Zschernack Valentina, Pinto Giuseppe, Friker Lea L, Klein Rebecca, Goschzik Tobias, Dörner Evelyn, Waha Andreas, Vokuhl Christian, Vatter Hartmut, Pietsch Torsten
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University Hospital Bonn, Bonn, Germany.
Institute of Neuropathology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
J Neurooncol. 2025 Apr 14. doi: 10.1007/s11060-025-05029-6.
Meningiomas are the most common primary intracranial tumors, with anaplastic variants linked to a poor prognosis. CDKN2A deletions are key markers of malignancy and were integrated into the 2021 WHO classification for anaplastic meningiomas. Both p16 and MTAP immunohistochemistry (IHC) are employed to assess CDKN2A loss, though each marker has limitations in accuracy to varying degrees.
This study analyzed the concordance between molecular methods - DNA methylation profiling, molecular inversion probe (MIP) analysis, targeted next-generation sequencing (NGS), and fluorescence in situ hybridization (FISH) - and protein expression of p16 and MTAP in nine anaplastic meningiomas.
We showed that while p16 loss correlated well, MTAP protein was still expressed in three cases despite homozygous CDKN2A deletions. In those three cases the MTAP gene was hemizygously deleted. Additionally, a FISH probe encompassing both genes generated misleading results.
Our results suggest that MTAP IHC can be unreliable as a sole surrogate for CDKN2A loss in anaplastic meningioma. Quantitative copy-number analysis via high-resolution chromosomal arrays enables precise determination of CDKN2A deletions. Given the therapeutic implications of WHO grading, accurate molecular testing is critical. We conclude that negative p16/MTAP IHC in high-grade meningiomas should prompt molecular analysis for CDKN2A deletions, and MTAP IHC should not be solely relied upon for classification.
脑膜瘤是最常见的原发性颅内肿瘤，间变性亚型预后较差。CDKN2A缺失是恶性肿瘤的关键标志物，并已纳入2021年世界卫生组织间变性脑膜瘤分类。p16和MTAP免疫组化（IHC）均用于评估CDKN2A缺失，尽管每种标志物在准确性上都有不同程度的局限性。
本研究分析了9例间变性脑膜瘤中分子方法——DNA甲基化谱分析、分子倒置探针（MIP）分析、靶向二代测序（NGS）和荧光原位杂交（FISH）——与p16和MTAP蛋白表达之间的一致性。
我们发现，虽然p16缺失相关性良好，但在3例中，尽管CDKN2A纯合缺失，MTAP蛋白仍有表达。在这3例中，MTAP基因半合子缺失。此外，包含这两个基因的FISH探针产生了误导性结果。
我们的结果表明，在间变性脑膜瘤中，MTAP免疫组化作为CDKN2A缺失的唯一替代指标可能不可靠。通过高分辨率染色体阵列进行定量拷贝数分析能够精确确定CDKN2A缺失。鉴于世界卫生组织分级的治疗意义，准确的分子检测至关重要。我们得出结论，高级别脑膜瘤中p16/MTAP免疫组化阴性应促使对CDKN2A缺失进行分子分析，且不应仅依赖MTAP免疫组化进行分类。
