Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis

Hélène Lasolle,Pascal Roy,Anne Wierinckx,Nathalie Sturm,Damien Sanlaville,Emmanuel Jouanneau,Bénédicte Decoudier,Alexandre Vasiljevic,Claire Bardel,Stephan Gaillard,Mad-Hélénie Elsensohn,Eudeline Alix,Christine Cortet,Philippe Bertolino,Clément Bonnefille,Amandine Ferrière,Gérald Raverot

doi:10.1186/s40478-020-01067-5

Abstract

The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min–max) = 38% (0–97) of probes) compared to corticotroph (11% (0–77)), somatotroph (5% (0–99)), gonadotroph (0% (0–10)) and immunonegative tumors (0% (0–17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn’t show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same ‘quiet’ profile, leaving the mechanism underlying tumorigenesis open to question.

Highlights

Pituitary neuroendocrine tumors (PitNETs) represent 10–15% of intra-cranial tumors among which most are benign and controlled by current therapeutic strategies
Clinico-pathological characteristics of those tumors are presented in Table 1, their mean post-operative follow-up was 8.3(3.5) years and tumor recurrence/progression occurred in 124 patients (64%) within 1.4(1.6) years after initial surgery
Here, we report the first study of a large multicentric cohort of PitNETs patients with standardized clinical follow-up, clear definition of recurrence and available pathology data, in which we analyzed the impact of chromosome instability on tumor prognosis

Summary

Introduction

Pituitary neuroendocrine tumors (PitNETs) represent 10–15% of intra-cranial tumors among which most are benign and controlled by current therapeutic strategies. While surgery is the first-line treatment, it can be associated with medical therapies. Despite these strategies, approximately 25–40% of PitNETs present a regrowth after surgery [15]. Various approaches have been proposed for the prediction of tumor behavior, including the study of pathological markers. While the recent WHO 2017 classification of PitNETs did not propose individual markers, it did identify a group of tumors with a high risk of recurrence, including sparsely granulated somatotroph tumors, lactotroph tumors in men, Crooke’s cell tumors, silent corticotroph tumors (SCT), and the newly introduced pluri-hormonal Pit-1-positive tumor [10].

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