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

Pérez-Rivas, Luis Gustavo; Simon, Julia; Albani, Adriana; Tang, Sicheng; Roeber, Sigrun; Assié, Guillaume; Deutschbein, Timo; Fassnacht, Martin; Gadelha, Mônica R.; Hermus, A.R.M.M.; Stalla, Günter; Tichomirowa, María A.; Rotermund, Roman; Flitsch, Jörg; Buchfelder, Michael; Nasi‐Kordhishti, Isabella; Honegger, Jürgen; Thorsteinsdottir, Jun; Saeger, Wolfgang; Herms, Jochen; Reincke, Martín; Theodoropoulou, Marily

doi:10.1186/s40478-022-01437-1

Cited by 13 publications

(16 citation statements)

References 55 publications

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“…In four of eight corticotroph and one of three lactotroph PitNETs with a TP53 mutation, we sequenced the tissue specimen from the first resection and the TP53 mutation was present. These findings are congruent with prior literature, which suggests that TP53 mutations are most commonly early events but can also develop later in the natural history by convergent evolution [ 39 , 40 , 50 ].…”

Section: Resultssupporting

confidence: 92%

“…While the aggressive, treatment-refractory tumors had a higher frequency of gene mutations than the benign tumors, not all treatment-refractory cases were explained by gene-level alterations. Collectively, only 61% (15/23) of patients had oncogenic or likely oncogenic mutations demonstrated previously to be associated with worse prognosis: TP53 , ATRX , DAXX , or SF3B1 [ 12 , 20 , 39 , 50 ]. Based on these observations, we hypothesized that alternative molecular features contribute to aggressive, treatment-refractory behavior.…”

Section: Resultsmentioning

confidence: 99%

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Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors

Lin,

Rudneva,

Richards

et al. 2024

Acta Neuropathol

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Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10−10 and p = 8.5 × 10−9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10−4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10−8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70–0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors

Lin,

Rudneva,

Richards

et al. 2024

Acta Neuropathol

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“…We found TP53 mutations in 3.3% of analyzed corticotroph PitNETs, which is notably less than 10.5% reported by Perez−Rivas LG et al. ( 42 ) and 22.7% described by Uzilov et al. ( 43 ).…”

Section: Discussioncontrasting

confidence: 67%

“…Very recent studies, that followed discovery of TP53 mutations in exome-seq results of USP8 -wt tumors ( 7 ) confirmed their incidence in corticotroph PitNETs. The mutations were found in 9/86 ( 42 ) and 5/22 ( 43 ) patients that were included in sequencing of TP53 coding regions or exome-seq, respectively. Our results show that mutations in this gene occur in corticotroph PitNETs but with lower frequency in our cohort than in previously reported groups of patients.…”

Section: Discussionmentioning

confidence: 99%

Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors

Pękul,

Szczepaniak,

Kober

et al. 2024

Front. Endocrinol.

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IntroductionCorticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing’s disease (CD), however, some remain clinically silent. Recurrent USP8, USP48, BRAF and TP53 mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs.MethodsStudy included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in USP8, USP48 and BRAF with Sanger sequencing, while 128 of these patients were screened for TP53 mutations with next generation sequencing and immunohistochemistry.ResultsUSP8 mutations were found in 41% CD and 8,5% silent tumors, while USP48 mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, non-invasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No BRAF mutations were found. Four TP53 mutations were identified (2 in CD, 2 in silent tumors) in tumors with size >10mm including 3 invasive ones. They were found in Crooke’s cell and sparsely granulated tumors. Tumors with missense TP53 mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift TP53 variant had low protein expression. TP53 mutation was a poor prognostic factor in CD according to uni- and multivariate survival analyses in spite of low mutations frequency.ConclusionsWe confirmed high prevalence of USP8 mutations and low incidence of USP48 and TP53 mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. TP53 mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD.

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“…This cellular localization may explain why the relatively small coricotroph tumors caused more dura mater defects in the sellar turcica than other subtype tumors in the present study. In addition, corticotroph tumors with TP53 mutations, which constitute 6-10% of all pituitary tumors, have been reported to be more invasive and more malignant [17], comprising up to 45% of aggressive pituitary tumors and pituitary carcinomas [18].…”

Section: Differences In Origin Among Subtypes and Invasion To Surroun...mentioning

confidence: 99%

Differences in invasiveness and recurrence rate among nonfunctioning pituitary neuroendocrine tumors depending on tumor subtype

Taguchi

Kinoshita

Amatya

et al. 2023

Preprint

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Purpose To clarify the invasiveness to surrounding structures and recurrence rate of each subtype of nonfunctioning pituitary neuroendocrine tumor (Pit-NETs) according to the WHO 2022 classification. Methods This retrospective study utilized data from 292 patients with nonfunctioning Pit-NETs treated with initial transsphenoidal surgery. Recurrence was evaluated on 163 patients who were available for a magnetic resonance imaging follow-up ≥36 months. All tumors were assessed by immunohistochemical staining for Pit-1, T-PIT, and GATA3. Invasiveness to surrounding structures was evaluated based on intraoperative findings. Results Cavernous sinus invasion was found in 47.5% of null cell tumors, 50.0% of Pit-1 lineage tumors, 31.8% of corticotroph tumors, and 18.3% of gonadotroph tumors. Dura mater defects in the floor of sellar turcica, indicating dural invasion, were found in 44.3% of null cell tumors, 36.4% of corticotroph tumors, 16.7% of Pit-1 lineage tumors, and 17.3% of gonadotroph tumors. In logistic regression analysis, Pit-1 (OR 5.90, 95%CI 1.71–20.4, P = 0.0050) and null tumors (OR 4.14, 95%CI 1.86–9.23, P = 0.0005) were associated with cavernous sinus invasion. Recurrence was found in 8 (4.9%) patients, but without significant differences between tumor subtypes. No tumor showed immunoreactivity for hormone antibodies (8/101 vs. 0/62, P = 0.0246). Conclusion Among nonfunctioning Pit-NETs, Pit-1 lineage tumors tend to invade the cavernous sinus, corticotroph tumors may produce dura mater defects in the sellar turcica, and null cell tumors tend to cause both. Pit-NETs without pituitary hormone may have a higher recurrence rate.

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

Cited by 13 publications

References 55 publications

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors

Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors

Differences in invasiveness and recurrence rate among nonfunctioning pituitary neuroendocrine tumors depending on tumor subtype

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