A Multi-institutional Pooled Analysis Demonstrates That Circulating miR-371a-3p Alone is Sufficient for Testicular Malignant Germ Cell Tumor Diagnosis

Piao, Jin; Lafin, John T.; Scarpini, Cinzia G.; Nuño, Michelle M.; Syring, Isabella; Dieckmann, K.; Belge, Gazanfer; Ellinger, Jörg; Amatruda, James F.; Bagrodia, Aditya; Krailo, Mark; Frazier, A. Lindsay; Murray, Matthew J.

doi:10.1016/j.clgc.2021.08.006

Cited by 22 publications

(20 citation statements)

References 21 publications

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“…Here we document profound expression of both miR-371a and miR-302d in all iGCT sera including serum of biomarker-negative patients. Thus, not only miR-371a but also miR-302d added value in the diagnosis of iGCT especially in biomarker-negative patients, but did not outperform miR-371a as recently been noticed in a multi-institutional pooled miRNA analysis in testicular GCT (Piao et al 2021). MiRNA analysis may be influenced by various preand post-analytical variables and normalization strategies (Myklebust et al 2019).…”

Section: Discussionmentioning

confidence: 88%

MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors

Schönberger

Mohseni

Ellinger

et al. 2022

J Cancer Res Clin Oncol

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Purpose Intracranial germ cell tumors (iGCT) comprise germinoma and non-germinoma. Their diagnosis predominantly relies on biopsy as only one-fifth of patients present with elevated biomarkers (AFP/ß-HCG) in serum or cerebrospinal fluid (CSF). MicroRNAs (miR/miRNA) have emerged as non-invasive biomarkers in extracranial GCT and may potentially facilitate non-invasive diagnosis in iGCT. Methods We analyzed eight miRNAs in serum and CSF from the miR-371~373- and miR-302/367-clusters and four miRNAs differentially expressed in iGCT tissue (miR-142-5p/miR-146a-5p/miR-335-5p/miR-654-3p) from eight iGCT patients (age 10–33 years) and 12 control subjects by pre-amplified RT-qPCR. MiR-30b-5p (serum) and miR-204-5p (CSF) acted as reference genes. ΔCt-values were expressed as $$2^{{ - \Delta \Delta C_{{\text{t}}} }}$$ 2 - Δ Δ C t after standardization against controls. Results Between iGCT and control patients’ serum ΔCt-values of miR-371a-3p (p = 0.0159), miR-372-3p (p= 0.0095, miR-367 (p = 0.0190), miR-302a (p = 0.0381) and miR-302d-3p (p = 0.0159) differed significantly. Discriminatory pattern in CSF was similar to serum as miR-371a (p = 0.0286), miR-372-3p (p = 0.0028), miR-367-3p (p = 0.0167) and miR-302d-3p (p = 0.0061) distinguished between patients and controls. Abundant $$2^{{ - \Delta \Delta C_{{\text{t}}} }}$$ 2 - Δ Δ C t levels of each of these miRNAs were found across all serum and CSF samples including biomarker-negative patients. Conclusion With the largest data set so far, we underline the suitability of miR-371a, miR-372, miR-367 and miR-302d in serum and CSF for diagnosis of iGCT, particularly in biomarker-negative germinoma. Diagnosis of iGCT by miRNA analysis is a feasible and valid approach, particularly as serum can be readily obtained by a less invasive procedure. MiRNA analysis may discriminate iGCT from other tumors with similar radiological findings and may allow to monitor response to therapy as well as early relapse during follow-up.

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Section: Discussionmentioning

confidence: 88%

MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors

Schönberger

Mohseni

Ellinger

et al. 2022

J Cancer Res Clin Oncol

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“…The high sensitivity and specificity of miR-371a-3p at diagnosis (consistently over 85% [34]; 85.7% and 100% respectively in our study, Supplementary Table S1) is related to its expression pattern during embryogenesis, a process that (T)GCTs closely resemble [9,10]; also, the high relative levels detected in several body fluids is illustrated by the various GCT cell lines, which actively secrete this microRNA into the culture medium [33] (Figure 4A,B). The exact targets and mechanisms regulated miR-371a-3p are still under-explored [38]; however, miR-371a-3p is for now the best and most versatile non-invasive biomarker (actually the most informative player within the miR-371-373 cluster [39]) for TGCT patients, useful for diagnosis, follow-up, prediction of response to therapy and prediction of viable disease after chemotherapy. The main critic directed to miR-371a-3p has been the lower performance in detecting TE [21] (and also GCNIS [40]) compared to other histological subtypes, not fulfilling the requirements of an informative and reliable marker in these contexts; this was also evidenced by the present study, with less than half of TE being detected and only 3/5 GCNIS (Figure 1, Table 2), in line with earlier findings [41].…”

Section: Discussionmentioning

confidence: 99%

Combining Hypermethylated RASSF1A Detection Using ddPCR with miR-371a-3p Testing: An Improved Panel of Liquid Biopsy Biomarkers for Testicular Germ Cell Tumor Patients

Lobo

Zogchel

Nuru

et al. 2021

Cancers

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The classical serum tumor markers used routinely in the management of testicular germ cell tumor (TGCT) patients—alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG)—show important limitations. miR-371a-3p is the most recent promising biomarker for TGCTs, but it is not sufficiently informative for detection of teratoma, which is therapeutically relevant. We aimed to test the feasibility of hypermethylated RASSF1A (RASSF1AM) detected in circulating cell-free DNA as a non-invasive diagnostic marker of testicular germ cell tumors, combined with miR-371a-3p. A total of 109 serum samples of patients and 29 sera of healthy young adult males were included, along with representative cell lines and tumor tissue samples. We describe a novel droplet digital polymerase chain reaction (ddPCR) method for quantitatively assessing RASSF1AM in liquid biopsies. Both miR-371a-3p (sensitivity = 85.7%) and RASSF1AM (sensitivity = 86.7%) outperformed the combination of AFP and HCG (sensitivity = 65.5%) for TGCT diagnosis. RASSF1AM detected 88% of teratomas. In this representative cohort, 14 cases were negative for miR-371a-3p, all of which were detected by RASSF1AM, resulting in a combined sensitivity of 100%. We have described a highly sensitive and specific panel of biomarkers for TGCT patients, to be validated in the context of patient follow-up and detection of minimal residual disease.

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“… 75 – 77 No combination of miRNAs adds to the diagnostic accuracy of miR-371a-3p and cannot reliably detect TE. 74 , 78 While mir-375 has been suggested to detect TE and be used in combination with miR-371a-3p, subsequent studies have found it to be non-informative. 72 , 77 , 79 , 80 Mir-885-5p and miR-448 were then suggested for TE detection, however, this could not be validated in further studies too.…”

Section: Discussionmentioning

confidence: 99%

The utility of cfDNA in TGCT patient management: a systematic review

et al. 2022

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Background: Testicular germ cell tumors (TGCTs) are the most common young male malignancy with a steadily rising incidence. Standard clinical practice is radical orchidectomy of suspicious lumps followed by histopathological diagnosis and tumor subtyping. This practice can lead to complications and quality of life issues for the patients. Liquid biopsies, especially cell-free DNA (cfDNA), promised to be true surrogates for tissue biopsies, which are considered dangerous to perform in cases of testicular tumors. In this study, we have performed a systematic review on the potential of cfDNA in TGCT patient management, its potential challenges in translation to clinical application and possible approaches in further research. Materials & Methods: The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines on EuropePMC and PUBMED electronic databases, with the last update being on October 21, 2021. Due to the high heterogeneity in identified research articles, we have performed an overview of their efficacy. Results: Eight original articles have been identified on cfDNA in TGCT patients published from 2004 to 2021, of which six had more than one TGCT patient enrolled and were included in the final analysis. Three studies investigated cfDNA methylation, one has investigated mutations in cfDNA, two have investigated cfDNA amount, and one has investigated cfDNA integrity in TGCT. The sensitivity of cfDNA for TGCT was found to be higher than in serum tumor markers and lower than miR-371a-3p, with comparable specificity. cfDNA methylation analysis has managed to accurately detect teratoma in TGCT patients. Conclusion: Potential challenges in cfDNA application to TGCT patient management were identified. The challenges relating to the biology of TGCT with its low mutational burden and low cfDNA amounts in blood plasma make next-generation sequencing (NGS) methods especially challenging. We have also proposed possible approaches to help find clinical application, including a focus on cfDNA methylation analysis, and potentially solving the challenge of teratoma detection.

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A Multi-institutional Pooled Analysis Demonstrates That Circulating miR-371a-3p Alone is Sufficient for Testicular Malignant Germ Cell Tumor Diagnosis

Cited by 22 publications

References 21 publications

MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors

MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors

Combining Hypermethylated RASSF1A Detection Using ddPCR with miR-371a-3p Testing: An Improved Panel of Liquid Biopsy Biomarkers for Testicular Germ Cell Tumor Patients

The utility of cfDNA in TGCT patient management: a systematic review

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