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      Clinical utility of plasma miR‐371a‐3p in germ cell tumors


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          Germ cell tumours predominantly of the testis ((T)GCTs) are remarkably chemotherapy sensitive. However, a small proportion of patients fail to be cured with cisplatin‐based combination chemotherapy. miR‐371a‐3p is a new liquid biopsy biomarker for (T)GCTs. The aim of this study was to evaluate clinical utility of plasma miR‐371a‐3p level in patients starting systemic chemotherapy. Patients were included before the first cycle (N = 180) and second cycle (N = 101) of systemic first line chemotherapy, treated between July 2010 and May 2017. Plasma miR‐371a‐3p levels were measured with the ampTSmiR test and compared to disease characteristics and outcome. Pretreatment plasma miR‐371a‐3p levels were increased in 51.7% of cases and associated with number of metastatic sites, presence of lung, retroperitoneal, and mediastinal lymph node metastases, S – stage, IGCCCG risk group, and response to therapy. Patients with a negative pretreatment plasma level had better progression‐free survival ( PFS) and overall survival ( OS) compared to patients being positive for miR‐371a‐3p (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.09‐0.71, =  0.02 for PFS and HR = 0.21, 95% CI 0.07‐0.67, =  0.03 for OS, respectively). Patients negative for miR‐371a‐3p in both samples had a superior PFS (HR = 0.10, 95% CI 0.01‐21.49, P = 0.02) and OS (HR = 0.08, 95% CI 0.01‐27.81, P = 0.008) compared to patients with miR‐371a‐3p positive in both samples (multivariate analyses were non‐significant). In total 68% of the patients were S0. This study demonstrates clinical value of plasma miR‐371a‐3p level in chemotherapy naïve (T)GCT patients starting first line of chemotherapy to predict prognosis.

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          International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.

          Cisplatin-containing chemotherapy has dramatically improved the outlook for patients with metastatic germ cell tumors (GCT), and overall cure rates now exceed 80%. To make appropriate risk-based decisions about therapy and to facilitate collaborative trials, a simple prognostic factor-based staging classification is required. Collaborative groups from 10 countries provided clinical data on patients with metastatic GCT treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and models were validated on an independent data set. Data were available on 5,202 patients with nonseminomatous GCT (NSGCT) and 660 patients with seminoma. Median follow-up time was 5 years. For NSGCT the following independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH); and presence of nonpulmonary visceral metastases (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM. Integration of these factors produced the following groupings: good prognosis, comprising 60% of GCT with a 91% (89% to 93%) 5-year survival rate; intermediate prognosis, comprising 26% of GCT with a 79% (75% to 83%) 5-year survival rate; and poor prognosis, comprising 14% of GCT (all with NSGCT) with a 48% (42% to 54%) 5-year survival rate. An easily applicable, clinically based, prognostic classification for GCT has been agreed on between all the major clinical trial groups who are presently active worldwide. This should be used in clinical practice and in the design and reporting of clinical trials to aid international collaboration and understanding.
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            High-throughput microRNAome analysis in human germ cell tumours.

            Testicular germ cell tumours (GCTs) of adolescents and adults can be subdivided into seminomas (referred to as dysgerminomas of the ovary) and non-seminomas, all referred to as type II GCTs. They originate from carcinoma in situ (CIS), being the malignant counterparts of primordial germ cells (PGCs)/gonocytes. The invasive components mimic embryogenesis, including the stem cell component embryonal carcinoma (EC), the somatic lineage teratoma (TE), and the extra-embryonic tissues yolk sac tumour (YST) and choriocarcinoma (CH). The other type is the so-called spermatocytic seminomas (SS, type III GCT), composed of neoplastic primary spermatocytes. We reported previously that the miRNAs hsa-miR 371-373 cluster is involved in overruling cellular senescence induced by oncogenic stress, allowing cells to become malignant. Here we report the first high-throughput screen of 156 microRNAs in a series of type II and III GCTs (n = 69, in duplicate) using a quantitative PCR-based approach. After normalization to allow inter-sample analysis, the technical replicates clustered together, and the previous hsa-miRNA 371-373 cluster finding was confirmed. Unsupervised cluster analysis demonstrated that the cell lines are different from the in vivo samples. The in vivo samples, both normal and malignant, clustered predominantly based on their maturation status. This parallels normal embryogenesis, rather than chromosomal anomalies in the tumours. miRNAs within a single cluster showed a similar expression pattern, implying common regulatory mechanisms. Normal testicular tissue expressed most discriminating miRNAs at a higher level than SE and SS. Moreover, differentiated non-seminomas showed overexpression of discriminating miRNAs. These results support the model that miRNAs are involved in regulating differentiation of stem cells, retained in GCTs. Copyright 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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              Serum Levels of MicroRNA miR-371a-3p: A Sensitive and Specific New Biomarker for Germ Cell Tumours.

              Clinical management of germ cell tumours (GCTs) relies on monitoring of serum tumour markers. However, the markers α-fetoprotein (AFP), the β-subunit of human chorionic gonadotropin (bHCG), and lactate dehydrogenase (LDH) are expressed in <60% of GCT cases.

                Author and article information

                l.looijenga@erasmusmc.nl , l.looijenga@princesmaximacentrum.nl
                J Cell Mol Med
                J. Cell. Mol. Med
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                07 December 2018
                February 2019
                : 23
                : 2 ( doiID: 10.1111/jcmm.2019.23.issue-2 )
                : 1128-1136
                [ 1 ] Translational Research Unit Faculty of Medicine Comenius University and National Cancer Institute Bratislava Slovakia
                [ 2 ] 2nd Department of Oncology Faculty of Medicine Comenius University and National Cancer Institute Bratislava Slovakia
                [ 3 ] Department of Pathology Laboratory for Experimental Patho‐Oncology Erasmus MC University Medical Center Cancer Institute Rotterdam The Netherlands
                [ 4 ] Cancer Research Institute Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia
                [ 5 ] 1st Department of Oncology Faculty of Medicine Comenius University and St. Elisabeth Cancer Institute Bratislava Slovakia
                [ 6 ] Princess Maxima Center Pediatric Oncology Utrecht The Netherlands
                [ 7 ]Present address: Prinses Máxima Centrum for Pediatric Oncology Utrecht The Netherlands
                Author notes
                [*] [* ] Correspondence

                Leendert H. J. Looijenga, Department of Pathology, Laboratory for Experimental Patho‐Oncology, Erasmus MC University Medical Center, Cancer Institute, Rotterdam, The Netherlands.

                Emails: l.looijenga@ 123456erasmusmc.nl , l.looijenga@ 123456princesmaximacentrum.nl

                © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 2, Tables: 4, Pages: 9, Words: 7288
                Funded by: Dutch Cancer Society
                Award ID: 13‐6001
                Funded by: Slovak Ministry of Education VEGA
                Award ID: 1/0043/18
                Funded by: Slovak Research and Development Agency
                Original Article
                Original Articles
                Custom metadata
                February 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.5.6 mode:remove_FC converted:28.01.2019

                Molecular medicine
                mir‐371a‐3p,prognostic liquid biopsy biomarker,(testicular) germ cell tumours


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