ECE2021 Oral Communications Oral Communications 13: Pituitary and Neuroendocrinology (6 abstracts)
TP53 mutations in functional corticotroph tumours: prevalence and clinical relevance
Luis Gustavo Perez-Rivas 1 , Julia Simon 1 , Adriana Albani 1 , Roman Rotermund 2 , Ad R. M M. Hermus 3 , Guillaume Assié 4 , 5 , Monica Gadelha 6 , Timo Deutschbein 7 , Jörg Flitsch 2 , Jürgen Honegger 8 , Walter Rachinger 9 , Günter Stalla 1 , 10 , Martin Reincke 1 & Marily Theodoropoulou 1
1Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany, Endocrinology, Munich, Germany; 2Universitätskrankenhaus Hamburg-Eppendorf, Hamburg, Germany, Neurosurgery, Hamburg, Germany; 3Division of Endocrinology, Radboud University Medical Centre, Internal Medicine, Nijmegen, Netherlands; 4Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France; 5Center for Rare Adrenal Diseases, Hôpital Cochin, Endocrinology, Paris, France; 6Division of Endocrinology, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 7Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Internal Medicine I, Würzburg, Germany; 8University Hospital Tübingen, Neurosurgery, Tübingen, Germany; 9Neurochirurgische Klinik und Poliklinik, Klinikum der LMU München, Munich, Germany; 10Medicover Neuroendocrinology, Munich, Germany
Introduction
TP53 mutations have been rarely reported in pituitary tumours. Recently two exploratory exome sequencing studies have identified somatic TP53 mutations in a small number of functional corticotroph tumours (6/18 and 4/10) with USP8 wild type (wt) status, suggesting that they may be more frequent than previously thought. Nevertheless, the clinical impact of those mutations is still unknown.
Aim
To determine the prevalence of TP53 mutations in a cohort of USP8wt tumours and to identify clinical features associated with TP53 mutations.
Methods
We analysed samples from 54 patients with USP8wt corticotroph tumours, (47 females, 7 males), 43 diagnosed with Cushing’s disease (CD) and 11 with corticotroph tumour progression after bilateral adrenalectomy/Nelson syndrome (CTP/NS). An additional cohort of 23 patients with USP8 mutant (mut) tumours was included for comparison (23 females, 14 CD and 9 CTP/NS). In total, 63 tumours were fresh frozen and 14 formalin-fixed paraffin embedded. The complete TP53 coding region was amplified by PCR with specific primers and sequenced using the Sanger method.
Results
8 single-nucleotide variants in 7 samples (prevalence 13% in USP8wt tumours) were annotated in ClinVar database as pathogenic, likely pathogenic, or uncertain significance but evidence of protein function alteration. All of them were predicted as pathogenic in the COSMIC database. Mutations were detected in heterozygosis and were located in exon 5 (c.398T>A, p.Met133Lys), exon 6 (c.644G>A, p.Ser215Asn), exon 7 (c.714T>A, p.Cys238X; c.718A>G, p.Ser240Gly; and c.773A>C, p.Glu258Ala), exon 8 (2 unrelated patients with c.818G>A; p.Arg273His) and exon 10 (c.1009C>G; p.Arg337Gly). One long deletion was found in one case, but no indels. No mutation was found in USP8mut samples. Mutations were more frequent in CTP/NS than in CD (36% vs 7%, P = 0.025). We found association with: older age at diagnosis (TP53mut 52 ± 21 vs. USP8mut 36 ± 12 vs. wt 41 ± 14 years old, P = 0.046; TP53mut vs USP8mut, P = 0.04), lower frequency of total tumour resection (TP53mut 0% vs. USP8mut 83% vs wt 63%, P = 0.015), higher invasion rate (TP53 100% vs USP8mut 44% vs wt 48%, P = 0.012) and lower survival (TP53mut 50% vs. USP8mut 95% vs. wt 94%, P = 0.012). After stratification in CD or CTP/NS Total resection and survival lost statistical significance but CTP/NS patients with TP53 mutations trended towards lower survival rate (25% vs 89% USP8mut, 86% wt, P = 0.069). No differences were found regarding tumour size or hormone levels.
Conclusion
TP53 mutations are more frequent in CTP/NS than in CD and may be related to a more aggressive tumour behaviour.
Volume 73
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Endocrine Abstracts
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