Tumor cell-free DNA detection in CSF for primary CNS lymphoma diagnosis

Rimelen, Valérie; Ahle, Guido; Pencreach, Erwan; Zinniger, N.; Debliquis, Agathe; Zalmaï, L; Harzallah, Inès; Hurstel, Remy; Alamome, Isabelle; Lamy, F.; Voirin, Jimmy; Drénou, Bernard

doi:10.1186/s40478-019-0692-8

Cited by 55 publications

(46 citation statements)

References 13 publications

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“…Furthermore, microRNA profiles or selected microRNAs in the peripheral blood of PCNSL patients seem to be associated with survival of patients under therapy [37–39]. In addition, the detection of tumor-specific cell-free DNA in the CSF of CNSL patients shows promise as a reliable marker in a subset of CNSL patients [22]. Similarly, other studies have been published about cell-free tumor DNA in the blood or in vitreous biopsies of CNSL patients [40–42], illustrating the feasibility to detect tumor-specific mutations in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…In HIV-positive patients with CNSL, Epstein-Barr virus DNA in the CSF can be used as a diagnostic biomarker [8]. In HIV-negative patients, several other biomarkers have been described, such as interleukin-10 [9–12], IL-6 [9, 10, 12], CXCL13 [11], neopterin [13], β-microglobulin [10, 14], osteopontin [15], sCD27 [16], specific microRNAs [17–21], and cell-free DNA [22], with varying diagnostic utility.…”

Section: Introductionmentioning

confidence: 99%

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APRIL and BAFF: novel biomarkers for central nervous system lymphoma

et al. 2019

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Background Early diagnosis of CNS lymphoma (CNSL) is essential for successful therapy of this rapidly progressing brain tumor. However, in patients presenting with focal brain lesions, fast and reliable diagnosis of PCNSL remains a challenge. A proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) are important factors in the pathophysiology, diagnosis, and prognosis of systemic B cell malignancies. However, their utility as biomarkers for the diagnosis of CNSL and their effects on CNSL cells remain unclear. Methods In this prospective study, we analyzed the levels of APRIL and BAFF in the cerebrospinal fluid (CSF) of 116 patients with suspected focal brain lesions, including 53 CNSL patients. Additionally, we serially measured their levels during chemotherapy and relapse. Furthermore, we analyzed the effect of APRIL and BAFF on two B cell lymphoma cell lines using proliferation, viability, and chemotaxis assays. Results CSF levels of APRIL and BAFF reliably differentiated CNSL from other focal brain lesions (including primary and metastatic brain tumors, autoimmune-inflammatory lesions, and neuroinfectious lesions) with a specificity of 93.7% (APRIL, BAFF) and a sensitivity of 62.3% (APRIL) and 47.1% (BAFF). Serial CSF analysis of CNSL patients during chemotherapy and relapse demonstrates a close correlation of APRIL CSF levels and the course of this disease. In vitro, APRIL and BAFF showed anti-apoptotic effects during MTX treatment and mediated chemotaxis of malignant B cells. Conclusion This study extends the spectrum of valuable diagnostic biomarkers in CNSL. In patients with focal brain lesions, measurement of APRIL in CSF could help accelerating the diagnosis of CNSL. Moreover, our results highlight an important role of APRIL and BAFF in the pathophysiology of CNSL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

APRIL and BAFF: novel biomarkers for central nervous system lymphoma

et al. 2019

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“…Other non‐cell‐based approaches such as neopterin or osteopontin quantification in the CSF, as well as detection of cfDNA, have been the subject of several publications recently, but further studies are still needed . Of note, we evaluated IGH PCR on cfDNA obtained from CSF supernatants on a limited number of samples of the training cohort, which yielded several interesting preliminary results.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, cytokine quantification (CQ), such as interleukin (IL)‐10 and IL‐6 in CSF, has yielded promising results . Cell‐free DNA (cfDNA) and liquid biopsies are also of growing interest . Nevertheless, no consensus recommendations for an optimal diagnostic CSF work‐up are available yet.…”

Section: Introductionmentioning

confidence: 99%

Optimization of CSF biological investigations for CNS lymphoma diagnosis

et al. 2019

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Diagnosis of lymphoma leptomeningeal dissemination is challenging and relies on a wide array of methods. So far, no consensus biological guidelines are available. This increases the chance of intra-and interpractice variations, despite the shared concern to perform the minimum amount of tests while preserving clinically relevant results. We evaluated a training cohort of 371 cerebrospinal fluid (CSF) samples from patients with putative lymphomatous central nervous system (CNS) localization using conventional cytology (CC), flow cytometry (FCM), molecular clonality assesment by PCR and cytokine quantification (CQ). This led us to propose a biological algorithm, which was then verified on a validation cohort of 197 samples. The samples were classified according to the clinical context and the results of each technique were compared. Using all four techniques was not useful for exclusion diagnosis of CNS lymphoma (CNSL), but they proved complementary for cases with suspected CNSL.This was particularly true for CQ in primary CNSL. Overall, diagnosis can be obtained with a two-step approach. The first step comprises CC and FCM, as results are available quickly and FCM is a sensitive method. Both PCR and CQ can be postponed and performed in a second step, depending on the results from the first step and the clinical context.The proposed algorithm missed none of the CNSL samples of the validation cohort. Moreover, applying this algorithm would have spared 30% of PCR tests and 20% of CQ over a one-year period, without compromising clinical management.

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“…CSF cytology and immunophenotyping by flow cytometry are currently used as alternatives to stereotactic biopsy in patients with suspected PCNSL. Using CSF as a source for cfDNA shows increased clinical sensitivity relative to plasma cfDNA testing (86%), and MYD88 L265P mutations may be detected even in the absence of positive cytology or flow cytometry (Rimelen et al, 2019). MYD88 L265P mutations are specific to PCNSL and have not been reported in other brain tumors such as GBM (Nakamura et al, 2016;Fontanilles et al, 2017), making this a particularly appealing biomarker.…”

Section: Cns Lymphomamentioning

confidence: 99%