Anaplastic Meningioma in a 6-year-old with Somatic YAP1::MAML2 Fusion and Multiple Endocrine Neoplasia Type 4 (MEN4) Syndrome

Abstract

Meningiomas are the most common primary brain tumors in adults but much less frequent in children. Many subtypes exist, including anaplastic (malignant) meningioma, which accounts for less than 20% of pediatric tumors. Meningiomas can arise in association with cancer predisposition syndromes due to germline variants in genes such as NF2, MEN1 and SMARCE1. This report describes a 6-year-old boy diagnosed with anaplastic meningioma who was treated with surgery and focal radiation therapy. The family consented to participate in the Texas KidsCanSeq clinical genomics study. Analysis of germline and tumor samples detected a single germline finding of a CDKN1B pathogenic frameshift variant associated with Multiple Endocrine Neoplasia Type 4 (MEN4) without somatic loss of the other allele. Tumor analysis revealed a YAP1::MAML2 fusion, which has been previously reported in pediatric meningiomas not associated with NF2. YAP1::MAML2 fusion is a known driver for development of meningioma, but the role of the germline CDKN1B variant in the absence of a tumor second hit is unclear. This case highlights the importance of performing combined tumor and germline molecular genetic analysis of rare tumors to help clarify the risk of development of cancer in patients with rare cancer predisposition syndromes.

Introduction

Meningiomas are the most common primary brain tumors in adults with prevalence estimated to be 97.5/100,000 in the United States [1,2]. Meningiomas are classified in three grades. Grade 1 meningiomas are low grade, slow growing, and account for 80% of meningiomas. Grade 2 (atypical) and III (anaplastic) meningiomas are more aggressive, with poorer prognosis and account for around 15–20% and 1–4% of meningiomas respectively [1,3–5]. Inactivation of NF2 is the most common molecular abnormality reported in meningioma, occurring in 40–60% of tumors; and germline NF2 variants associated with neurofibromatosis type 2 (NF2) have been reported in 40% of individuals diagnosed with solitary meningioma before age 25 [6,7]. Several other cancer predisposition syndromes have been associated with increased risk of developing meningiomas including multiple endocrine neoplasia type 1 (MEN1) (OMIM# 131100), SMARCE1-associated familial meningioma (OMIM# 607174), and Gorlin syndrome (OMIM #s 109400 and 620343) [6]. Although clinically similar to MEN1, meningiomas have thus far rarely been described in multiple endocrine neoplasia type 4 (MEN4) (OMIM# 610755) associated with germline variants in CDKN1B[8].

Case Presentation

Clinical Presentation

Our patient presented as a 6-year-old boy with several days of headache, vomiting and decreased alertness. A non-contrast head CT showed intracranial hemorrhage associated with a large right frontotemporal mass. Follow up imaging with MRI of brain and spine and magnetic resonance angiography (MRA) brain revealed a 6.6 × 6.2 × 5.2 cm T1 hypointense, T2 hyperintense, heterogeneously enhancing hemorrhagic mass arising near the right inferior frontal lobe with suprasellar extension. Internal hemorrhage and necrosis were present. Patient underwent a partial resection; pathologic analysis reported anaplastic meningioma (WHO grade 3). After multi-disciplinary discussions, the patient underwent two additional attempts to debulk the tumor resulting in 90% removal followed by focal radiation therapy (59.40cGy in 33 fractions) using Intensity Modulated Radiation Therapy (IMRT) given the anaplastic histology. The family consented to participate in an Institutional Review Board approved Baylor College of Medicine multi-institutional genomic study of patients with childhood cancers (Texas KidsCanSeq), which included both tumor and germline sequencing [9,10].

Subsequent MRI scans showed stable residual disease, however, three years later, the patient underwent right craniotomy for surgical clipping of a right middle cerebral artery (MCA) aneurysm. The procedure was complicated by hemorrhagic hydrocephalus, and a ventriculoperitoneal (VP) shunt was placed. No new focal neurologic deficits were noted post-MCA clipping but newly required anti-epileptic treatment for worsening refractory seizures. Follow-up imaging 5 years after initial presentation demonstrated stable residual tumor.

Genomic Analysis

Tumor and germline sequencing was performed as per KidsCanSeq study procedures after patient consent [9,10]. A tumor sample from the initial resection was analyzed with an institutional targeted DNA and RNA NGS panel (Texas Children’s Hospital (TCH) solid tumor comprehensive panel) in a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, which identified 35 RNA fusion reads supporting an in-frame YAP1::MAML2 fusion, joining exon 6 of YAP1 (NM_001130145.3) at chr11:102080295 to exon 2 of MAML2 (NM_032427.4) at chr11:95826681, both genes on chromosome 11q and transcribed in opposite direction. The chimeric YAP1::MAML2 protein is predicted to retain the N-terminal TEAD-binding and two WW domains of YAP1 fused to the MAML2 transcriptional activation domain. Identical YAP1::MAML2 fusions have previously been described in pediatric meningiomas not associated with NF2 [11–13]. Two variants of uncertain significance (VUS) in KMT2C (c.1402C>A (p.Pro468)) and TSC2 (c.1820C>T (p.Ala607Val)) in the tumor sample were also reported without further evidence of oncogenicity.

Germline exome sequencing from blood DNA revealed a heterozygous pathogenic CDKN1B (NM_004064.4) c.295_305del (p.Cys99Glyfs*22) frameshift variant [10]. This variant is absent from germline databases including gnomAD and ClinVar but has been reported 4 times in the COSMIC database of tumor variants (ID: COSV57430356). Parental DNA analysis confirmed maternal transmission of the CDKN1B variant. A germline RAD51C VUS (ClinVar Variation ID: 188317) was also reported without significant evidence of pathogenicity.

More extensive tumor genomic profiling with tumor exome and transcriptome sequencing confirmed the YAP1::MAML2 fusion and the CDKN1B c.295_305del variant (0.40 VAF) described above with no additional CDKN1B variants or loss of heterozygosity reported in the tumor. No other variants of established or potential significance, including in NF2, were reported in these tumor studies.

Discussion

Combined tumor and germline analysis revealed a somatic YAP1::MAML2 fusion and a pathogenic germline CDKN1B variant in this child with anaplastic meningioma. Both of these findings were of interest to the clinical team due to potential biological relevance and prior associations in the literature. Therefore, both somatic and molecular data are further described.

YAP1 is a transcription coactivator with downstream effects in the Hippo pathway, which regulates cell proliferation and apoptosis [14]. YAP1::MAML2 fusions in pediatric meningioma have previously been described [11,12]. Moreover, YAP1::MAML2 fusions have been demonstrated in mouse models to drive tumors that resemble NF2-mutant meningiomas likely given the role of the NF2 protein product, merlin, as a negative regulator of YAP/TAZ signaling [6,12]. Given the established role of YAP1 fusions as oncogenic drivers in meningioma without NF2 alterations, this somatic finding is expected to contribute to the development of meningioma in this case.

Germline CDKN1B variants, such as the one reported in our patient, have been associated with Multiple Endocrine Neoplasia Type 4 (MEN4), a syndrome with clinical similarity to MEN1 that was first described in 2006 and remains a rare diagnosis [15,16]. A recent systematic review showed only 65 cases of MEN4 syndrome from 2006 to 2022 of which 48 patients were symptomatic [17]. MEN1, first described in 1954, is notably better understood and characterized by parathyroid, anterior pituitary, and neuroendocrine pancreatic tumors, which have also been described in patients with MEN4 [15,18]. Meningiomas have been associated with MEN1, although they are not considered a core cancer in the disorder. In spite of the small number of MEN4 cases in the literature, there is one adult patient reported with MEN4 who developed a cerebral meningioma [8,19]. While the clinical similarity of MEN1 and MEN4 along with prior case reports support the potential association of MEN4 and meningioma, the lack of a second somatic hit in the tumor does not support this assertion in our patient. It is therefore unclear whether the germline CDKN1B variant may have contributed to tumorigenesis.

Without genetic analysis of our patient, we would not have uncovered the possible underlying genetic alterations associated with our patient’s rare pediatric anaplastic meningioma. This case shows the importance of both germline and somatic profiling to better understand the pathogenesis and ultimately find a cure or treatment. However, though genetic screening may give us further insight into these disease processes, it may also lead to additional uncertainty or ambiguity as was the case for this family who have thus far been reluctant to discuss and pursue surveillance and/or cascade testing for the MEN4 diagnosis in other family members. This may be influenced by limited risk perception as there was no maternal history of MEN4 phenotypes reported at the time of disclosure (40 years of age). It is critical to acknowledge and be aware of the effect germline findings in particular can have on the patient and their family members. Newly described or rare cancer predisposition syndromes such as MEN4 may not have clear associations with patients’ clinical presentation and may also lack management and screening guidelines. A culturally sensitive and personally adaptive approach should be used by genetic counselors and/or other ordering providers, e.g. oncologists, when discussing diagnosis of a cancer predisposition disorder. When additional support is needed, the inclusion of other disciplines such as a psychologist or chaplain may facilitate adjustment as families receive and process the diagnosis.

Overall, this case highlights the importance of molecular analysis of rare tumors, combined with germline testing to increase the understanding of cancer development in patients with rare cancer predisposing syndromes, while acknowledging the implications of the results to the patient and family members.

Fig 1.

A: MRI T1-weighted scan post contrast, sagittal section of the brain at presentation in 2015. B: MRI axial pre-contrast T1-weighted image of the brain at presentation in 2015. C: MRI T1-weighted scan post contrast, sagittal section of the brain prior to radiation in 2015. D: MRI T1-weighted scan post contrast, axial section of the brain prior to radiation in 2015. E: Sagittal section of radiation therapy field. F: Axial section of radiation therapy field. G: MRI T1-weighted scan post contrast, sagittal section of the brain 6 years after radiation treatment. H: MRI T1-weighted scan post contrast, axial section of the brain 6 years after radiation treatment.

Fig 2.

A-C: Hematoxylin and eosin (H&E) staining demonstrates whorling architecture (thin arrows) and necrosis (*) (A and B) in addition to tumor invasion into brain parenchyma (thick arrow) (C). D: SSTR2, a specific immunomarker for meningioma, strongly labels whorling meningothelial cells. (A and C: 100 magnification; B and D: 200 magnification). E: Integrative Genomics Viewer (IGV) visualization of aligned tumor RNA sequencing reads demonstrating the YAP1::MAML2 fusion with YAP1 to the left of dotted line, and MAML2 to right. F: Illustration of YAP1::MAML2 fusion product with domains modified from image generated by https://proteinpaint.stjude.org/[20].