. Dacic
• Journal: Modern Pathology
• Published: 2016;29(1):14-24
• Cited by: 115 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n=25, 29%), hemizygous NF2 loss (n=30, 35%), and/or loss of BAP1 protein expression (n=49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progression-free survival (P<0.02) and poor overall survival (P<0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (P<0.01) and overall survival rate of 18% with a median of 8 months (P<0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

In plain English

This retrospective study examined tumors from 86 patients with malignant peritoneal mesothelioma who had cytoreductive surgery with heated chemotherapy inside the abdomen (CRS with HIPEC) at the University of Pittsburgh Medical Center between 2001 and 2014. The authors checked the tumors for losses of the CDKN2A and NF2 genes and for loss of BAP1 protein. Asbestos exposure was documented in 18 of the 72 patients (25%) whose medical history was available. The authors found no statistically significant link between asbestos exposure and any of these alterations. Homozygous CDKN2A deletions were found in 25 tumors (29%), hemizygous NF2 loss in 30 (35%), and loss of BAP1 protein in 49 (57%). Patients whose tumors had both CDKN2A and NF2 changes had a 2-year progression-free survival rate of 9% (median 6 months) and a 2-year overall survival rate of 18% (median 8 months). This combination remained an independent prognostic factor after adjusting for age, peritoneal cancer index, completeness of cytoreduction and extent of invasion. Loss of BAP1 protein was not associated with outcome. The authors concluded that CDKN2A and NF2 testing may guide treatment decisions, but that further studies are required.

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 linked to patient outcomes. CDKN2A and NF2 were assessed by fluorescence in situ hybridization, and BAP1 protein by immunohistochemistry.
• Who was studied: 86 patients with malignant peritoneal mesothelioma who underwent CRS with HIPEC at the University of Pittsburgh Medical Center, 2001 to 2014. Well-differentiated peritoneal mesotheliomas were excluded. Patients were aged 19 to 83 years, and 60 of 86 (70%) were male.
• Exposure: The study examined tumor alterations, not asbestos, and no fiber types were studied. Asbestos exposure was recorded from patient records. It was documented in 18 of the 72 patients (25%) whose past medical history was available.
• Main results:
  • At least one of the three alterations (homozygous CDKN2A deletion, hemizygous NF2 loss, or absent BAP1 nuclear expression) was found in 68 of 86 tumors (79%).
  • Homozygous CDKN2A deletion was found in 25 tumors (29%).
  • NF2 deletions, all hemizygous, were found in 30 of 86 tumors (35%).
  • Loss of BAP1 nuclear protein expression was found in 49 of 86 tumors (57%).
  • No statistically significant association was found between asbestos exposure and homozygous CDKN2A deletion (P = 0.371) or hemizygous NF2 loss (P = 0.784).
  • No statistically significant association was found between asbestos exposure and BAP1 status (P = 0.783).
  • Among all 86 patients, the 2-year progression-free survival rate was 31% (median 15 months) and the 2-year overall survival rate was 54% (median 29 months).
  • Patients with homozygous CDKN2A deletions had a 2-year progression-free survival rate of 14% (vs 38%, P = 0.013; median 12 months). Their 2-year overall survival rate was 34% (vs 62%, P = 0.026; median 17 months).
  • Patients with hemizygous NF2 loss had a 2-year progression-free survival rate of 18% (vs 38%, P = 0.010; median 10 months). Their 2-year overall survival rate was 33% (vs 66%, P = 0.011; median 21 months).
  • Patients whose tumors had both homozygous CDKN2A deletion and hemizygous NF2 loss (11 tumors) had a 2-year progression-free survival rate of 9% (median 6 months, P = 0.002). Their 2-year overall survival rate was 18% (median 8 months, P = 0.001).
  • In multivariate analysis, combined CDKN2A deletion and NF2 loss was an independent prognostic factor. The hazard ratio was 2.38 (95% CI 1.15 to 4.94, P = 0.019) for progression-free survival and 4.7 (95% CI 1.76 to 9.39, P = 0.001) for overall survival.
  • BAP1 status showed no statistically significant difference in 2-year progression-free survival (P = 0.921) or overall survival (P = 0.780).
  • Loss of BAP1 correlated with older mean patient age (57.0 vs 48.3 years, P = 0.006).
• The authors' conclusion: The authors concluded that CDKN2A and NF2 fluorescence in situ hybridization analysis may guide treatment decisions for patients with malignant peritoneal mesothelioma, although further studies are required. They also suggested that patients with both alterations may not benefit from aggressive CRS and HIPEC, and that this warrants additional studies.
• Limitations the authors state:
  • The study was retrospective, and not all patients were treated the same way.
  • 20% of patients received chemotherapy before surgery.
  • There were few non-epithelioid tumors, including only two sarcomatoid mesotheliomas.

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1, CDKN2A, Peritoneal Mesothelioma, Cytoreductive Surgery, Homozygous Deletion, Overall Survival, Fluorescence In Situ Hybridization (FISH), Immunohistochemistry.

Related studies

• 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)
• Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma — C. Glass, L.M. Sholl, et al. (2020)
• Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens — H.C. Hwang, B.S. Sheffield, et al. (2016)
• 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)
• BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma — S.M. McGregor, J. McElherne, et al. (2017)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)

Browse more research in Modern Pathology, or return to medical research.