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, João; Zogchel, Lieke M. J. van; Nuru, Mohammed G.; Gillis, Ad J. M.; Schoot, C. Ellen van der; Tytgat, Godelieve A.M.; Looijenga, Leendert H. J.

doi:10.3390/cancers13205228

Cited by 23 publications

(27 citation statements)

References 57 publications

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“…The final study investigated RASSF1A methylation in blood serum of 98 TGCT patients (21 SEs and 77 NSEs) and 29 HT. 15 Nineteen of 21 SE patients, 66 of 77 NSE patients, and 0 of 29 HT had detectable RASSF1A hypermethylation. This meant a sensitivity of 87% for TGCT, 91% for SE, and 86% for NSE, with 100% specificity in all cases.…”

Section: Resultsmentioning

confidence: 92%

“… 42 Its use has been demonstrated in large patient groups, by various research groups and in comprehensive metanalyses. 15 We have selected prominent articles on STM and miR-371a-3p found within the results of our systematic review results and the reference list search. Only those studies on STM that had data on the combined sensitivity and specificity of all three biomarkers were used for the comparison.…”

Section: Discussionmentioning

confidence: 99%

“…While miRNA-371a-3p will most certainly be introduced to the clinic, an aspect of TGCT remains unsolved, namely, TE detection and GCNIS detection. 2 , 15 , 73 , 75 So far, results indicate that miR-371a-3p cannot be used to screen pre-invasive TGCT, making testicular biopsy and immunohistochemistry the only GCNIS detection method. 75 While eight miRNAs have been found specific for TGCT, none of them has been able to identify TE.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…RASSF1A M detected 88% of teratomas. The combination of both biomarkers detects disease (including teratoma) with a sensitivity of 100% [45]. AFP-alpha-fetoprotein, β-hCG-beta-human chorionic gonadotropin, LDH-lactate dehydrogenase, GCTs-malignant germ cell tumors, a estimated.…”

Section: Serum Micrornas As New Biomarkers In Gctsmentioning

confidence: 99%

“…RASSF1A M detected 88% of teratomas. The combination of both biomarkers detects disease (including teratoma) with a sensitivity of 100% [ 45 ].…”

Section: Serum Tumor Markersmentioning

confidence: 99%

Diagnostic, Prognostic and Predictive Markers in Pediatric Germ Cell Tumors—Past, Present and Future

2022

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Germ cell tumors (GCTs) are a heterogenous group of neoplasms in children and young adults, in which serum tumor markers have been demonstrated to be highly sensitive diagnostic and monitoring tools. The known "old" serum biomarkers, alpha-fetoprotein (AFP), human choriogonadotropin (β-hCG) and lactate dehydrogenase (LDH), have some limitations in sensitivity and specificity. MIRNAs from the miR-371~373 (chromosomal locus 19q13.41) and miR-302/367 (4q25) clusters are universally over-expressed in malignant GCT tissue samples. The levels of miRNAs from these clusters are elevated in the serum. They seem to be highly sensitive and specific in malignant GCTs diagnosis and disease assessment during treatment and follow-up. The aim of our review was to present the role of serum tumor markers in the clinical staging, treatment monitoring and follow-up of pediatric patients with GCTs and show new possibilities. The serum levels of miRNAs seem to be a new, promising essential tool in the clinical management of GCTs.

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Differentially expressed messenger RNA/proteins can distinguish teratoma from necrosis in postchemotherapy retroperitoneal lymph node dissection tissue

Nestler

Kremer

Brandenstein

et al. 2022

Cancer

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Background Before postchemotherapy retroperitoneal lymph node dissection (pcRPLND), in patients with metastasized germ cell tumors (GCTs), those harboring necrosis (NEC) cannot be distinguished from those who have teratoma (TER), resulting in relevant overtreatment, whereas microRNA‐371a‐3p may be predictive for viable GCT. The purpose of this study was to explore messenger RNA (mRNA) and proteins to distinguish TER from NEC in pcRPLND tissue. Methods The discovery cohort consisted in total of 48 patients, including 16 each with TER, viable GCT, and NEC. Representative areas were microdissected. A NanoString panel and proteomics were used to analyze 770 genes and >5000 proteins. The most significantly and differentially expressed combination of both parameters, mRNA and its associated protein, between TER and NEC was validated using immunohistochemistry (IHC) in an independent validation cohort comprising 66 patients who were not part of the discovery cohort. Results The authors observed that anterior gradient protein 2 homolog (AGR2) and keratin, type I cytoskeletal 19 (KRT19) were significantly differentially expressed in TER versus NEC in mRNA and protein analyses (proteomics). The technical validation using IHC was successful in the same patients. These proteins were further validated by IHC in the independent patient cohort and exhibited significantly higher levels in TER versus NEC (p < .0001; area under the curve, 1.0; sensitivity and specificity, 100% each). Conclusions The current study demonstrated that KRT19 and AGR2 mRNA and protein are overexpressed in TER versus NEC in pcRPLND tissue and might serve as a future diagnostic target to detect TER, for instance, by functional imaging, to avoid overtreatment. Plain language summary The proteins and the corresponding genes called AGR2 and KRT19 can differentiate between teratoma and necrosis in remaining tumor masses after chemotherapy in patients who have metastasized testicular cancer. This may be a way to improve presurgical diagnostics and to reduce the current overtreatment of patients with necrosis only, who could be treated sufficiently by surveillance.

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

Cited by 23 publications

References 57 publications

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

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

Diagnostic, Prognostic and Predictive Markers in Pediatric Germ Cell Tumors—Past, Present and Future

Differentially expressed messenger RNA/proteins can distinguish teratoma from necrosis in postchemotherapy retroperitoneal lymph node dissection tissue

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