MTAP and P16 IHC As Markers for CDKN2A/B Loss in Meningiomas

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Oct 16

PMID 39409918

Authors

Hanim I Ozkizilkaya

Anjali Vinocha

Antonio Dono

Oluwaseun Basit Ogunbona

Gokce A Toruner

Phyu P Aung

Carlos Kamiya Matsuoka

Yoshua Esquenazi

Franco DeMonte

Leomar Y Ballester

Affiliations

Soon will be listed here.

Abstract

Background: Homozygous cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss is one of the parameters that support the designation of meningiomas as Central Nervous System (CNS) WHO grade 3 tumors. Evaluation of CDKN2A/B by sequencing or Fluorescence in situ hybridization (FISH) is costly and not always readily accessible. An immunohistochemistry (IHC)-based marker for the evaluation of CDKN2A/B loss would provide faster results at a lower cost.

Methods: This retrospective study included patients diagnosed with meningioma at our institution between 2016 and 2019. Archival tumor tissue was used for analysis. MTAP immunohistochemistry (IHC) was performed at various dilutions (1:1200, 1:400, 1:200, 1:100) using two different antibodies, and p16 IHC was conducted simultaneously. These analyses were carried out at two different institutions. To determine the sensitivity and specificity of MTAP and p16 as surrogate markers for CDKN2A/B loss, FISH was utilized as the gold standard.

Results: Overall, 46/49 tumors showed strong MTAP staining (94%) at institution 1, and 44/49 (90%) showed either faint positive or positive results at institution 2. One grade 3 meningioma that demonstrated homozygous loss by FISH also showed loss of MTAP expression by IHC. One grade 2 meningioma showed regional loss by FISH and variable MTAP expression under different IHC conditions. MTAP expression evaluation was superior at a dilution of 1:100 with the Abnova Anti-MTAP Monoclonal antibody.

Conclusions: P16 expression was variable and did not correlate with either MTAP expression or FISH results. MTAP IHC is a promising surrogate marker for the evaluation of status in meningiomas.

References

Satomi K, Ohno M, Matsushita Y, Takahashi M, Miyakita Y, Narita Y . Utility of methylthioadenosine phosphorylase immunohistochemical deficiency as a surrogate for CDKN2A homozygous deletion in the assessment of adult-type infiltrating astrocytoma. Mod Pathol. 2020; 34(4):688-700. DOI: 10.1038/s41379-020-00701-w. View

Wach J, Basaran A, Arlt F, Vychopen M, Seidel C, Barrantes-Freer A . CDKN2A/B deletions are strongly associated with meningioma progression: a meta-analysis of individual patient data. Acta Neuropathol Commun. 2023; 11(1):189. PMC: 10685484. DOI: 10.1186/s40478-023-01690-y. View

Han G, Yang G, Hao D, Lu Y, Thein K, Simpson B . 9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy. Nat Commun. 2021; 12(1):5606. PMC: 8460828. DOI: 10.1038/s41467-021-25894-9. View

Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K . Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry. Lung Cancer. 2017; 104:98-105. DOI: 10.1016/j.lungcan.2016.12.017. View

Serra S, Chetty R . . J Clin Pathol. 2018; 71(10):853-858. DOI: 10.1136/jclinpath-2018-205216. View

Lou L, Li J, Qin M, Tian X, Guo W, Li Y . Correlation of MTAP immunohistochemical deficiency with CDKN2A homozygous deletion and clinicopathological features in pleomorphic xanthoastrocytoma. Brain Tumor Pathol. 2022; 40(1):15-25. DOI: 10.1007/s10014-022-00447-0. View

Geyer L, Wolf T, Chenard M, Cebula H, Schott R, Noel G . p16 Immunohistochemical Expression as a Surrogate Assessment of CDKN2A Alteration in Gliomas Leading to Prognostic Significances. Cancers (Basel). 2023; 15(5). PMC: 10000516. DOI: 10.3390/cancers15051512. View

Louis D, Perry A, Wesseling P, Brat D, Cree I, Figarella-Branger D . The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021; 23(8):1231-1251. PMC: 8328013. DOI: 10.1093/neuonc/noab106. View

Ammendola S, Caldonazzi N, Simbolo M, Piredda M, Brunelli M, Poliani P . H3K27me3 immunostaining is diagnostic and prognostic in diffuse gliomas with oligodendroglial or mixed oligoastrocytic morphology. Virchows Arch. 2021; 479(5):987-996. PMC: 8572829. DOI: 10.1007/s00428-021-03134-1. View

10.

Sasaki S, Takeda M, Hirose T, Fujii T, Itami H, Uchiyama T . Correlation of MTAP Immunohistochemistry With CDKN2A Status Assessed by Fluorescence In Situ Hybridization and Clinicopathological Features in CNS WHO Grade 2 and 3 Meningiomas: A Single Center Cohort Study. J Neuropathol Exp Neurol. 2021; 81(2):117-126. DOI: 10.1093/jnen/nlab127. View

11.

Porcel J . Pleural mesothelioma. Med Clin (Barc). 2022; 159(5):240-247. DOI: 10.1016/j.medcli.2022.03.007. View

12.

Ostrom Q, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan J . CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol. 2021; 23(12 Suppl 2):iii1-iii105. PMC: 8491279. DOI: 10.1093/neuonc/noab200. View

13.

Illei P, Ladanyi M, Rusch V, Zakowski M . The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions. Cancer. 2003; 99(1):51-6. DOI: 10.1002/cncr.10923. View

14.

Patro C, Biswas N, Pingle S, Lin F, Anekoji M, Jones L . MTAP loss: a possible therapeutic approach for glioblastoma. J Transl Med. 2022; 20(1):620. PMC: 9791736. DOI: 10.1186/s12967-022-03823-8. View

15.

Piepkorn M . Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol. 2000; 42(5 Pt 1):705-22; quiz 723-6. DOI: 10.1067/mjd.2000.104687. View

16.

Savola S, Nardi F, Scotlandi K, Picci P, Knuutila S . Microdeletions in 9p21.3 induce false negative results in CDKN2A FISH analysis of Ewing sarcoma. Cytogenet Genome Res. 2007; 119(1-2):21-6. DOI: 10.1159/000109614. View

17.

Carter M, Durham A, Miedema J, Harms P, Chan M, Patel R . Molecular testing of borderline cutaneous melanocytic lesions: SNP array is more sensitive and specific than FISH. Hum Pathol. 2018; 86:115-123. DOI: 10.1016/j.humpath.2018.12.002. View

18.

Savarese T, Crabtree G, Parks Jr R . 5'-Methylthioadenosine phosphorylase-L. Substrate activity of 5'-deoxyadenosine with the enzyme from Sarcoma 180 cells. Biochem Pharmacol. 1981; 30(3):189-99. DOI: 10.1016/0006-2952(81)90077-0. View

19.

Chapel D, Schulte J, Berg K, Churg A, Dacic S, Fitzpatrick C . MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma. Mod Pathol. 2019; 33(2):245-254. DOI: 10.1038/s41379-019-0310-0. View

20.

Tang V, Lu R, Mirchia K, Van Ziffle J, Devine P, Lee J . Loss of p16 expression is a sensitive marker of CDKN2A homozygous deletion in malignant meningiomas. Acta Neuropathol. 2023; 145(4):497-500. PMC: 10020299. DOI: 10.1007/s00401-023-02544-6. View