A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma

Connolly, Ian D.; Li, Yingmei; Pan, Wenying; Johnson, Eli; You, Linya; Vogel, Hannes; Ratliff, John K.; Gephart, Melanie Hayden

doi:10.1007/s11060-017-2557-y

Cited by 33 publications

(22 citation statements)

References 29 publications

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“…The promoting effect of DNA on tau aggregation was observed in a wide range from 10 to 1000 ng. The use of these concentrations were informed by the range of cerebrospinal fluid DNA concentrations observed in patients with different diseases: 1 – 600 ng/mL [48-50]. The sources of bacterial and fungal DNA were selected based on the literature and personal data that showed associations of certain microorganisms with AD.…”

Section: Discussionmentioning

confidence: 99%

Bacterial DNA promotes Tau aggregation

Tetz¹,

Pinho²,

Soto³

et al. 2019

Preprint

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A hallmark feature of Alzheimer’s disease (AD) and other tauopathies is the misfolding, aggregation and cerebral accumulation of tau deposits. Compelling evidence indicates that misfolded tau aggregates are neurotoxic, producing synaptic loss and neuronal damage. Misfolded tau aggregates are able to spread the pathology from cell-to-cell by a prion like seeding mechanism. The factors implicated in the initiation and progression of tau misfolding and aggregation are largely unclear. In this study, we evaluated the effect of DNA extracted from diverse prokaryotic and eukaryotic cells in tau misfolding and aggregation. Our results show that DNA from various, unrelated gram-positive and gram-negative bacteria results in a more pronounced tau misfolding compared to eukaryotic DNA. Interestingly, a higher effect in promoting tau aggregation was observed for DNA extracted from certain bacterial species previously detected in the brain, CSF or oral cavity of patients with AD. Our findings indicate that microbial DNA may play a previously overlooked role in the propagation of tau protein misfolding and AD pathogenesis, providing a new conceptual framework that positions the compromised blood-brain and intestinal barriers as important sources of microbial DNA in the CNS, opening novel opportunities for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Bacterial DNA promotes Tau aggregation

Tetz¹,

Pinho²,

Soto³

et al. 2019

Preprint

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“…Several studies have, in the past, demonstrated that a CSFbased liquid biopsy may not be feasible in genetically diverse, anatomically sequestered, and low-grade CNS tumors. 4,7,10,30 The most important factor that is associated with CSF-ctDNA levels is anatomical sequestration. Jimenez et al described three CNS barriersthe BBB, the blood-CSF barrier of the choroid plexus and arachnoid membrane, and the CSF-parenchyma barrier of the ependymalas potentially usable for tumor studies.…”

Section: Anatomical Constraints Of Cns Tumorsmentioning

confidence: 99%

“…31 In cases where parenchyma or arachnoid membranes surround a tumor, the diffusive ability of tumor-derived DNA to diffuse into the CSF could be limited significantly due to the presence of the blood-CSF barrier and the CSFparenchyma barrier. 4,10,30 Connolly et al 30 encapsulated entirely by the brain or spinal cord parenchyma. Interestingly, all four low-grade gliomas directly adjacent to the CSF reservoir did not have reliably detectable ctDNA.…”

Section: Anatomical Constraints Of Cns Tumorsmentioning

confidence: 99%

“…Furthermore, the treatment of most primary CNS tumors includes total surgical resection with or without adjuvant radiotherapy and chemotherapy, but aggressive resection must be balanced with the risk of adjacent normal tissue injury, and recurrence occurs commonly in patients with subtotal resection. 30 Surveillance neuroimaging and tumor biomarkers are commonly used to monitor recurrence or progression after subtotal resection of primary CNS tumors, but these are traditional techniques with low sensitivity and specificity that do not provide a timely detection recurrence or progression. The presence of ctDNA in the CSF may serve as a biomarker for the early detection of tumor recurrence or progression, even before neuroimaging and tumor biomarkers recognize relapsed lesions.…”

Section: Determining Recurrence or Progressionmentioning

confidence: 99%

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<p>Clinical Applications of Cerebrospinal Fluid Circulating Tumor DNA as a Liquid Biopsy for Central Nervous System Tumors</p>

Yan¹,

Zhu²,

Yu³

2020

OTT

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Central nervous system (CNS) malignancies are associated with poor prognosis, as well as exceptional morbidity and mortality, likely as a result of low rates of early diagnosis and limited knowledge of the tumor growth and resistance mechanisms, dissemination, and evolution in the CNS. Monitoring patients with CNS malignancies for treatment response and tumor recurrence can be challenging because of the difficulty and risks of brain biopsies and the low specificity and sensitivity of the less invasive methodologies that are currently available. Therefore, there is an urgent need to detect and validate reliable and minimally invasive biomarkers for CNS tumors that can be used separately or in combination with current clinical practices. The circulating tumor DNA (ctDNA) of cerebrospinal fluid (CSF) samples can outline the genetic landscape of entire CNS tumors effectively and is a promising, suitable biomarker, though its role in managing CNS malignancies has not been studied extensively. This review summarizes recent studies that explore the diagnostic, prognostic, and predictive roles of CSF-ctDNA as a liquid biopsy with primary and metastatic CNS malignancies.

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“…Interestingly, Connolly et al . analysed CSF and blood samples of three cases of grade II intramedullary ependymomas without identifying any alteration in blood or in CSF . In this regard, other variables such as CSF flow alterations may affect cfDNA circulation and liquid biopsy sensitivity.…”

Section: Circulating Cell‐free Nucleic Acids Analysismentioning

confidence: 99%

Review: Peering through a keyhole: liquid biopsy in primary and metastatic central nervous system tumours

Bertero

Siravegna

Rudà

et al. 2019

Neuropathology Appl Neurobio

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2019) Neuropathology and Applied Neurobiology 45, 655-670 Peering through a keyhole: liquid biopsy in primary and metastatic central nervous system tumours Tumour molecular profiling by liquid biopsy is being investigated for a wide range of research and clinical purposes. The possibility of repeatedly interrogating the tumour profile using minimally invasive procedures is helping to understand spatial and temporal tumour heterogeneity, and to shed a light on mechanisms of resistance to targeted therapies. Moreover, this approach has been already implemented in clinical practice to address specific decisions regarding patients' follow-up and therapeutic management. For central nervous system (CNS) tumours, molecular profiling is particularly relevant for the proper characterization of primary neoplasms, while CNS metastases can significantly diverge from primary disease or extra-CNS metastases, thus compelling a dedicated assessment. Based on these considerations, effective liquid biopsy tools for CNS tumours are highly warranted and a significant amount of data have been accrued over the last few years. These results have shown that liquid biopsy can provide clinically meaningful information about both primary and metastatic CNS tumours, but specific considerations must be taken into account, for example, when choosing the source of liquid biopsy. Nevertheless, this approach is especially attractive for CNS tumours, as repeated tumour sampling is not feasible. The aim of our review was to thoroughly report the state-of-the-art regarding the opportunities and challenges posed by liquid biopsy in both primary and secondary CNS tumours.

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A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma

Cited by 33 publications

References 29 publications

Bacterial DNA promotes Tau aggregation

Bacterial DNA promotes Tau aggregation

<p>Clinical Applications of Cerebrospinal Fluid Circulating Tumor DNA as a Liquid Biopsy for Central Nervous System Tumors</p>

Review: Peering through a keyhole: liquid biopsy in primary and metastatic central nervous system tumours

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