Application of miRNAs in the diagnosis and monitoring of testicular germ cell tumours

Almstrup, Kristian; Lobo, João; Mørup, Nina; Belge, Gazanfer; Meyts, Ewa Rajpert‐De; Looijenga, Leendert H. J.; Dieckmann, Klaus‐Peter

doi:10.1038/s41585-020-0296-x

Cited by 75 publications

(77 citation statements)

References 97 publications

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“…The STMs have been used for decades with good results, however, for a large proportion of TGCT patients, no suitable STMs exist. Several studies have shown that the miRNAs, miR-367-3p, miR-371a-3p, miR-372-3p and miR-373-3p can outperform STMs in diagnostic performance (for review, see Almstrup et al [8]). In particular, miR-371a-3p has shown great sensitivity in several independent studies [10,13,17].…”

Section: Discussionmentioning

confidence: 99%

“…To better compare studies across different populations and the diagnostic performance of different labs, international guidelines and standardization of the assays are needed. Additionally, common spike-in controls and endogenous miRNA controls would facilitate direct comparisons between labs and the applied methodology [8]. Furthermore, we chose a cut-off value of Ct = 40, which is practical in a clinical routine with day-to-day analysis.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Circulating miRNA Biomarkers of Testicular Germ Cell Tumors during Therapy and Follow-up―A Copenhagen Experience

Mørup

Meyts

Juul

et al. 2020

Cancers

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New microRNA-based serum biomarkers (miRNA-367-3p, -371a-3p, -372-3p, and -373-3p) have shown great potential for the detection of testicular germ cell tumors (TGCTs), but few studies have investigated the clinical utility and performance of these tests in treatment monitoring. In this study, circulating miRNA levels were measured, together with serum tumor markers alpha-fetoprotein (AFP), β-subunit of human chorionic gonadotropin (β-HCG) and lactate dehydrogenase (LDH) in 406 consecutive blood samples obtained during the treatment and follow-up of 52 TGCT patients at the Copenhagen University Hospital. After testing three different methods of RNA isolation from peripheral blood and PCR quantification in a subset of samples (n = 15), the best performing setup of targeted isolation of miRNAs inside and outside exosomes was selected to analyze all samples. At primary diagnosis, the miRNAs significantly outperformed the serum tumor markers, with a sensitivity and specificity of 78% and 100% (based on 40 patients), respectively. The picture was not as clear when patient trajectories were investigated, with both positive and negative signals for miRNAs and serum tumor markers. To establish whether measuring miRNAs adds value beyond the primary diagnosis, large prospective clinical trials comparing miRNAs and classical tumor markers during the treatment and follow-up of TGCT patients are needed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of Circulating miRNA Biomarkers of Testicular Germ Cell Tumors during Therapy and Follow-up―A Copenhagen Experience

Mørup

Meyts

Juul

et al. 2020

Cancers

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“…In this work, we aimed to explore the expression of CRIPTO in liquid biopsy samples of patients with TGCTs and of infertile males, extending our previous work [16] and providing novel insight on the role of this pathway in regulating this balance between tumor development and infertility. We additionally aimed at correlating our findings with the relative levels of miR-371a-3p, the most promising TGCT liquid biopsy biomarker identified to date [27].…”

Section: Discussionmentioning

confidence: 99%

“…A detailed clinical description of this serum cohort is presented in Table 5. Median age at diagnosis of the TGCT patients was 29 years (interquartile range [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]; although significantly lower than in the control group, there was no significant correlation between age of controls/TGCT patients and CRIPTO levels (p = 0.750, r s = −0.47; p = 0.112, r s = −1.44) or miR-371a-3p levels (p = 0.754, r s = −0.46; p = 0.528, r s = 0.62). Most tumors were NS (n = 190, 87.6%), and among these the majority were mixed tumors (n = 147, 77.4%).…”

Section: Patients and Samplesmentioning

confidence: 99%

CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males

Spiller

Lobo

Boellaard

et al. 2020

Cancers

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miR-371a-3p is currently the most informative reported biomarker for germ cell tumors (GCTs). Another developmental-related biomarker, CRIPTO, is involved in the regulation of pluripotency and germ cell fate commitment. We aimed to assess the value of CRIPTO as a diagnostic and prognostic biomarker of testicular GCTs (TGCTs) and also to assess its presence in seminal plasma samples, compared with miR-371a-3p. In total, 217 and 94 serum/seminal plasma samples were analyzed. CRIPTO was quantified using ELISA and miR-371a-3p using bead-based isolation followed by RT-qPCR. Methylation profiling (EPIC array) for the CRIPTO promoter region was undertaken in 35 TGCT tissues plus four (T)GCT cell lines. Significantly higher CRIPTO concentration was found in sera of non-seminomas compared to controls (p = 0.0297), and in stage II/III disease compared to stage I (p = 0.0052, p = 0.0097). CRIPTO concentration was significantly positively correlated with miR-371a-3p levels in serum (r = 0.16) and seminal plasma (r = 0.40). CRIPTO/miR-371a-3p levels were significantly higher in seminal plasma controls when compared to serum controls (p = 0.0001, p < 0.0001). CRIPTO/miR-371a-3p were detected both in normospermic and azoospermic males, and levels were higher in TGCTs compared to GCNIS-only. We have provided the largest dataset of evaluation of CRIPTO in serum and seminal plasma of GCTs, showing its potential value as a biomarker of the disease.

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“…Biomarkers are important in oncology, and are more recently including miRNas (18,37). A few studies have pro led meningioma tumors, suggesting potential circulating biomarkers, including miRNAs, that could advance cancer diagnosis and prognosis (26,38,39).…”

Section: Discussionmentioning

confidence: 99%

miR-9-1 Is a New Circulating Biomarker for Higher-grade Meningioma Regulated via the EGFR-FOS Network

Daniele¹,

Negroni²,

Ferluga³

et al. 2020

Preprint

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Background: Meningiomas are the most common primary CNS tumors. According to the World Health Organization Classification (WHO), they are classified as benign (grade I), atypical (grade II), and anaplastic/malignant (grade III). Chemotherapy has proven ineffective in treating these tumors, which are primarily managed by surgery, radiotherapy, or a combination of them. Morbidity and mortality correlate with meningioma grade. Currently, risk assessment for treatment is based on the radiological assessment of tumor size, tumor growth rate, and/or clinical progression of symptoms. Methods: We performed a cancer miRNA array in an in vitro model of meningioma in order to identify circulating biomarkers in meningioma patients. We validated the miRNA biomarker candidate in cells and tissues and analyzed its regulation. We then investigated expression in tissues and blood. Results: We identified miR-9-1 as significantly overexpressed in atypical and anaplastic cells compared to benign. We further demonstrated that miR-9-1 overexpression is due to increased levels of FOS via upregulation of the EGFR receptor, and showed that miR-9-1 and FOS are upregulated in a cohort of higher-grade meningioma biopsies. Next, we isolated circulating exosomes from meningioma patients’ serum samples, and found higher levels of miR-9-1 in higher-grade compared to low-grade meningiomas patients. Conclusions: Overall, our study shows overexpression and the mechanism of miR-9-1 regulation and suggests miR-9-1 as a novel circulating biomarker candidate to identify tumor grade in meningioma.

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Application of miRNAs in the diagnosis and monitoring of testicular germ cell tumours

Cited by 75 publications

References 97 publications

Evaluation of Circulating miRNA Biomarkers of Testicular Germ Cell Tumors during Therapy and Follow-up―A Copenhagen Experience

Evaluation of Circulating miRNA Biomarkers of Testicular Germ Cell Tumors during Therapy and Follow-up―A Copenhagen Experience

CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males

miR-9-1 Is a New Circulating Biomarker for Higher-grade Meningioma Regulated via the EGFR-FOS Network

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