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Additional file 9: Table S1. Clinical data of the samples in this work.

Yue Li,1,* wentao Liu,1,* Xiaoyan Zhang,2,* Yu Fang,2 Xiaolong Yue,1 Xin Zhang,2 Qifan He,2 Na Fu,1 Sizhen Wang,2 Tonghui Ma,2 Dalin Li1 1Oncology Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China; 2Department of Translational Medicine, Genetron Health (Beijing) Technology, Co. Ltd., Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dalin LiOncology Department, Harbin Medical University Cancer Hospital, Haping Road No. 150, Nangang District, Harbin, Heilongjiang, People’s Republic of ChinaEmail lidalin0906@163.comTonghui MaMedical Department, Genetron Health (Beijing) Technology, Co. Ltd., Building 11, Zone 1, 8 Life Science Parkway, Changping District, Beijing, People’s Republic of ChinaEmail tonghuima0818@sina.comAbstract: Ovarian clear cell carcinoma (OCCC) is a rare type of epithelial ovarian cancer characterized by a chemoresistant phenotype and high-grade tumor. Conventional therapies for OCCC include surgery and chemotherapy. However, these OCCC treatment approaches are characterized by a high risk of relapse and drug resistance resulting in poor prognosis. Therefore, alternative therapeutic approaches are required to achieve better outcomes. In this study, a PIK3CA p.R88Q mutation and PD-L1 expression with a tumor proportion score of 10% was explored in a patient who presented with rapid recurrence after surgery and unsuccessful postoperative chemotherapy. Based on the clinical condition and the patient preference, she was administered a novel combinatorial therapy comprising mTOR inhibitor everolimus, which is a well-known and potent inhibitor of the PI3K/AKT signaling pathway, and the anti-PD-1 antibody toripalimab. Treatment with this combinatorial therapy showed good prognosis, with more than eight months of disease control, and no severe adverse events were observed. The findings of this study provide a novel and effective strategy for OCCC patients. To the best of our knowledge, this is the first study to report a new combination regimen of immunotherapy (everolimus plus toripalimab) for solid tumors. Everolimus is not only an antitumor targeted drug but also an immunosuppressant; it’s combination with immunotherapy is controversial. This is the first report to demonstrate that it has a synergistic effect.Keywords: ovarian clear cell carcinoma, PIK3CA mutation, high PD-L1 expression, everolimus, toripalimab

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease., Brainstem gliomas are heterogenous in terms of clinical outcome and disease etiology. Here, the authors present a genetic and epigenetic landscape of brainstem gliomas, finding distinct epigenetic clusters associated with unique genetic and clinical profiles.

The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTpWT-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTpWT-IDHWT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1., Glioblastoma can be classified based on IDH and TERT promoter mutations, but ~20% of glioblastoma do not have these mutations (TERTpWT-IDHWT glioblastoma). Here, the authors present a genetic landscape of TERTpWT-IDHWT glioblastoma, identifying a telomerase-positive subgroup driven by TERT-structural rearrangements and an ALT-positive subgroup with mutations in ATRX or SMARCAL1.