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Vall d’Hebron University Hospital (HUVH), has evidenced that circulating tumor DNA (ctDNA) in the cerebrospinal fluid (CSF) of patients with diffuse gliomas can be used to both complement and more effectively facilitate diagnosis and prognosis with greater precision.
Published today ahead of print and open access in Clinical Cancer Research, a study led by Joan Seoane, Director of Translational Research at the Vall d´Hebron Institute of Oncology (VHIO) and ICREA Professor, and first authored by Francisco Martínez-Ricarte, Neurosurgeon, the Vall d’Hebron University Hospital (HUVH), has evidenced that circulating tumor DNA (ctDNA) in the cerebrospinal fluid (CSF) of patients with diffuse gliomas can be used to both complement and more effectively facilitate diagnosis and prognosis with greater precision.
Previous pioneering research directed by Joan Seoane and published in Nature Communications showed a groundbreaking proof-of-concept that cerebrospinal fluid (CSF) can be exploited as a liquid biopsy since it contains ctDNA. Importantly, this development promised new hope for patients with gliomas since a liquid biopsy in CSF, obtained by lumbar puncture, might better guide what, when and how much therapy. It could also offer a much less invasive and risky approach versus traditional procedures used to extract brain tissue samples.
“This earlier study showed that CSF contains DNA from tumors and can therefore be used as liquid biopsy for the less invasive, more effective policing of brain tumors. One major obstacle in applying liquid biopsy to brain cancer has been that circulating tumor DNA levels for gliomas are very low in plasma. Importantly, we detected circulating tumor DNA in CSF at such high levels that were able to identify and characterize tumors with a high degree of sensitivity”, reflects Joan Seoane, corresponding author of the present study.
Based on the repertoire of genomic alterations in these tumors, Joan and co-collaborators including other researchers and clinical investigators at VHIO, oncologists, pathologists and neurosurgeons located across the Vall d’Hebron Barcelona Hospital Campus, sought to further advance this research by identifying a set of gene mutations in CSF ctDNA in order to more effectively classify this tumor type. To do so, they developed a platform to both simultaneously and speedily genotype mutations in 7 genes by targeted sequencing.
While the genomic characterization of these tumors enables a more precise molecular diagnosis, accessing tumor tissue for sequencing – due to their very location – is complex and sometimes supposes high-risk surgical procedures and stereotatic biopsies, neither of which can guarantee access to a truly representative part of the tumor. The classification of brain malignancies is also particularly complex due to their ever changing intra-tumor heterogeneity which consequently demands the in-depth and serial analysis of their evolving genomic landscapes in response to treatment or during disease relapse.
Establishing the molecular make-up of gliomas is however, particularly critical since they are the most common primary tumor of the brain and include different subtypes with a diverse prognosis, depending on the grade.
“By analyzing the mutational status of these 7 genes we classified up to 80% of tumors under study. Given that each subtype effectively exhibited diverse median overall survival, our research represents an important forward step in better guiding surgical risk-benefit assessment and clinical management based on the molecular classification of individual patients’ tumors”, explains Joan Seoane.
These latest findings have not only unmasked the molecular characteristics of diffuse gliomas using CSF ctDNA as a liquid biopsy, but also promise a more precise and rapid diagnosis that could ultimately help to steer treatment decision making matched to the classification of these tumors. . This novel approach could, in the future, also be used to more closely monitor the course of disease and response to therapy.
“While this pivotal study represents a potentially practice-changing approach in more precisely steering the surgical and clinical management of these patients, future studies with larger numbers of patients will be necessary to further demonstrate that ctDNA in cerebrospinal fluid can be used as a liquid biopsy to more accurately diagnose brain tumors and avoid risky surgical procedures”, concludes Francisco Martínez Ricarte, neurosurgeon of the HUVH, researcher of the Neurotraumatology and Neurosurgery Research Unit (UNINN) and first author of the paper.
The research published today lays important foundations for a forthcoming study to be fueled by a 1M euro grant received from the Spanish Association against Cancer (AECC). Led by Joan Seoane, this project is focused on glioblastoma and brain metastasis and will be carried out through a multidisciplinary Consortium, connecting the expertise of various leading researchers across different Spanish research centers of excellence.
The team, specialized in brain cancer, will seek to identify novel biomarkers, potentiate anti-cancer therapies, as well as develop new and less invasive approaches in molecular diagnostics towards better characterizing brain cancer and more precisely tailoring treatments to individual patients.
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