Germline mutations in MEN1 are associated with the tumorigenesis of pituitary adenoma associated with meningioma

Abstract

Pituitary adenoma and meningioma are two of the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease, the tumorigenesis of which remains unclear. Therefore, the aim of the present study was to investigate the tumorigenesis of PAM. A total of 8,197 patients with pituitary adenoma were analyzed. Furthermore, the clinical data of 57 patients with PAM were compared with patients with multiple endocrine neoplasia 1 (MEN-1) syndrome. Whole exome sequencing (WES) was performed on 23 samples from patients with PAM and the germline mutation was verified by Sanger sequencing. The age of tumor penetrance (age of patients at diagnosis) for PAM was significantly higher than that for patients with MEN-1. Compared with MEN-1 patients, there was a significant association between PAM and female sex (P=0.004). Clonal analysis and phylogenetic tree construction suggested that the pituitary adenoma and meningioma in PAM don't originate from a common progenitor. WES revealed that 5/23 PAM samples had the recurrent germline mutation MEN1 c.1523G>A; p.G508D, which may be a genetic risk factor for PAM. Compared with patients with sporadic pituitary adenoma, the difference was statistically significant (P=0.0004). Compared with wild-type MEN1, there was a significant association between the MEN1 mutation and recurrence of pituitary adenoma, young age and larger diameter of the meningioma. The present study indicated that germline mutations in MEN1 may be associated with the tumorigenesis of PAM.

Pituitary adenoma in patients with multiple endocrine neoplasia type 1: a cohort study

“…In our series, three adenomas were over-secreting at the time of progression in Hardy's classification, suggesting that tumour progression could have been diagnosed by monitoring hormonal secretion followed by MRI, even in the absence of systematic MRI follow-up. Conversely, the presence of a meningioma (the prevalence of which is higher in MEN1 patients (18,19)) will necessarily influence the monitoring rate of subsequent brain and pituitary imaging.…”

<p>Cushing’s Disease Caused by a Pituitary Microadenoma Coexistent with a Meningioma: A Case Report and Literature Review</p>

“…Recurrence of pituitary adenoma, younger age, and larger size of meningioma have been shown to be significantly associated with MEN1 mutation. 16 …”

“…International Journal of General Medicine 2020:13 1246 pituitary adenoma, younger age, and larger size of meningioma have been shown to be significantly associated with MEN1 mutation. 16 Mathuriya et al 17 suggested that hormones may contribute to the occurrence of meningiomas.…”

Beyond the “3 Ps”: A critical appraisal of the non-endocrine manifestations of multiple endocrine neoplasia type 1

“…Thus far there has been no strong evidence supporting a role of MEN1 in the pathogenesis of meningiomas ( 118 ). Zhu and colleagues recently studied tumors from patients diagnosed with both pituitary adenoma and meningioma (PAM) ( 119 , 120 ). In their first study of 57 PAM patients, tumors from PAM patients, compared with “sporadic” pituitary adenomas or meningiomas, had lower MEN1 expression and, in turn, hyperactivation of the mTOR signaling pathway ( 119 ).…”

“…In their first study of 57 PAM patients, tumors from PAM patients, compared with “sporadic” pituitary adenomas or meningiomas, had lower MEN1 expression and, in turn, hyperactivation of the mTOR signaling pathway ( 119 ). A follow up study reported that 5/23 patients with PAM harbored a germline missense MEN1 variant (c.1523G>A; p.G508D), but none of those patients had other MEN1 clinical manifestations and thus did not have MEN1 ( 120 ). This variant is also considered benign or likely benign by ClinVar ( 121 ).…”