title: BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.
abstract: BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis.
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637; Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792. Electronic address: smcgregor@wisc.edu.
authors: Stephanie M
authors: SM
authors: McGregor
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address: james.mcelherne@uchospitals.edu.
authors: James
authors: J
authors: McElherne
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address: aminor@contextualgenomics.com.
authors: Agata
authors: A
authors: Minor
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address: jkramey@bsd.uchicago.edu.
authors: Jennifer
authors: J
authors: Keller-Ramey
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address: rydunning89@gmail.com.
authors: Ryan
authors: R
authors: Dunning
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address: aliya.husain@uchospitals.edu.
authors: Aliya N
authors: AN
authors: Husain
authors: Department of Surgery, Loyola University, Maywood, IL 60153. Electronic address: Wickii.Vigneswaran@lumc.edu.
authors: Wickii
authors: W
authors: Vigneswaran
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address: cfitzpat@bsd.uchicago.edu.
authors: Carrie
authors: C
authors: Fitzpatrick
authors: Department of Pathology, University of Chicago Medicine, Chicago, IL 60637. Electronic address: thomas.krausz@uchospitals.edu.
authors: Thomas
authors: T
authors: Krausz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001706:Biopsy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D008654:Mesothelioma / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D010997:Pleural Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012307:Risk Factors; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis*; D043222:Ubiquitin Thiolesterase / Q000032:analysis*
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1 immunohistochemistry; CDKN2A (p16) FISH; Diagnosis; Malignant pleural mesothelioma; Prognosis