ATRT-07. CLINICAL APPLICABILITY OF C19MC MIRNA DETECTION IN LIQUID BIOPSIES OF ETMR PATIENTS
Sibylle MadlenerJulia FurtnerNatalia StepienDaniel SenfterLisa MayrMaximilian ZeydaLeon GramssBarbara AistleitnerSabine Spiegl‐KreineckerElisa RivellesChristian DorferKarl RösslerThomas CzechAmedeo A. AziziAndreas PeyrlDaniela Lötsch-GojoLeonhard MüllauerChristine HaberlerIrene SlavcJohannes Gojo
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Abstract:
Abstract Embryonal tumor with multilayered rosettes (ETMR) is a distinct central nervous system tumor entity which is characterized by dysregulation of oncogenic micro RNAs (miRNA). In the majority of cases (approx. 90%), tumors are characterized by amplification of the C19MC locus accompanied by a fusion of this locus to the TTYH1 gene. Beside the very young age of the patients, ETMR is a highly aggressive brain tumor with a dismal clinical outcome. About half of the patients relapse within the first 6 months despite intensive therapy. Based on these facts, a more rapid diagnosis as well as more accurate and faster detection of tumor response or tumor relapse would significantly improve the management of these severely affected young patients. Liquid biopsy has emerged as a highly promising tool to enable minimal invasive detection of molecular parameters to facilitate diagnosis and patient monitoring. Here, we developed a miRNA based liquid biopsy tool and performed a comprehensive profiling of the miRNA landscape in 11 ETMR tumor tissues and matching liquid biopsy samples of patients. The screening of the initial liquid biopsy samples (plasma or serum) taken at diagnosis revealed distinctly enriched miRNA levels. Further, we evaluated the use of the miRNA levels as a longitudinal tumor-monitoring tool. We detected decreasing levels after tumor resection and in long-term survivors and vice versa increasing levels in patients with progressive tumor disease. In conclusion, we developed a reliable and fast method with a turnaround time of only 4 hours between blood draw and analysis of the aberrant expressed miRNA in liquid biopsy samples of ETMR patients correlating with the clinical course of the individual patient.Keywords:
Liquid biopsy
A liquid biopsy is a minimally invasive or non-invasive method to analyze a range of tumor material in blood or other body fluids, including circulating tumor cells (CTCs), cell-free DNA (cfDNA), messenger RNA (mRNA), microRNA (miRNA), and exosomes, which is a very promising technology. Among these cancer biomarkers, plasma cfDNA is the most widely used in clinical practice. Compared with a tissue biopsy of traditional cancer diagnosis, in assessing tumor heterogeneity, a liquid biopsy is more reliable because all tumor sites release cfDNA into the blood. Therefore, a cfDNA liquid biopsy is less invasive and comprehensive. Moreover, the development of next-generation sequencing technology makes cfDNA sequencing more sensitive than a tissue biopsy, with higher clinical applicability and wider application. In this publication, we aim to review the latest perspectives of cfDNA liquid biopsy clinical significance and application in cancer diagnosis, treatment, and prognosis. We introduce the sequencing techniques and challenges of cfDNA detection, analysis, and clinical applications, and discuss future research directions.
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近年, 従来の組織生検 (Tissue Biopsy) とは異なる概念である Liquid Biopsy が注目されている. Liquid Biopsy は低侵襲で腫瘍を網羅的かつ包括的に評価できる可能性が示唆されており, 診断や治療前の予後予測だけでなく, 繰り返し行える採取の簡便さゆえ, 治療中のモニタリングへの活用にも期待が高まっている. 本稿では Liquid Biopsy のバイオマーカーの中心である末梢血循環癌細胞 (circulating tumor cells; CTCs) と末梢血循環 DNA (circulating extracellular nucleic acids 〔cell-free DNA; cfDNA〕)／末梢血循環腫瘍 DNA (circulating tumor DNA; ctDNA) について紹介し, 癌治療への応用の可能性を考えたい.
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Liquid biopsy is a relatively newer addition to pathology. Unlike conventional biopsy, it is non-invasive and provides a plethora of information. The constituents of liquid biopsy are: Circulating tumour cells (CTC), cell-free DNA (cf-DNA), cell-free RNA (cf-RNA) and Extracellular vesicles (EV). The samples for liquid biopsy are collected from blood, urine, saliva, and body fluids. The constituents of the liquid biopsy are isolated by physical, immunological or both methods. Predominantly advanced polymerase chain reactions or next-generation sequencing are done on the DNA of the sample. The potential application of liquid biopsy is cancer screening, prediction of disease progression, management and the detection of minimal residual disease. The present chapter discusses the various aspects of liquid biopsy.
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With the development of molecular biology, liquid biopsy has been the hot spot in the research of tumor precision therapy. Liquid biopsy technology has been found having high value in areas such as diagnosis, treatment and evaluation of tumor. Compared with traditional tissue biopsy, liquid biopsy technology is not only less invasive and can be performed repea-tedly at various times to monitor tumor in real time, but it also has a distinct advantage in reflecting the heterogeneity of tumor. This review introduced circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) which was the most studied in liquid biopsy, mainly focusing on the detection technology and application in esophageal cancer.
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Esophageal neoplasms; Translational medicine; Liquid biopsy technology; Circulating tumor cell; Circulating tumor DNA; Diagnosis; Therapy
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Liquid biopsy is a relatively new entity. This non‐invasive technique provides real‐time information about a tumour. The liquid biopsy contains circulating tumour cells, cell‐free DNA and exosomes. The main indications for liquid biopsy include early diagnosis, screening, detection of minimal residual disease, designing personalised treatment and predicting biological behaviour of the tumour. In this review, we discuss various aspects of liquid biopsy and compare it with conventional biopsy.
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Abstract Gastric cancer (GC) is a high-incidence cancer worldwide. Most patients are diagnosed at an advanced stage, by which time they have limited treatment options and poor prognosis. Early diagnosis and precise treatment are important. In the past few years, emerging research has been conducted on the use of non-invasive liquid biopsy, with its advantages of minimal invasiveness and repeated sampling, to monitor tumor occurrence and recurrence in real time and to evaluate prognosis and treatment response. Many studies have demonstrated the potential of liquid biopsy in GC, and the detection of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating free DNA (cfDNA), and exosomes has achieved gratifying results. In this review, we summarize evolving technologies for and information regarding liquid biopsy, the most recently discovered GC liquid biopsy biomarkers, and ongoing clinical trials and discuss the challenges and application prospects of liquid biopsy in GC.
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Tumor mutation load (TML) has been proposed as a biomarker of patient response to immunotherapy in several studies. TML is usually determined by tumor biopsy DNA (tDNA) whole exome sequencing (WES), therefore TML evaluation is limited by informative biopsy availability. Circulating cell free DNA (cfDNA) provided by liquid biopsy is a surrogate specimen to biopsy for molecular profiling. Nevertheless performing WES on DNA from plasma is technically challenging and the ability to determine tumor mutation load from liquid biopsies remains to be demonstrated. In the current study, WES was performed on cfDNA from 32 metastatic patients of various cancer types included into MOSCATO 01 (NCT01566019) and/or MATCHR (NCT02517892) molecular triage trials. Results from targeted gene sequencing (TGS) and WES performed on cfDNA were compared to results from tumor tissue biopsy. In cfDNA samples, WES mutation detection sensitivity was 92% compared to targeted sequencing (TGS). When comparing cfDNA-WES to tDNA-WES, mutation detection sensitivity was 53%, consistent with previously published prospective study comparing cfDNA-TGS to tDNA-TGS. For samples in which presence of tumor DNA was confirmed in cfDNA, tumor mutation load from liquid biopsy was correlated with tumor biopsy. Taken together, this study demonstrated that liquid biopsy may be applied to determine tumor mutation load. Qualification of liquid biopsy for interpretation is a crucial point to use cfDNA for mutational load estimation.
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Liquid biopsy involves the analysis of cell-free nucleic acids, mainly circulating free DNA (cfDNA), in bodily fluids such as blood. The obtaining of specimens is easier for patients and less invasive than tissue biopsy, but the method has certain limitations.This review is based on pertinent publications retrieved by a selective literature search.Because the concentration of cfDNA in plasma is less than 0.001%, special amplifying techniques must be used to enable a search for specific mutations. Liquid biopsy can be used in patients with non-small cell lung cancer (NSCLC) if no tissue is available for biopsy; when performed for this indication, it has 67% sensitivity and 94% specificity. If liquid biopsy does not reveal a mutation, this may be due either to the absence of the mutation in the tumor or to the inadequate sensitivity of the measuring technique. This uncertainty associated with negative findings can be reduced by the simultaneous demonstration of reference mutations derived from a primary tumor tissue analysis. In comparison to tissue studies, the search for tumor-specific mutations by liquid biopsy is 70% sensitive and 69% specific; this corresponds to a positive predictive value of 86% and a negative predictive value of 46%.Liquid biopsy and tumor tissue analysis are complementary, rather than alternative, techniques for therapeutically relevant genetic investigation of tumors. Comparative studies are needed so that further indications can be determined for liquid biopsy in the diagnostic evaluation of cancer.
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Tumour diagnosis is conventionally done by radiological findings and invasive surgical biopsy. Of late non-invasive technique where blood sample, urine and body fluids are used to extract circulating tumour cells (CTC) and genetic material for cancer diagnosis and treatment which is called as “Liquid Biopsy”.1,2 In this technique the liquid sample is used to isolate CTC, circulating tumour DNA (ctDNA), RNA, Exosomes and proteins which are shed by tumour cells into blood circulation, body fluids or urine in most of the cancers depending on the site of the can-cer. This technique enables non-invasive profiling of solid tumours, the results which can be comparable with that of tissue biopsy.3,4,5,6,7 As tissue biopsy is single biopsy, it gives only spatially and temporary snap shot of genetic makeup of cancer tissue unlike liquid biopsy, where samples can be taken at repeated intervals and it reveals the dynamic and heterogenei-ty of the cancer tissue.[8] Originally liquid biopsy was used to analyze CTC. At present it mainly analyzes ctDNA. However CTC and ctDNA are complementary technologies which can be used in parallel. As ctDNA is a potential surrogate for the entire tumour genome, it is many times referred as “Liquid Biopsy”.9,10 The different components of liquid biopsy are CTC, ctDNA, RNA, Exosomes, Proteins and Platelets.
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Liquid biopsy, a non-invasive method of analyzing cancer biomarkers in blood and other bodily fluids, has emerged as a promising approach for cancer diagnosis and monitoring of treatment response. The three main types of liquid biopsy include Circulating Tumor Cells (CTCs), Cell-Free DNA (cfDNA), and Extracellular Vesicles (EVs). Liquid biopsy offers several advantages over traditional tissue biopsy, including minimal invasiveness, ability to monitor disease progression in real-time, and potential for early cancer detection. However, challenges and limitations associated with liquid biopsy remain, such as the need for standardized protocols and assays, and the potential for false positives and negatives. Despite these challenges, liquid biopsy has shown great promise in clinical applications, such as monitoring of treatment response and resistance, and the identification of actionable mutations for targeted therapy. In conclusion, liquid biopsy holds great potential for improving cancer diagnosis and management, and ongoing research efforts will continue to refine and expand its clinical applications.
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