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TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome.

ABSTRACT: Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.

SUBMITTER: Perez-Rivas LG

PROVIDER: S-EPMC9484083 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome.

Perez-Rivas Luis Gustavo LG Simon Julia J Albani Adriana A Tang Sicheng S Roeber Sigrun S Assié Guillaume G Deutschbein Timo T Fassnacht Martin M Gadelha Monica R MR Hermus Ad R AR Stalla Günter K GK Tichomirowa Maria A MA Rotermund Roman R Flitsch Jörg J Buchfelder Michael M Nasi-Kordhishti Isabella I Honegger Jürgen J Thorsteinsdottir Jun J Saeger Wolfgang W Herms Jochen J Reincke Martin M Theodoropoulou Marily M

Acta neuropathologica communications 20220919 1

Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tum ...[more]

PMID: 36123588

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Project description:Purpose: The most clearly established genetic hallmark in oligodendroglial tumors (OTs) is the combined loss of 1p/19q, a molecular alteration characteristic of tumors responding to therapy. Markers of tumoral progression have not yet been studied. Experimental Design: Novel markers of tumoral progression in OTs were sought through gene expression profiling analysis. Results: Unsupervised hierarchical cluster analysis classified OTs into two main groups associated with tumoral grade, independent of histological subtype and 1p/19q status. Differential gene expression analysis between low- and high-grade OTs revealed that only cell cycle-related genes were significantly upregulated in high-grade OTs. Among the deregulated genes, NDRG2 downregulation was detected in high-grade OTs with combined loss of 1p/19q. Expression analysis revealed low transcript levels of NDRG2 relative to non-tumoral brain tissue in 45% (9/20) of high-grade OTs. Furthermore, the low transcript levels of NDRG2 were significantly associated with a worse clinical outcome in patients. Transcript levels of NDRG2 were associated with promoter hypermethylation, which was detected in 38.4% (10/26) of high-grade OTs. The treatment of glioma cell lines T98 and LN18 with demethylating agents increased the mRNA expression levels of NDRG2 relative to the control cell line. Additionally, cell proliferation was significantly reduced and cell cycle was arrested in G1 phase after treatment with demethylating agents. Conclusions: Taken together, our results suggest that NDRG2 is a candidate tumor suppressor gene in OTs whose inactivation could be involved in tumoral progression and worse patient survival. The microarray study involved 28 glioma samples including oligodendrogliomas and oligoastrocytomas WHO grade II and III. Six non-tumoral brain tissues were used as controls, two of which were purchased from Stratagene (La Jolla, CA) and Clontech (Mountain View, CA). RNAs from several cell lines (Universal Human RNA, Stratagene, La Jolla, CA) was used as a standard reference in all hybridizations

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TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome.

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TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome.

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