EPCO-04. GENOMIC AND EPIGENOMIC HALLMARKS OF SCHWANNOMATOSIS SCHWANNOMAS

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often, painful neuronal tumors called schwannomas (SWNs). Very little is known about the epigenomic and genomic alterations in SWNTS related SWNs (SWNTS-SWNs) other than germline mutations in SMARCB1 and LZTR1 plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q. Herein, we have comprehensively established the specific molecular signatures of SWNTS-SWNs. We found that tumor anatomic location was associated with pain and distinct DNA methylation and transcriptional signatures. DNA sequencing revealed several novel non-22q deletions, specifically in LZTR1-mutant cases. Whole-genome sequencing identified novel recurrent structural rearrangements. Further, chromosomal aberrations in SWNTS-SWNs were accompanied by increased transcription of mismatch repair genes. Our transcriptome analysis detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, more commonly in LZTR1-mutant tumors. In addition, we identified the specific genetic, epigenetic, and transcriptional hallmarks of painful SWNs that may be harnessed to develop new treatments for this debilitating syndrome.

Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.

Incidence and Outcomes of CNS Tumors in Chinese Children: Comparative Analysis With the Surveillance, Epidemiology, and End Results Program

PURPOSE Despite being the most common pediatric solid tumors, incidence and outcome of CNS tumors in Chinese children have not been systematically reported. We addressed this knowledge gap by comparing the epidemiology of pediatric CNS tumors in Hong Kong and the United States. PATIENTS AND METHODS Data between 1999 and 2016 from a population-based cancer registry in Hong Kong, China, on patients < 18 years old with CNS tumors (Hong Kong cohort) and from the US SEER Program (Asian/Pacific Islander and all ethnicities) were compared. Incidence and overall survival (OS) by histology were evaluated. RESULTS During the study period, 526 children were newly diagnosed with CNS tumors in Hong Kong (crude incidence rate, 2.47 per 100,000; 95% CI, 2.26 to 2.69). Adjusted incidences were significantly lower in the Hong Kong (2.51; 95% CI, 2.30 to 2.74) than in the SEER (Asian/Pacific Islander: 3.26; 95% CI, 2.97 to 3.57; P < .001; all ethnicities: 4.10 per 100,000; 95% CI, 3.99 to 4.22; P < .001) cohorts. Incidences of germ cell tumors (0.57 v 0.24; P < .001) were significantly higher, but those of glial and neuronal tumors (0.94 v 2.61; P < .001), ependymomas (0.18 v 0.31; P = .005), and choroid plexus tumors (0.08 v 0.16; P = .045) were significantly lower in Hong Kong compared with SEER (all ethnicities) cohorts. Compared with the SEER (Asian/Pacific Islander) cohort, histology-specific incidences were similar except for a lower incidence of glial and neuronal tumors in Hong Kong (0.94 v 1.74; P < .001). Among cohorts, OS differed only for patients with glial and neuronal tumors (5-year OS: Hong Kong, 52.5%; SEER [Asian/Pacific Islander], 73.6%; SEER [all ethnicities], 79.9%; P < .001). CONCLUSION We identified important ethnic differences in the epidemiology of CNS tumors in Chinese children. These results will inform the development of pediatric neuro-oncology services in China and aid further etiologic studies.

Pituitary Gangliocytoma Producing TSH and TRH: A Review of “Gangliocytomas of the Sellar Region”

Purpose Pituitary gangliocytomas (GCs) are rare neuronal tumors that present with endocrinological disorders, such as acromegaly, amenorrhea-galactorrhea syndrome, and Cushing’s disease. Most pituitary GCs coexist with pituitary adenomas pathologically and are diagnosed as mixed gangliocytoma-adenomas. Herein, we report a case of 45-year-old man who presented with the syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) and discuss the pathogenesis of pituitary GCs. Methods Pituitary magnetic resonance imaging showed an 8-mm homogeneous and poorly enhanced mass inside the pituitary gland. Endoscopic transsphenoidal surgery was performed under a preoperative diagnosis of thyrotroph adenoma. However, the tumor was finally diagnosed as gangliocytoma without an adenomatous component. The tumor was further analyzed via immunohistochemistry and electron microscopy. Additionally, we searched MEDLINE and PubMed for previously published cases of isolated pituitary GCs and analyzed the reported clinicopathological findings. Results The patient showed complete clinical and endocrinological recovery after an operation. The tumor was positive for thyrotropin (TSH), TSH-releasing hormone (TRH), Pit-1, GATA-2, and most neuronal markers. Electron microscopy demonstrated the presence of intracytoplasmic secretory granules and neuronal processes. Co-secreting hypothalamic and pituitary hormone inside the tumor indicated autocrine/paracrine endocrinological stimulation. Conclusion Herein, we report a case of SITSH caused by an isolated pituitary gangliocytoma, expressing both TSH and TRH, which, to our best knowledge, is the first reported case of such a condition. The multidirectional differentiation and multihormonal endocrine characteristics of these tumors indicate that they are a member of neuroendocrine neoplasms, further supporting that they are derived from neural crest cells.