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Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma

Abstract

BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) by a hybrid-capture next-generation sequencing (NGS) panel including complete coverage of coding and splicing regions for BAP1, CDKN2A/MTAP, NF2, and TP53 and correlated molecular findings with diagnostic immunostains for BAP1, MTAP, Merlin, and p53, respectively. Fifty-seven reactive mesothelial proliferations served as benign comparators. Loss of BAP1, MTAP, and Merlin protein expression were, respectively, 54%, 46%, and 52% sensitive and 100% specific for mesothelioma. Two-marker immunopanels of BAP1 + MTAP, BAP1 + Merlin, and MTAP + Merlin were 79%, 85%, and 71% sensitive for mesothelioma, while a three-marker immunopanel of BAP1 + MTAP + Merlin was 90% sensitive. Diffuse (mutant-pattern) p53 immunostaining was seen in only 6 (7%) tumors but represented the only immunohistochemical abnormality in 2 cases. Null-pattern p53 was not specific for malignancy. An immunopanel of BAP1 + MTAP + Merlin + p53 was 93% sensitive for mesothelioma, and panel NGS detected a pathogenic alteration in BAP1, MTAP, NF2, and/or TP53 in 95%. Together, 83 (99%) of 84 tumors showed a diagnostic alteration by either immunohistochemistry or panel NGS. Adding Merlin to the standard BAP1 + MTAP immunopanel increases sensitivity for mesothelioma without sacrificing specificity. p53 immunohistochemistry and panel NGS with complete coverage of BAP1, CDKN2A/MTAP, TP53, and NF2 may be useful in diagnostically challenging cases.

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Fig. 1: Summary of immunohistochemical and molecular findings.
Fig. 2: BAP1 and MTAP.
Fig. 3: p53.
Fig. 4: Merlin.
Fig. 5: Proposed diagnostic algorithm.

Data availability

Sequencing data from this study is publicly available through the AACR Genie database. Other datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Mark Buchanan (histotechnologist), Liping Yuan MD, (laboratory manager), and the Brigham and Women’s Hospital Immunohistochemistry Laboratory (under the supervision of Mei Zheng) for their help with this study. This was work supported by grants from the National Cancer Institute (grant number RO1 CA120528-12) and the United States Department of Defense (grant number W81XWH-17-1-0373). Dr. Chapel’s work is supported by the Ovarian Cancer Research Alliance [Ann Schreiber Mentored Investigator Award; grant number 650320].

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D.B.C., J.L.H., and L.M.S. performed study concept and design; D.B.C. and L.M.S. performed acquisition of clinical and pathological data; R.B. and J.B. identified and consented patients for OncoPanel testing and procured patient specimens; D.B.C. performed statistical analyses and drafted the manuscript, and all authors read and approved the final paper.

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Correspondence to David B. Chapel.

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Competing interests

D.B.C. work is supported by the Ovarian Cancer Research Alliance [Ann Schreiber Mentored Investigator Award; grant number 650320]. L.M.S. reports consulting income to her institution from Genentech and Lilly, and research funding from Genentech. J.L.H. reports consulting income from Aadi Bioscience and TRACON Pharmaceuticals. R.B. reports no direct conflicts, but reports current support for other research activities, including grants from the National Institute of Biomedical Imaging and Bioengineering (grant number EB025964-02) and the National Heart, Lung, and Blood Institute, as well as participation in industry grants to Brigham and Women’s Hospital from Merck, Roche, Genentech, Verastem, Gritstone, Siemens, Bicycle Therapeutics, Epizime, and Bayer and philantrophic funding to Brigham and Women’s Hospital from the International Mesothelioma Program. R.B. also reports equity interest in Navigation Sciences and holds patents through the Brigham and Women’s Hospital license to Navigation Sciences. J.B. reports no conflicts.

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Chapel, D.B., Hornick, J.L., Barlow, J. et al. Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01081-z

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