Intratumoral heterogeneity of CDKN2A deletions in IDH-mutant astrocytoma

Excerpt

An updated 2021 World Health Organization (WHO) Classification of tumors of the central nervous system (CNS) (5th ed.) requires traditional histology-based diagnostics of some tumor types (e.g., diffuse gliomas) to be replaced with a multi-layered approach that combines histologic features and molecular information in an integrated manner [3]. Molecular workup is thus mandatory for not only determining such tumor types, but assessing its prognosis by malignancy (CNS WHO grade). A notable example of a genomic alteration with evolving prognostic value in brain tumors is the loss of the tumor suppressor gene cyclin dependent kinase inhibitor 2A (CDKN2A) [8]. CDKN2A homozygous deletion (HD) is now considered a CNS WHO grade 4 marker in isocitrate dehydrogenase gene (IDH)-mutant astrocytomas, even in the absence of necrosis and/or microvascular proliferation on histology [3]. The golden standard for the detection of CDKN2A HD is by such direct methods as fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA), and its status could also be suggested by surrogate immunohistochemical (IHC) markers of p16 and methylthioadenosine phosphorylase (MTAP) [7]. However, potential pitfalls for genetic testing in cancer including diffuse gliomas could derive from their genetic heterogeneity and mosaicisim [4], which could not only complicate the accurate molecular diagnosis of the tumor, but affect the efficacy of molecular-targeting therapeutics [6]. Notably, it has not been reported so far whether such genetic heterogeneity could be represented in CDKN2A HD of IDH-mutant astrocytomas, which would be potentially a critical issue since it could segregate CNS WHO grade 4 tumors from them. We herein describe a case of IDH‐mutant astrocytoma which showed intratumoral heterogenous CDKN2A HD with FISH analyses to discuss the biologic significance of genetic heterogeneity in the progression of diffuse gliomas and the potential pitfall of bulk, comprehensive methods of MLPA and next-generation sequencing (NGS). All methods and protocols related to human subjects were approved by each institutional review board of Ethics Committee, and the investigations were carried out in accordance with each institutional review board‐approved protocol and Declaration of Helsinki, 2013. …