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1. Molecular and translational advances in meningiomas

Author

Suppiah S., Nassiri F., Bi W. L., Dunn I. F., Hanemann C. O., Horbinski C. M., Hashizume R., James C. D., Mawrin C., Noushmehr H., Perry A., Sahm F., Sloan A., Von Deimling A., Wen P. Y., Aldape K., Zadeh G., Au K., Barnhartz-Sloan J., Brastianos P. K., Butowski N., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Griffith B., Herold-Mende C., Huang R. Y., James D., Jenkinson M. D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mansouri A., McDermott M., Munoz D., Ng H. -K., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N. O., Selman W., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J. C., Tsang D., Vogelbaum M. A., Deimling A. V., Walbert T., Westphal M., Workewych A. M., Suppiah S., Nassiri F., Bi W.L., Dunn I.F., Hanemann C.O., Horbinski C.M., Hashizume R., James C.D., Mawrin C., Noushmehr H., Perry A., Sahm F., Sloan A., Von Deimling A., Wen P.Y., Aldape K., Zadeh G., Au K., Barnhartz-Sloan J., Brastianos P.K., Butowski N., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Griffith B., Herold-Mende C., Huang R.Y., James D., Jenkinson M.D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mansouri A., McDermott M., Munoz D., Ng H.-K., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N.O., Selman W., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J.C., Tsang D., Vogelbaum M.A., Deimling A.V., Walbert T., Westphal M., and Workewych A.M.

Subjects
Cancer Research, Supplement Articles, Genomics, Intracranial Neoplasm, sporadic meningioma, Bioinformatics, World health, Translational Research, Biomedical, Meningioma, 03 medical and health sciences, biomolecular, 0302 clinical medicine, Meningeal Neoplasms, otorhinolaryngologic diseases, medicine, Recurrent disease, Humans, Meningeal Neoplasm, Molecular Targeted Therapy, xenograft, Stage (cooking), neoplasms, MENINGIOMA, business.industry, cell line, Prognosis, medicine.disease, Combined Modality Therapy, nervous system diseases, 3. Good health, Clinical trial, Oncology, 030220 oncology & carcinogenesis, Neurology (clinical), genetic, business, epigenetic, 030217 neurology & neurosurgery
Abstract

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

Published
2019
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2. Life after surgical resection of a meningioma: a prospective cross-sectional study evaluating health-related quality of life

Author

Nassiri F., Price B., Shehab A., Au K., Cusimano M. D., Jenkinson M. D., Jungk C., Mansouri A., Santarius T., Suppiah S., Teng K. X., Toor G. S., Zadeh G., Walbert T., Drummond K. J., Aldape K., Barnhartz-Sloan J., Bi W. L., Brastianos P. K., Butowski N., Carlotti C., Dimeco F., Dunn I. F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C. O., Herold-Mende C., Horbinski C., Huang R. Y., James D., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H. -K., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Sahm F., Saladino A., Schichor C., Schultz D., Schmidt N. O., Selman W., Sloan A., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J. C., Tsang D., Vogelbaum M. A., Deimling A. V., Wen P. Y., Westphal M., Workewych A. M., Nassiri F., Price B., Shehab A., Au K., Cusimano M.D., Jenkinson M.D., Jungk C., Mansouri A., Santarius T., Suppiah S., Teng K.X., Toor G.S., Zadeh G., Walbert T., Drummond K.J., Aldape K., Barnhartz-Sloan J., Bi W.L., Brastianos P.K., Butowski N., Carlotti C., Dimeco F., Dunn I.F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C.O., Herold-Mende C., Horbinski C., Huang R.Y., James D., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H.-K., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Sahm F., Saladino A., Schichor C., Schultz D., Schmidt N.O., Selman W., Sloan A., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J.C., Tsang D., Vogelbaum M.A., Deimling A.V., Wen P.Y., Westphal M., and Workewych A.M.

Subjects
Male, cognition, Cancer Research, medicine.medical_specialty, Cross-sectional study, insomnia, Population, Neurosurgery, Supplement Articles, meningioma, surgery, Meningioma, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Internal medicine, Meningeal Neoplasms, otorhinolaryngologic diseases, medicine, Humans, Longitudinal Studies, Prospective Studies, Prospective cohort study, education, education.field_of_study, business.industry, COGNIÇÃO, Cognition, Middle Aged, Prognosis, medicine.disease, humanities, 3. Good health, health-related quality of life, Cross-Sectional Studies, Oncology, 030220 oncology & carcinogenesis, Quality of Life, Female, fatigue, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies, Cohort study
Abstract

Background Few studies have evaluated the health-related quality of life (HRQoL) of patients with meningiomas. Here, we report the largest prospective, longitudinal cross-sectional cohort study of HRQoL in meningiomas to date, in order to identify possible actionable determinants of global HRQoL. Methods Adults who had undergone resection of a grade I intracranial meningioma and were in routine follow-up at a single large tertiary center underwent HRQoL assessment using the QLQ-C30 questionnaire administered opportunistically at follow-up visits. Averaged transformed QLQ-C30 scores at 12-month intervals were compared with scores from a normative reference population, with reference to known minimal clinically meaningful difference (CMD) in scores. To evaluate for possible determinants of changes in global HRQoL, global HRQoL scores were correlated (Spearman's Rho) with subdomain and symptom scores and with interval time from surgical resection. Results A total of 291 postoperative patients with histologically confirmed and surgically treated grade I meningiomas consented to participation and a total of 455 questionnaires were included for analysis. Patients with meningiomas reported reduced global HRQoL at nearly every 12-month interval with clinically and statistically significant impairments at 12, 48, 108, and 120 months postoperative compared with the normative population (P < 0.05). Meningioma patients at the 12-month interval also reported a reduction of each subdomain of HRQoL assessment (P < 0.05); however, a CMD was only seen in cognitive functioning. Physical, emotional, cognitive, and social subdomains, as well as fatigue and sleep/insomnia, were significantly associated with global HRQoL at the first 12-month interval. Overall, there was no significant correlation between time from surgery and global HRQoL or the subdomain functional or symptom sections of the QLQ-C30. Conclusions Meningioma patients report considerable limitations in HRQoL for more than 120 months after surgery, particularly in cognitive, emotional, and social function, as well as suffering significant fatigue and sleep impairment compared with a normative reference population. The majority of these reported functional impairments and symptoms are strongly associated with global HRQoL and thus can be considered determinants of global HRQoL that if treated, have the potential to improve HRQoL for our meningioma patients. This hypothesis requires future study of targeted interventions to determine their efficacy.

Published
2019
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3. DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

Author

Nassiri F., Mamatjan Y., Suppiah S., Badhiwala J. H., Mansouri S., Karimi S., Saarela O., Poisson L., Gepfner-Tuma I., Schittenhelm J., Ng H. -K., Noushmehr H., Harter P., Baumgarten P., Weller M., Preusser M., Herold-Mende C., Tatagiba M., Tabatabai G., Sahm F., Von Deimling A., Aldape K., Au K., Barnhartz-Sloan J., Bi W. L., Brastianos P. K., Butowski N., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Dunn I. F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C. O., Horbinski C., Huang R. Y., James D., Jenkinson M. D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Malta T. M., Mawrin C., McDermott M., Munoz D., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N. O., Selman W., Sloan A., Spears J., Snyder J., Tirapelli D., Tonn J. C., Tsang D., Vogelbaum M. A., Wen P. Y., Walbert T., Westphal M., Workewych A. M., Zadeh G., Aldape K. D., Nassiri F., Mamatjan Y., Suppiah S., Badhiwala J.H., Mansouri S., Karimi S., Saarela O., Poisson L., Gepfner-Tuma I., Schittenhelm J., Ng H.-K., Noushmehr H., Harter P., Baumgarten P., Weller M., Preusser M., Herold-Mende C., Tatagiba M., Tabatabai G., Sahm F., Von Deimling A., Aldape K., Au K., Barnhartz-Sloan J., Bi W.L., Brastianos P.K., Butowski N., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Dunn I.F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C.O., Horbinski C., Huang R.Y., James D., Jenkinson M.D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Malta T.M., Mawrin C., McDermott M., Munoz D., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N.O., Selman W., Sloan A., Spears J., Snyder J., Tirapelli D., Tonn J.C., Tsang D., Vogelbaum M.A., Wen P.Y., Walbert T., Westphal M., Workewych A.M., Zadeh G., and Aldape K.D.

Subjects
Oncology, Cancer Research, medicine.medical_specialty, recurrence, predictor, ESTUDOS DE VALIDAÇÃO, Meningioma, nomogram, Internal medicine, medicine, Biomarkers, Tumor, Meningeal Neoplasms, Humans, Survival rate, Retrospective Studies, Oncotype DX Breast Cancer Assay, business.industry, Hazard ratio, Cancer, Disease Management, Retrospective cohort study, Nomogram, DNA Methylation, medicine.disease, Prognosis, Gene Expression Regulation, Neoplastic, Survival Rate, Clinical research, Basic and Translational Investigations, Neurology (clinical), methylation, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

Published
2019

4. Advances in multidisciplinary therapy for meningiomas

Author

Brastianos P. K., Galanis E., Butowski N., Chan J. W., Dunn I. F., Goldbrunner R., Herold-Mende C., Ippen F. M., Mawrin C., McDermott M. W., Sloan A., Snyder J., Tabatabai G., Tatagiba M., Tonn J. C., Wen P. Y., Aldape K., Nassiri F., Zadeh G., Jenkinson M. D., Raleigh D. R., Au K., Barnhartz-Sloan J., Bi W. L., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Giannini C., Griffith B., Hashizume R., Hanemann C. O., Horbinski C., Huang R. Y., James D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mansouri A., Munoz D., Noushmehr H., Ng H. -K., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N. O., Selman W., Spears J., Suppiah S., Tirapelli D., Tsang D., Vogelbaum M. A., Deimling A. V., Walbert T., Westphal M., Workewych A. M., Brastianos P.K., Galanis E., Butowski N., Chan J.W., Dunn I.F., Goldbrunner R., Herold-Mende C., Ippen F.M., Mawrin C., McDermott M.W., Sloan A., Snyder J., Tabatabai G., Tatagiba M., Tonn J.C., Wen P.Y., Aldape K., Nassiri F., Zadeh G., Jenkinson M.D., Raleigh D.R., Au K., Barnhartz-Sloan J., Bi W.L., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Giannini C., Griffith B., Hashizume R., Hanemann C.O., Horbinski C., Huang R.Y., James D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mansouri A., Munoz D., Noushmehr H., Ng H.-K., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N.O., Selman W., Spears J., Suppiah S., Tirapelli D., Tsang D., Vogelbaum M.A., Deimling A.V., Walbert T., Westphal M., and Workewych A.M.

Subjects
Oncology, Cancer Research, medicine.medical_treatment, Supplement Articles, meningioma, Systemic therapy, surgery, 0302 clinical medicine, Meningeal Neoplasms, Trabectedin, Cancer, clinical trial, targeted therapy, Prognosis, Combined Modality Therapy, 3. Good health, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, International Consortium on Meningiomas, Patient Safety, Meningioma, medicine.drug, medicine.medical_specialty, Oncology and Carcinogenesis, Antineoplastic Agents, Radiosurgery, 03 medical and health sciences, Internal medicine, medicine, otorhinolaryngologic diseases, Humans, Meningeal Neoplasm, Oncology & Carcinogenesis, neoplasms, business.industry, Neurosciences, Evaluation of treatments and therapeutic interventions, medicine.disease, RADIOTERAPIA, Brain Disorders, nervous system diseases, Clinical trial, Radiation therapy, radiation, Neurology (clinical), Cranial Irradiation, business, 030217 neurology & neurosurgery
Abstract

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas.

Published
2019

5. Imaging and diagnostic advances for intracranial meningiomas

Author

Huang R. Y., Bi W. L., Griffith B., Kaufmann T. J., La Fougere C., Schmidt N. O., Tonn J. C., Vogelbaum M. A., Wen P. Y., Aldape K., Nassiri F., Zadeh G., Dunn I. F., Au K., Barnhartz-Sloan J., Brastianos P. K., Butowski N., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Hashizume R., Hanemann C. O., Herold-Mende C., Horbinski C., James D., Jenkinson M. D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mansouri A., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H. -K., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Selman W., Sloan A., Spears J., Snyder J., Suppiah S., Tabatabai G., Tatagiba M., Tirapelli D., Tsang D., Deimling A. V., Walbert T., Westphal M., Workewych A. M., Huang R.Y., Bi W.L., Griffith B., Kaufmann T.J., La Fougere C., Schmidt N.O., Tonn J.C., Vogelbaum M.A., Wen P.Y., Aldape K., Nassiri F., Zadeh G., Dunn I.F., Au K., Barnhartz-Sloan J., Brastianos P.K., Butowski N., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Hashizume R., Hanemann C.O., Herold-Mende C., Horbinski C., James D., Jenkinson M.D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mansouri A., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H.-K., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Selman W., Sloan A., Spears J., Snyder J., Suppiah S., Tabatabai G., Tatagiba M., Tirapelli D., Tsang D., Deimling A.V., Walbert T., Westphal M., and Workewych A.M.

Subjects
Cancer Research, medicine.medical_specialty, Neuroimaging, Supplement Articles, Multimodal Imaging, perfusion, Meningioma, 03 medical and health sciences, 0302 clinical medicine, Medical imaging, medicine, Meningeal Neoplasms, Humans, Meningeal Neoplasm, Radiation treatment planning, medicine.diagnostic_test, business.industry, imaging, Magnetic resonance imaging, medicine.disease, radiology, 3. Good health, Tumor detection, RADIOLOGIA, PET, Oncology, 030220 oncology & carcinogenesis, Radiological weapon, Neurology (clinical), Radiology, business, 030217 neurology & neurosurgery, CT, MRI
Abstract

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine.

Published
2019

6. Subgroup and subtype‑specifc outcomes in adult medulloblastoma

Author

Konstantin Okonechnikov, Charles G. Eberhart, Roger E. McLendon, Ian F. Pollack, Stefan M. Pfister, Kyle S. Smith, Shin Jung, Noriyuki Kijima, Alexandre Vasiljevic, Karisa C. Schreck, Oksana Absalyamova, Paul A. Northcott, Daniela Pretti da Cunha Tirapelli, Rajeev Vibhakar, Sarah Leary, Olga Zheludkova, Kay K.W. Li, Lakshmikirupa Sundaresan, Seung-Ki Kim, Hallie Coltin, Jaume Mora, Erwin G. Van Meir, Wiesława Grajkowska, Marcel Kool, Daniel W. Fults, Pim J. French, Caterina Giannini, Andreas von Deimling, Jennifer A. Chan, Andrey Golanov, Linda M. Liau, Scott Raskin, Michael D. Taylor, Joshua B. Rubin, Cécile Faure-Conter, Roger J. Packer, Luca Massimi, William A. Weiss, Peter Hauser, Andrey Korshunov, Lola B. Chambless, Patryk Skowron, Carlos Gilberto Carlotti, Vijay Ramaswamy, Marie Lise C. van Veelen, Marina Ryzhova, Damian Stichel, Nalin Gupta, Johan M. Kros, Coltin H., Sundaresan L., Smith K.S., Skowron P., Massimi L., Eberhart C.G., Schreck K.C., Gupta N., Weiss W.A., Tirapelli D., Carlotti C., Li K.K.W., Ryzhova M., Golanov A., Zheludkova O., Absalyamova O., Okonechnikov K., Stichel D., von Deimling A., Giannini C., Raskin S., Van Meir E.G., Chan J.A., Fults D., Chambless L.B., Kim S.-K., Vasiljevic A., Faure-Conter C., Vibhakar R., Jung S., Leary S., Mora J., McLendon R.E., Pollack I.F., Hauser P., Grajkowska W.A., Rubin J.B., van Veelen M.-L.C., French P.J., Kros J.M., Liau L.M., Pfister S.M., Kool M., Kijima N., Taylor M.D., Packer R.J., Northcott P.A., Korshunov A., Ramaswamy V., Neurosurgery, Neurology, and Pathology

Subjects
Male, Oncology, Adult, medicine.medical_specialty, Adult Medulloblastoma, Adolescent, medicine.medical_treatment, DNA methylation profiling, Pathology and Forensic Medicine, Cohort Studies, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Risk Factors, GLI2, Internal medicine, Biomarkers, Tumor, medicine, Humans, Medulloblastoma, Sonic hedgehog, Cerebellar Neoplasms, Risk stratification, Chemotherapy, biology, business.industry, Molecular groups, medicine.disease, Molecular group, NEOPLASIAS CEREBRAIS, Progression-Free Survival, 3. Good health, Radiation therapy, PTCH1, 030220 oncology & carcinogenesis, Cohort, biology.protein, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

Published
2021

7. Heterogeneity within the PF-EPN-B ependymoma subgroup

Author

Almos Klekner, David W. Ellison, Vijay Ramaswamy, Betty Luu, Marcel Kool, David Shih, Eugene Hwang, Andrey Korshunov, Mariarita Santi, Michal Zapotocky, Juliette Hukin, Marta M. Alonso, Hendrik Witt, Caterina Giannini, Stephen C. Mack, Thomas E. Merchant, Tanvi Sharma, Ulrich Schüller, Marie Lise C. van Veelen, Jennifer A. Chan, Kristian W. Pajtler, Martin Sill, Christopher Dunham, Amulya A. Nageswara Rao, Benjamin Y. Lu, Maura Massimino, Sarah Leary, Daniela Pretti da Cunha Tirapelli, Eric S. Lipp, Tong Lin, Andrew J. Grossbach, Massimo Zollo, Carlos Gilberto Carlotti, Eric Bouffet, Matthias A. Karajannis, Terri S. Armstrong, Jaume Mora, Jens Martin Hübner, Ben Ho, Charles G. Eberhart, Lola B. Chambless, Roger E. McLendon, Veronica Ferrucci, Linda M. Liau, Kenneth Aldape, Florence M.G. Cavalli, Claudia C. Faria, Stefan M. Pfister, Sridharan Gururangan, Shin Jung, Pim J. French, Michael D. Taylor, Uri Tabori, Lyndsey Emery, Marina Ryzhova, Johan M. Kros, Mark R. Gilbert, Cavalli F.M.G., Hubner J.-M., Sharma T., Luu B., Sill M., Zapotocky M., Mack S.C., Witt H., Lin T., Shih D.J.H., Ho B., Santi M., Emery L., Hukin J., Dunham C., McLendon R.E., Lipp E.S., Gururangan S., Grossbach A., French P., Kros J.M., van Veelen M.-L.C., Rao A.A.N., Giannini C., Leary S., Jung S., Faria C.C., Mora J., Schuller U., Alonso M.M., Chan J.A., Klekner A., Chambless L.B., Hwang E.I., Massimino M., Eberhart C.G., Karajannis M.A., Lu B., Liau L.M., Zollo M., Ferrucci V., Carlotti C., Tirapelli D.P.C., Tabori U., Bouffet E., Ryzhova M., Ellison D.W., Merchant T.E., Gilbert M.R., Armstrong T.S., Korshunov A., Pfister S.M., Taylor M.D., Aldape K., Pajtler K.W., Kool M., Ramaswamy V., Neurology, Pathology, Neurosurgery, Cavalli, Florence M. G., Hübner, Jens-Martin, Sharma, Tanvi, Luu, Betty, Sill, Martin, Zapotocky, Michal, Mack, Stephen C., Witt, Hendrik, Lin, Tong, Shih, David J. H., Ho, Ben, Santi, Mariarita, Emery, Lyndsey, Hukin, Juliette, Dunham, Christopher, Mclendon, Roger E., Lipp, Eric S., Gururangan, Sridharan, Grossbach, Andrew, French, Pim, Kros, Johan M., van Veelen, Marie-Lise C., Rao, Amulya A. Nageswara, Giannini, Caterina, Leary, Sarah, Jung, Shin, Faria, Claudia C., Mora, Jaume, Schüller, Ulrich, Alonso, Marta M., Chan, Jennifer A., Klekner, Almo, Chambless, Lola B., Hwang, Eugene I., Massimino, Maura, Eberhart, Charles G., Karajannis, Matthias A., Lu, Benjamin, Liau, Linda M., Zollo, Massimo, Ferrucci, Veronica, Carlotti, Carlo, Tirapelli, Daniela P. C., Tabori, Uri, Bouffet, Eric, Ryzhova, Marina, Ellison, David W., Merchant, Thomas E., Gilbert, Mark R., Armstrong, Terri S., Korshunov, Andrey, Pfister, Stefan M., Taylor, Michael D., Aldape, Kenneth, Pajtler, Kristian W., Kool, Marcel, and Ramaswamy, Vijay

Subjects
Oncology, Ependymoma, Male, PFA, Posterior fossa, PFB, Infratentorial Neoplasms, Kaplan-Meier Estimate, Subgrouping, Cohort Studies, 0302 clinical medicine, Age Factor, Young adult, Child, Cancer, DNA Copy Number Variation, Infratentorial Neoplasm, Age Factors, Methylation, Orvostudományok, Middle Aged, Subependymoma, 030220 oncology & carcinogenesis, DNA methylation, Female, Human, Adult, medicine.medical_specialty, DNA Copy Number Variations, Adolescent, CITOGENÉTICA, Clinical Sciences, Biology, Klinikai orvostudományok, Article, Clustering, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Rare Diseases, Clinical Research, Internal medicine, Genetics, medicine, Humans, Microarray Analysi, Neurology & Neurosurgery, Microarray analysis techniques, Gene Expression Profiling, Human Genome, Neurosciences, DNA Methylation, Microarray Analysis, medicine.disease, Brain Disorders, Brain Cancer, Gene expression profiling, Neurology (clinical), Cohort Studie, 030217 neurology & neurosurgery
Abstract

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Published
2018

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