Serum miRNA Predicts Viable Disease after Chemotherapy in Patients with Testicular Nonseminoma Germ Cell Tumor

Leão, Ricardo; Agthoven, Ton van; Figueiredo, Arnaldo; Jewett, Michael A.S.; Fadaak, Kamel; Sweet, Joan; Ahmad, Ardalan E.; Anson‐Cartwright, Lynn; Chung, Peter; Hansen, Aaron R.; Warde, Padraig; Castelo‐Branco, Pedro; O’Malley, Martin; Bedard, Philippe L.; Looijenga, Leendert H. J.; Hamilton, Robert J.

doi:10.1016/j.juro.2018.02.068

Cited by 117 publications

(113 citation statements)

References 30 publications

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“…We reported an AUC of 0.951, with an 89% specificity and 90% sensitivity for miR‐371a‐3p and an AUC of 0.962 for the combination of the miRs with specificity of 92% and sensitivity of 91% . However, in our most recent studies addition of the extra miRs compared to miR‐371a‐3p did not improve the outcome . In addition, other studies are based on only using miR‐371 …”

Section: Discussionmentioning

confidence: 70%

“…14 However, in our most recent studies addition of the extra miRs compared to miR-371a-3p did not improve the outcome. 13,18 In addition, other studies are based on only using miR-371. 10,16,21 In this large translational study we showed for the first time an association between plasma miR-371a-3p level and several disease characteristics including sites of metastases, serum tumour markers, IGCCCG prognostic group or favourable response to chemotherapy measured at the time just prior to the start of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…It allowed early detection of relapse of a single mixed tumour and distinguished intracranial malignant GCTs from intracranial non‐GCTs at the time of diagnosis . In addition, the ampTSmiR test targeting miR‐371a‐3p used in our laboratory is more sensitive than the conventional TGCTs protein serum biomarkers for the detection of residual disease and relapse . In conclusion, miR‐371a‐3p is the most promising miRNA for the detection of (T)GCTs in body fluids to date, performed with a highly sensitive and specific multiplexed pre‐amplification quantitative real‐time PCR (qRT‐PCR) technique …”

Section: Introductionmentioning

confidence: 95%

“…15 In addition, the ampTSmiR test targeting miR-371a-3p used in our laboratory is more sensitive than the conventional TGCTs protein serum biomarkers for the detection of residual disease and relapse. 13,14,18 In conclusion, miR-371a-3p is the most promising miRNA for the detection of (T)GCTs in body fluids to date, performed with a highly sensitive and specific multiplexed pre-amplification quantitative real-time PCR (qRT-PCR) technique. 10,14 However, in spite of the fact that miR-371a-3p is a promising new specific biomarker for (T)GCTs, data related to its clinical utility are still limited.…”

mentioning

confidence: 99%

“…10,14 However, in spite of the fact that miR-371a-3p is a promising new specific biomarker for (T)GCTs, data related to its clinical utility are still limited. [9][10][11][12]18 The aim of this study was to evaluate clinical utility of plasma miR-371a-3p level in chemo-naïve GCTs patients starting systemic chemotherapy.…”

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confidence: 99%

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

Mego

Agthoven

Gronesova

et al. 2018

J Cellular Molecular Medi

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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, P = 0.02 for PFS and HR = 0.21, 95% CI 0.07‐0.67, P = 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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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Mego

Agthoven

Gronesova

et al. 2018

J Cellular Molecular Medi

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Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors

et al. 2021

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Testicular germ cell tumors (TGCTs) are the most common cancers in men aged 15–39 years and are divided into two major groups, seminomas and nonseminomas. Novel treatment options are required for these patients, to limit side effects of chemotherapy. We hypothesized that promoter methylation of relevant homologous recombination (HR) genes might be predictive of response to poly‐ADP ribose polymerase inhibitors (PARPis) in TGCTs. We report a study pipeline combining in silico, in vitro, and clinical steps. By using several databases and in silico tools, we identified BRCA1, RAD51C, PALB2, RAD54B, and SYCP3 as the most relevant genes for further investigation and pinpointed specific CpG sites with pronounced negative correlation to gene expression. Nonseminomas displayed significantly higher methylation levels for all target genes, where increased methylation was observed in patients with more differentiated subtypes and higher disease burden. We independently performed second‐line targeted validation in tissue series from TGCT patients. A moderate and/or strong anti‐correlation between gene expression (assessed by RNA‐sequencing) and promoter methylation (assessed by 450k array) was found, for all of the targets. As a proof of concept, we demonstrated the sensitivity of TGCT cell lines to Olaparib, which associated with differential methylation levels of a subset of targets, namely BRCA1 and RAD51C. Our findings support the use of HR genes promoter methylation as a predictor of the therapeutic response to PARPis in patients with TGCT.

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Predictive capacity of a miRNA panel in identifying teratoma in post‐chemotherapy consolidation surgeries

et al. 2022

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Objectives To investigate the utility of a novel serum miRNA biomarker panel to distinguish teratoma from nonmalignant necrotic/fibrotic tissues or nonviable tumours in patients with NSGCT undergoing post‐chemotherapy consolidation surgery. Patients and methods We prospectively collected pre‐surgical serum samples from 22 consecutive testicular NSGCT patients with residual NSGCT after chemotherapy undergoing post‐chemotherapy consolidation surgery. We measured serum miRNA expression of four microRNAs (miRNA‐375, miRNA‐200a‐3p, miRNA‐200a‐5p and miRNA‐200b‐3p) and compared with pathologic findings at time of surgery. Receiver operating characteristic (ROC) curves were performed to assess the ability of these miRNA to differentiate between teratoma and necrosis or viable malignancy. Results Twenty‐two patients with NSGCT were split into two groups based on pathology at time of post‐chemotherapy consolidation surgery (teratoma group vs. necrosis/fibrosis/viable tumour group, i.e., NFVT). Patients with teratoma were older at diagnosis compared with those patients with NFVT (median age 28.7 vs. 23.9). Patients with NFVT were more likely to have embryonal carcinoma in their primary tumour (81.8% vs. 27.3%; p = 0.01). The majority of patients in both groups were stage III (63.6% vs. 72.7%). In this analysis, none of the miRNAs had good sensitivity or specificity to predict teratoma. There was no significant association between the expression levels of the miRNAs and the presence of teratoma. There was no statistically significant correlation between any of the miRNAs and teratoma size. Conclusion This novel miRNA panel (miRNA‐375, miRNA‐200a‐3p, miRNA‐200a‐5p and miRNA‐200b‐3p) did not distinguish teratoma from nonmalignant necrotic/fibrotic tissues or nonviable tumours in patients with NSGCT undergoing post‐chemotherapy consolidation surgery.

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Serum miRNA Predicts Viable Disease after Chemotherapy in Patients with Testicular Nonseminoma Germ Cell Tumor

Abstract: Our study demonstrates for the first time the potential value of miR-371a-3p to predict viable germ cell tumors in residual masses after chemotherapy. Prospective studies are required to confirm clinical usefulness.

Cited by 117 publications

References 30 publications

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

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

Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors

Predictive capacity of a miRNA panel in identifying teratoma in post‐chemotherapy consolidation surgeries

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