Person:

Dunn, Ian

There has been a recent revolution in our understanding of the genetic factors that drive meningioma, punctuating an equilibrium that has existed since Cushing’s germinal studies nearly a century ago. A growing appreciation that meningiomas share similar biologic features with other malignancies has allowed extrapolation of management strategies and lessons from intra-axial central nervous system neoplasms and systemic cancers to meningiomas. These features include a natural proclivity for invasion, frequent intratumoral heterogeneity, and correlation between biologic profile and clinical behavior. Next-generation sequencing has characterized recurrent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA, which are collectively present in ~80% of sporadic meningiomas. Genomic features of meningioma further associate with tumor location, histologic subtype, and possibly clinical behavior. Such genomic decryption, along with advances in targeted pharmacotherapy, provides a maturing integrated view of meningiomas. We review recent advances in meningioma genomics and probe their potential applications in diagnostic, therapeutic, and prognostic frontiers.

Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.

Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.

Object

A considerable degree of variability exists in the anatomy of the sphenoid sinus, sella turcica, and surrounding skull base structures. The authors aimed to characterize neuroimaging and intraoperative variations in the sagittal and coronal surgical anatomy of healthy controls and patients with sellar lesions. Methods

Magnetic resonance imaging studies obtained in 100 healthy adults and 78 patients with sellar lesions were reviewed. The following measurements were made on midline sagittal images: sellar face, sellar prominence, sellar angle, tuberculum sellae angle, sellar-clival angle, length of planum sphenoidale, and length of clivus. The septal configuration of the sphenoid sinus was classified as either simple or complex, according to the number of septa, their symmetry, and their morphological features. The following measurements were made on coronal images: maximum width of the sphenoid sinus and sellar face, and the distance between the parasellar and midclivus internal carotid arteries. Neuroimaging results were correlated with intraoperative findings during endoscopic transsphenoidal surgery. Results

Three sellar floor morphologies were defined in normal adults: prominent (sellar angle of < 90°) in 25%, curved (sellar angle 90–150°) in 63%, flat (sellar angle > 150°) in 11%, and no floor (conchal sphenoid) in 1%. In healthy adults, the following mean measurements were obtained: sellar face, 13.4 mm; sellar prominence, 3.0 mm; sellar angle, 112°; angle of tuberculum sellae, 112°; and sellar-clival angle, 117°. Compared with healthy adults, patients with sellar lesions were more likely to have prominent sellar types (43% vs 25%, p = 0.01), a more acute sellar angle (102° vs 112°, p = 0.03), a more prominent sellar floor (3.8 vs 3.0 mm, p < 0.005), and more acute tuberculum (105° vs 112°, p < 0.01) and sellar-clival (105° vs 117°, p < 0.003) angles. A flat sellar floor was more difficult to identify intraoperatively and more likely to require the use of a chisel or drill to expose (75% vs 25%, p = 0.01). A simple sphenoid sinus configuration (no septa, 1 vertical septum, or 2 symmetric vertical septa) was noted in 71% of studies, and the other 29% showed a complex configuration (2 or more asymmetrical septa, 3 or more septa of any kind, or the presence of a horizontal septum). Intraoperative correlation was more challenging in cases with complex sinus anatomy; the most reliable intraoperative midline markers were the vomer, superior sphenoid rostrum, and bilateral parasellar and clival carotid protuberances. Conclusions

Preoperative assessment of neuroimaging studies is critical for characterizing the morphological characteristics of the sphenoid sinus, sellar floor, tuberculum sellae, and clivus. The flat sellar type identified in 11% of people) or a complex sphenoid sinus configuration (in 29% of people) may make intraoperative correlation substantially more challenging. An understanding of the regional anatomy and its variability can improve the safety and accuracy of transsphenoidal and extended endoscopic skull base approaches.

The main goal of brain tumor surgery is to maximize tumor resection while preserving brain function. However, existing imaging and surgical techniques do not offer the molecular information needed to delineate tumor boundaries. We have developed a system to rapidly analyze and classify brain tumors based on lipid information acquired by desorption electrospray ionization mass spectrometry (DESI-MS). In this study, a classifier was built to discriminate gliomas and meningiomas based on 36 glioma and 19 meningioma samples. The classifier was tested and results were validated for intraoperative use by analyzing and diagnosing tissue sections from 32 surgical specimens obtained from five research subjects who underwent brain tumor resection. The samples analyzed included oligodendroglioma, astrocytoma, and meningioma tumors of different histological grades and tumor cell concentrations. The molecular diagnosis derived from mass-spectrometry imaging corresponded to histopathology diagnosis with very few exceptions. Our work demonstrates that DESI-MS technology has the potential to identify the histology type of brain tumors. It provides information on glioma grade and, most importantly, may help define tumor margins by measuring the tumor cell concentration in a specimen. Results for stereotactically registered samples were correlated to preoperative MRI through neuronavigation, and visualized over segmented 3D MRI tumor volume reconstruction. Our findings demonstrate the potential of ambient mass spectrometry to guide brain tumor surgery by providing rapid diagnosis, and tumor margin assessment in near–real time.

Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1, which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection.

Purpose Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. Methods: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. Results: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. Conclusions: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.

There are no effective medical treatments for WHO grade III (anaplastic) meningioma. Patients with this high-grade malignancy have a median survival of less than two years. Therapeutics that modulate the mechanisms that inhibit local immune responses in the tumor microenvironment are showing significant and durable clinical responses in patients with treatment refractory high-grade tumors. We examined the immune infiltrate of 291 meningiomas including WHO grade I-III meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In anaplastic meningioma, there is a sharp decrease in the number of T cells, including the numbers of CD4+ and CD8+ T cells and cells expressing PD-1 and there is also an increase in the number of FOXP3 expressing immunoregulatory (Treg) cells. PD-L1 expression is increased in anaplastic meningioma – both mRNA and protein. Using patient derived meningioma cell, we confirm that PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. This work indicates that high-grade meningioma harbor an immunosuppressive tumor microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the aggressive phenotype of these tumors.

Background: Aberrant (\beta)-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate (\beta)-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active (\beta)-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized (\beta)-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1(\varepsilon)) as required specifically for the proliferation of breast cancer cells with activated (\beta)-catenin and confirm its role as a positive regulator of (\beta)-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated (\beta)-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/(\beta)-catenin signaling. We also find that expression of CK1(\varepsilon) is able to promote oncogenic transformation of human cells in a (\beta)-catenin-dependent manner. Conclusions/Significance: These studies identify CK1(\varepsilon) as a critical contributor to activated (\beta)-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active (\beta)-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors.