Preanalytical variables and analytes in liquid biopsy approach for brain tumors: A comprehensive review and recommendations from the RANO Group and the Brain Liquid Biopsy Consortium

Chetan Bettegowda¹, Houtan Noushmehr², Alessandra Affinito³, Manmeet S Ahluwalia⁴, Olaf Ansorge⁵, Katayoun Ayasoufi⁶, Stephen Bagley⁷, Jill Barnholtz-Sloan⁸, Myron Best⁹, Dieta Brandsma¹⁰, Chaya Brodie¹¹, Anke Brüning-Richardson¹², Ana Valeria Castro^{2

13}, Susan M Chang¹⁴, Gerolama Condorelli³, Ahmad Daher¹⁵, Vineet Datta¹⁶, John de Groot¹⁴, Pim French¹⁷, Evanthia Galanis¹⁸, Anna Golebiewska¹⁹, Petra Hamerlik²⁰, C Oliver Hanemann²¹, Matthias Holdhoff²², Jason Huse²³, Mustafa Khasraw⁶, Suzanne LeBlang²⁴, Beatrice Melin²⁵, Florent Mouliere²⁶, Claire O'Leary²⁷, Janusz Rak²⁸, Amitava Ray²⁹, Stephen Robinson³⁰, Ola Rominiyi³¹, Federico Roncaroli³², Roberta Rudà³³, Joan Seoane³⁴, Nik Sol¹⁰, Martin J van den Bent³⁵, Michael A Vogelbaum³⁶, Tobias Walbert^{37

38}, Colin Watts³⁹, Tobias Weiss³⁷, Michael Weller³⁷, Patrick Y Wen⁴⁰, Victoria Wykes⁴¹, Stephen Yip⁴², Susan C Short⁴³, Riccardo Soffietti⁴⁴

Affiliations

¹ Department of Neurosurgery, Johns Hopkins Khatib Brain Tumor Center, Johns Hopkins University, Baltimore, USA.
² Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA.
³ Department of Molecular Medicine and Medical Biotechnology, Federico II University, Napoli, Italy.
⁴ Miami Cancer Institute, and Florida International University, Miami, Florida, USA.
⁵ Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁶ Department of Neurosurgery, Duke University, Durham, North Carolina, USA.
⁷ University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
⁹ Department of Neurosurgery, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁰ Department of Neuro-Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹¹ Faculty of Life Sciences and the Institute of Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, Ramat-Gan, Israel.
¹² School of Applied Sciences, University of Huddersfield, Huddersfield, UK.
¹³ Department of Physiology, Michigan State University, East Lansing, MI, USA.
¹⁴ Division of Neuro-Oncology, Department of Neurosurgery, University of California, San Francisco, California, USA.
¹⁵ Department of Neurology& Rehabilitation, University of Illinois at Chicago, Chicago, Illinois, USA.
¹⁶ Department of Research and Innovations, Datar Cancer Genetics, Nasik, India.
¹⁷ Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
¹⁸ Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
²⁰ Division of Cancer Sciences, University of Manchester, Manchester, UK.
²¹ Peninsula Medical School, University of Plymouth, Plymouth, UK.
²² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
²³ Departments of Pathology and Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
²⁴ Clinical Relationships, Focused Ultrasound Foundation, Charlottesville, Virginia, USA.
²⁵ Department of Diagnostics and Intervention Oncology, Umeå University, Umeå Sweden.
²⁶ Cancer Research UK National Biomarker Centre, University of Manchester, UK.
²⁷ Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
²⁸ Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
²⁹ Apollo Hospitals and Exsegen Genomics Research, Hyderabad, India.
³⁰ Department of Biochemistry and Biomedicine, University of Sussex, Brighton, UK.
³¹ Division of Neuroscience, University of Sheffield and Department of Neurosurgery, Sheffield Teaching Hospitals, Sheffield, UK.
³² Division of Neuroscience, University of Manchester, Manchester, UK.
³³ Division of Neuro-Oncology, Department Neuroscience 'Rita Levi Montalcini', University of Turin, Turin, Italy.
³⁴ Vall d'Hebron Institute of Oncology (VHIO) and University, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
³⁵ Department Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
³⁶ Department of Neuro-Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
³⁷ Department of Neurology, University of Zurich, Zurich, Switzerland.
³⁸ Departments of Neurosurgery and Neurology, Wayne State University, Detroit, Michigan, USA.
³⁹ Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁴⁰ Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
⁴¹ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁴² Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁴³ Leeds Institute of Medical Research, The University of Leeds, Leeds, UK.
⁴⁴ Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.

PMID: 40884415
DOI: 10.1093/neuonc/noaf140

Preanalytical variables and analytes in liquid biopsy approach for brain tumors: A comprehensive review and recommendations from the RANO Group and the Brain Liquid Biopsy Consortium

Chetan Bettegowda et al. Neuro Oncol. 2025.

. 2025 Aug 30:noaf140.

doi: 10.1093/neuonc/noaf140. Online ahead of print.

Authors

Affiliations

¹ Department of Neurosurgery, Johns Hopkins Khatib Brain Tumor Center, Johns Hopkins University, Baltimore, USA.
² Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA.
³ Department of Molecular Medicine and Medical Biotechnology, Federico II University, Napoli, Italy.
⁴ Miami Cancer Institute, and Florida International University, Miami, Florida, USA.
⁵ Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁶ Department of Neurosurgery, Duke University, Durham, North Carolina, USA.
⁷ University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
⁹ Department of Neurosurgery, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁰ Department of Neuro-Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹¹ Faculty of Life Sciences and the Institute of Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, Ramat-Gan, Israel.
¹² School of Applied Sciences, University of Huddersfield, Huddersfield, UK.
¹³ Department of Physiology, Michigan State University, East Lansing, MI, USA.
¹⁴ Division of Neuro-Oncology, Department of Neurosurgery, University of California, San Francisco, California, USA.
¹⁵ Department of Neurology& Rehabilitation, University of Illinois at Chicago, Chicago, Illinois, USA.
¹⁶ Department of Research and Innovations, Datar Cancer Genetics, Nasik, India.
¹⁷ Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
¹⁸ Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
²⁰ Division of Cancer Sciences, University of Manchester, Manchester, UK.
²¹ Peninsula Medical School, University of Plymouth, Plymouth, UK.
²² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
²³ Departments of Pathology and Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
²⁴ Clinical Relationships, Focused Ultrasound Foundation, Charlottesville, Virginia, USA.
²⁵ Department of Diagnostics and Intervention Oncology, Umeå University, Umeå Sweden.
²⁶ Cancer Research UK National Biomarker Centre, University of Manchester, UK.
²⁷ Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
²⁸ Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
²⁹ Apollo Hospitals and Exsegen Genomics Research, Hyderabad, India.
³⁰ Department of Biochemistry and Biomedicine, University of Sussex, Brighton, UK.
³¹ Division of Neuroscience, University of Sheffield and Department of Neurosurgery, Sheffield Teaching Hospitals, Sheffield, UK.
³² Division of Neuroscience, University of Manchester, Manchester, UK.
³³ Division of Neuro-Oncology, Department Neuroscience 'Rita Levi Montalcini', University of Turin, Turin, Italy.
³⁴ Vall d'Hebron Institute of Oncology (VHIO) and University, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
³⁵ Department Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
³⁶ Department of Neuro-Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
³⁷ Department of Neurology, University of Zurich, Zurich, Switzerland.
³⁸ Departments of Neurosurgery and Neurology, Wayne State University, Detroit, Michigan, USA.
³⁹ Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁴⁰ Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
⁴¹ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁴² Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁴³ Leeds Institute of Medical Research, The University of Leeds, Leeds, UK.
⁴⁴ Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.

PMID: 40884415
DOI: 10.1093/neuonc/noaf140

Abstract

This review explores the pivotal role of preanalytical variables in bringing liquid biopsy approaches into the clinic for brain tumors. Preanalytical variables encompass a range of critical issues, from blood sample collection and handling to the impact of tumor heterogeneity and patient-specific factors. These variables introduce challenges such as false positives, false negatives, and variability in the analysis of tumor signals, which can hinder the diagnostic and prognostic utility of liquid biopsies. Understanding the nuances of preanalytical variables is essential for the successful implementation of liquid biopsy in clinical settings. This paper delves into strategies aimed at mitigating the influence of preanalytical variables by emphasizing the importance of standardized sample collection protocols, optimized sample processing and storage, quality control measures, and the integration of multiple liquid biopsy modalities.

Keywords: cfDNA; circulating tumor cells; clinical trials; extracellular vesicles; liquid biopsy; metabolites; microRNA; preanalytical variables; proteins; strategies.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Preanalytical variables and analytes in liquid biopsy approach for brain tumors: A comprehensive review and recommendations from the RANO Group and the Brain Liquid Biopsy Consortium

Affiliations

Preanalytical variables and analytes in liquid biopsy approach for brain tumors: A comprehensive review and recommendations from the RANO Group and the Brain Liquid Biopsy Consortium

Authors

Affiliations

Abstract

LinkOut - more resources

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