Uncovering the links between systemic hormones and oncogenic signaling in the pathogenesis of meningioma

A number of risk factors have been associated with meningioma development including radiation exposure (radiation-induced meningioma), female gender, germline mutations, high body mass index and hormone exposure (Figure 1). The relationship between meningioma risk and sex hormones has been of keen interest for decades, sparked by several observations. The most important of these has been the finding of estrogen receptor and progesterone receptor (PR) expression in a substantial portion of meningiomas [1.Perry A. Cai D.X. Scheithauer B.W. et al.Merlin, DAL-1, and progesterone receptor expression in clinicopathologic subsets of meningioma: a correlative immunohistochemical study of 175 cases.J Neuropathol Exp Neurol. 2000; 59: 872-879Crossref PubMed Scopus (159) Google Scholar, 2.Hsu D.W. Efird J.T. Hedley-Whyte E.T. Progesterone and estrogen receptors in meningiomas: prognostic considerations.J Neurosurg. 1997; 86: 113-120Crossref PubMed Scopus (305) Google Scholar]. In addition, a link between meningiomas and hormones has been supported by the skewed gender distribution of meningiomas [3.Wiemels J. Wrensch M. Claus E.B. Epidemiology and etiology of meningioma.J Neurooncol. 2010; 99: 307-314Crossref PubMed Scopus (692) Google Scholar]. Low-grade meningiomas develop two times more often in women than in men, and three times more often in women during peak reproductive years [3.Wiemels J. Wrensch M. Claus E.B. Epidemiology and etiology of meningioma.J Neurooncol. 2010; 99: 307-314Crossref PubMed Scopus (692) Google Scholar]. Pregnancy has also been linked with the growth of extant unresected low-grade meningiomas and tumor size can decrease postpartum [3.Wiemels J. Wrensch M. Claus E.B. Epidemiology and etiology of meningioma.J Neurooncol. 2010; 99: 307-314Crossref PubMed Scopus (692) Google Scholar, 4.Laviv Y. Bayoumi A. Mahadevan A. et al.Meningiomas in pregnancy: timing of surgery and clinical outcomes as observed in 104 cases and establishment of a best management strategy.Acta Neurochir (Wien). 2017; 10.1007/s00701-017-3146-8Google Scholar]. Moreover, exogenous hormone use has also been associated with meningioma risk [3.Wiemels J. Wrensch M. Claus E.B. Epidemiology and etiology of meningioma.J Neurooncol. 2010; 99: 307-314Crossref PubMed Scopus (692) Google Scholar]. These observations suggested that hormone receptor antagonists might be useful therapeutics for meningioma. However, despite the expression of PR in 30%–80% of meningiomas [1.Perry A. Cai D.X. Scheithauer B.W. et al.Merlin, DAL-1, and progesterone receptor expression in clinicopathologic subsets of meningioma: a correlative immunohistochemical study of 175 cases.J Neuropathol Exp Neurol. 2000; 59: 872-879Crossref PubMed Scopus (159) Google Scholar, 2.Hsu D.W. Efird J.T. Hedley-Whyte E.T. Progesterone and estrogen receptors in meningiomas: prognostic considerations.J Neurosurg. 1997; 86: 113-120Crossref PubMed Scopus (305) Google Scholar], PR antagonists have largely been unsuccessful in controlling meningioma growth. Encouraging results were observed in preclinical studies, yet, results have been mixed in clinical trials [5.Cossu G. Levivier M. Daniel R.T. Messerer M. The role of mifepristone in meningiomas management: a systematic review of the literature.BioMed Res Int. 2015; 2015: 267831Crossref PubMed Scopus (16) Google Scholar]. While studies enrolling limited numbers of patients (3–28 patients) have shown mostly favorable results, albeit with low response rates, a recently reported large, multicenter prospective, phase III clinical trial of the steroidal antiprogesterone mifepristone (RU-486), failed to demonstrate improvement in disease progression [6.Ji Y. Rankin C. Grunberg S. et al.Double-blind phase III randomized trial of the antiprogestin agent mifepristone in the treatment of unresectable meningioma: SWOG S9005.J Clin Oncol Off J Am Soc Clin Oncol. 2015; 33: 4093-4098Crossref PubMed Scopus (91) Google Scholar]. Over the last 5 years, much of the focus in the meningioma field has shifted away from exploring the role of hormone receptors in meningioma pathogenesis toward genomic studies. These efforts have been very fruitful. As such, genomic analyses of meningioma have garnered increasing attention. These genomics studies of meningioma have provided several fundamental observations. First, while somatic or germline mutations in the NF2 tumor suppressor gene underlie the development of many meningiomas, numerous cases have somatic alterations in a wide range of other genes including SMO, AKT1, PIK3CA, TRAF7, KLF4, and POLR2A [7.Clark V.E. Harmancı A.S. Bai H. et al.Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas.Nat Genet. 2016; 48: 1253-1259Crossref PubMed Scopus (192) Google Scholar, 8.Clark V.E. Erson-Omay E.Z. Serin A. et al.Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.Science. 2013; 339: 1077-1080Crossref PubMed Scopus (551) Google Scholar, 9.Abedalthagafi M. Bi W.L. Aizer A.A. et al.Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.Neuro Oncol. 2016; 18: 649-655Crossref PubMed Scopus (174) Google Scholar, 10.Brastianos P.K. Horowitz P.M. Santagata S. et al.Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.Nat Genet. 2013; 45: 285-289Crossref PubMed Scopus (420) Google Scholar, 11.Reuss D.E. Piro R.M. Jones D.T.W. et al.Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations.Acta Neuropathol. 2013; 125: 351-358Crossref PubMed Scopus (170) Google Scholar]. In addition, a subset of meningiomas arise in the setting of germline mutations in SMARCB1, SMARCE1 [12.Smith M.J. Germline and somatic mutations in meningiomas.Cancer Genet. 2015; 208: 107-114Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar] and BAP1 [13.Shankar G.M. Santagata S. BAP1 mutations in high-grade meningioma: implications for patient care.Neuro-Oncol. 2017; 19: 1447-1456Crossref PubMed Scopus (54) Google Scholar, 14.Shankar G.M. Abedalthagafi M. Vaubel R.A. et al.Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas.Neuro-Oncol. 2017; 19: 535-545PubMed Google Scholar]. While recurrent copy number alterations have long been associated with higher grade meningiomas, TERT promoter mutations [15.Sahm F. Schrimpf D. Olar A. et al.TERT promoter mutations and risk of recurrence in meningioma.J Nat Cancer Inst. 2016; 108: djv377Crossref Scopus (226) Google Scholar, 16.Abedalthagafi M.S. Bi W.L. Merrill P.H. et al.ARID1A and TERT promoter mutations in dedifferentiated meningioma.Cancer Genet. 2015; 208: 345-350Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar] and distinct methylation patterns [15.Sahm F. Schrimpf D. Olar A. et al.TERT promoter mutations and risk of recurrence in meningioma.J Nat Cancer Inst. 2016; 108: djv377Crossref Scopus (226) Google Scholar, 17.Sahm F. Schrimpf D. Stichel D. et al.DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis.Lancet Oncol. 2017; 18: 682-694Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar] have recently been linked to aggressive meningiomas. The aberrations underlying meningioma pathogenesis are, therefore, varied and many. Genomic studies of meningioma have also revealed links between these newly identified oncogenic drivers and tumor morphology, location within the cranium and level of chromosomal instability (CIN). For instance, meningiomas that harbor NF2 mutations generally are strongly associated with fibrous histology [8.Clark V.E. Erson-Omay E.Z. Serin A. et al.Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.Science. 2013; 339: 1077-1080Crossref PubMed Scopus (551) Google Scholar, 9.Abedalthagafi M. Bi W.L. Aizer A.A. et al.Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.Neuro Oncol. 2016; 18: 649-655Crossref PubMed Scopus (174) Google Scholar], those with chromosomal polysomies with angiomatous histology [18.Abedalthagafi M.S. Merrill P.H. Bi W.L. et al.Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5.Oncotarget. 2014; 5: 10596-10606Crossref PubMed Scopus (47) Google Scholar], those with KLF4/TRAF7 mutations with secretory features [11.Reuss D.E. Piro R.M. Jones D.T.W. et al.Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations.Acta Neuropathol. 2013; 125: 351-358Crossref PubMed Scopus (170) Google Scholar], and those with mutations in SMO, AKT1, PIK3CA, and POLR2A with meningothelial features [7.Clark V.E. Harmancı A.S. Bai H. et al.Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas.Nat Genet. 2016; 48: 1253-1259Crossref PubMed Scopus (192) Google Scholar, 8.Clark V.E. Erson-Omay E.Z. Serin A. et al.Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.Science. 2013; 339: 1077-1080Crossref PubMed Scopus (551) Google Scholar, 9.Abedalthagafi M. Bi W.L. Aizer A.A. et al.Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.Neuro Oncol. 2016; 18: 649-655Crossref PubMed Scopus (174) Google Scholar]. NF2-mutant meningiomas typically arise from the meninges covering the cerebral convexities or the posterior fossa of the skull base, and harbor increased CIN whereas many non-NF2 mutant meningiomas generally arise in the anterior or middle fossa of the skull base and lack CIN [7.Clark V.E. Harmancı A.S. Bai H. et al.Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas.Nat Genet. 2016; 48: 1253-1259Crossref PubMed Scopus (192) Google Scholar, 8.Clark V.E. Erson-Omay E.Z. Serin A. et al.Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.Science. 2013; 339: 1077-1080Crossref PubMed Scopus (551) Google Scholar, 9.Abedalthagafi M. Bi W.L. Aizer A.A. et al.Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.Neuro Oncol. 2016; 18: 649-655Crossref PubMed Scopus (174) Google Scholar]. The distinct pattern of mutations underlying meningioma arising in the anterior/middle cranial fossa versus those arising over the cerebral convexities may be explained by the embryological origin of the meninges from two sources—the meninges that cover the cerebral hemispheres derive from the neural crest, while those that cover portions of the skull base derive from the cephalic mesoderm [19.Richtsmeier J.T. Flaherty K. Hand in glove: brain and skull in development and dysmorphogenesis.Acta Neuropathol. 2013; 125: 469-489Crossref PubMed Scopus (147) Google Scholar]. In addition to expanding our understanding of the pathogenesis of meningioma, these genomic analyses have also highlighted the promise of targeted therapies for meningioma patients. Meningiomas with mutations in genes such as SMO, AKT1 and PIK3CA may be vulnerable to pathway-specific inhibitors [8.Clark V.E. Erson-Omay E.Z. Serin A. et al.Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.Science. 2013; 339: 1077-1080Crossref PubMed Scopus (551) Google Scholar, 10.Brastianos P.K. Horowitz P.M. Santagata S. et al.Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.Nat Genet. 2013; 45: 285-289Crossref PubMed Scopus (420) Google Scholar]. A recent report of a partial response and durable control of a metastatic AKT1 (E17K)-mutant meningothelial meningioma to a pan-AKT inhibitor underscores the role of PI3K/AKT oncogenic signaling in fostering meningioma growth [20.Weller M. Roth P. Sahm F. et al.Durable control of metastatic AKT1-mutant WHO grade 1 meningothelial meningioma by the AKT inhibitor, AZD5363.J Natl Cancer Inst. 2017; 109: 1-4Crossref PubMed Scopus (36) Google Scholar]. Amidst this intense focus on meningioma genomics, Peyre et al. have made a remarkable observation that redirects our attention back to earlier work on hormone receptors in meningioma, linking the hitherto disparate influences of sex hormones and oncogenic signaling in meningioma development [21.Peyre M. Gaillard S. de Marcellus C. et al.Progestin-associated shift of meningioma mutational landscape.Ann Oncol. 2018; 29: 681-686Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. In a cohort of 40 women who had meningiomas resected following long-term exposure to progesterone agonists (38 cyproterone acetate; 1 megestrol acetate; 1 chlormadinone acetate), the investigators found that over one-third of these patients (14 patients) had tumors with activating PIK3CA mutations compared with only 3% in a comparable population of women. All cases with PIK3CA mutations expressed PR in 50%–100% of the tumor cells. These progestin-associated meningiomas were frequently multiple suggesting synchronous primaries or seeding from a related clone and frequently occurred in the skull base. The progestin-associated meningiomas had neither PTEN loss nor PIK3R1 mutations, nor an increased frequency of AKT1-E17K mutations, suggesting a specific role for PIK3CA mutations in the pathogenesis of meningiomas in the setting of progesterone agonists. Interestingly, a shift in the spectrum of mutations has also been observed recently in radiation-induced meningiomas that are highly enriched for rearrangements in NF2 [22.Agnihotri S. Suppiah S. Tonge P.D. et al.Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas.Nat Commun. 2017; 8: 186Crossref PubMed Scopus (43) Google Scholar]. The work of Peyre et al. raises many important areas for further investigation. While the evidence to date suggests that PIK3CA-mutant meningiomas arise predominantly in women [8.Clark V.E. Erson-Omay E.Z. Serin A. et al.Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.Science. 2013; 339: 1077-1080Crossref PubMed Scopus (551) Google Scholar, 9.Abedalthagafi M. Bi W.L. Aizer A.A. et al.Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.Neuro Oncol. 2016; 18: 649-655Crossref PubMed Scopus (174) Google Scholar, 21.Peyre M. Gaillard S. de Marcellus C. et al.Progestin-associated shift of meningioma mutational landscape.Ann Oncol. 2018; 29: 681-686Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar], it remains unclear the fraction of these meningiomas that arise due to chronic exposure to progesterone agonists. The current study clearly suggests that continued exposure to progesterone agonists may drive the growth of PIK3CA-mutant meningiomas, yet PIK3CA-mutant meningioma cell lines or animal models are not yet available to test this hypothesis. In addition, using progesterone antagonists to treat a patient population stratified by PIK3CA mutation status has not yet attempted. Hence, while the current data suggest that PIK3CA-mutant meningiomas may be hormone-dependent cancers, further work is required. Interestingly, in a different study, patients who developed meningiomas—often multiple and in the skull base—during long-term use of cyproterone acetate, had stabilization of tumor growth and tumor regression after hormone withdrawal [23.Bernat A.L. Oyama K. Hamdi S. et al.Growth stabilization and regression of meningiomas after discontinuation of cyproterone acetate: a case series of 12 patients.Acta Neurochir (Wien). 2015; 157: 1741-1746Crossref PubMed Scopus (47) Google Scholar]. Presumably, based on insights from the current study, some but not all of the responsive patients in that cohort may have had PIK3CA-mutant meningiomas. Most importantly, why and how would progesterone foster the growth of PIK3CA-mutant meningiomas? One possibility is through the elevated levels of PR that have been associated with PIK3CA mutation in a study of nearly 20000 tumor samples (>40 cancer types) [24.Millis S.Z. Ikeda S. Reddy S. et al.Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors.JAMA Oncol. 2016; 2: 1565-1573Crossref PubMed Scopus (158) Google Scholar] or the alterations in hormone receptor binding that can result from PI3K-pathway activation [25.Bhat-Nakshatri P. Wang G. Appaiah H. et al.AKT alters genome-wide estrogen receptor alpha binding and impacts estrogen signaling in breast cancer.Mol Cell Biol. 2008; 28: 7487-7503Crossref PubMed Scopus (82) Google Scholar]. A myriad of possibilities exists for the interplay and cross-talk between the PI3K-pathway and PR activity. Valuable lessons may be learned from hormone-dependent cancers such as breast, endometrial and prostate cancers [26.Groner A.C. Brown M. Role of steroid receptor and coregulator mutations in hormone-dependent cancers.J Clin Invest. 2017; 127: 1126-1135Crossref PubMed Scopus (38) Google Scholar] in which genomic alterations in steroid hormone receptors including amplifications, splice variants and point mutations as well as alterations in hormone receptor cofactors have been identified. Despite the exciting progress in our understanding of meningioma pathogenesis, many questions remain. The fascinating link between sex hormones and the development of PIK3CA-mutant meningiomas that Peyre et al. have uncovered is assured to stimulate further efforts to integrate epidemiological, genomic and functional information. Such multifaceted approaches should reveal further insights into the complicated relationship between systemic hormonal and metabolic cues and the development of meningioma. None declared.