Combining urinary DNA methylation and cell-free microRNA biomarkers for improved monitoring of prostate cancer patients on active surveillance

Published on May 1, 2019in Urologic Oncology-seminars and Original Investigations2.882
· DOI :10.1016/J.UROLONC.2019.01.031
Fang Zhao7
Estimated H-index: 7
(Lunenfeld-Tanenbaum Research Institute),
Danny Vesprini33
Estimated H-index: 33
(Sunnybrook Research Institute)
+ 5 AuthorsBharati Bapat64
Estimated H-index: 64
(U of T: University of Toronto)
Sources
Abstract
Abstract Purpose Prostate cancer (CaP) patients with low-grade tumors are enrolled in active surveillance (AS) programs and monitored with digital rectal exams (DREs), prostate-specific antigen (PSA) tests, and periodic invasive biopsies. Patients are “reclassified” with higher-risk disease if they show signs of disease progression. However, AS patients who will reclassify cannot be easily identified upfront and suffer morbidities associated with biopsy. Biomarkers derived from noninvasively obtained specimens such as serum or urine samples are promising alternatives to monitor patients with clinically insignificant cancer. Previously, we have characterized and validated a urinary DNA methylation panel and a serum miRNA panel for the prediction of patient reclassification in 2 independent AS cohorts. In this exploratory study, we have investigated cell-free miRNAs in the urinary supernatant combined with urinary DNA methylation markers to form an integrative panel for prediction of AS patient reclassification. Methods Post-DRE urine was collected from 103 CaP patients on active surveillance. Urinary sediment DNA methylation levels of selected genes were previously analyzed using qPCR-based MethyLight assay. Using qRT-PCR, we analyzed the urinary supernatants for relative quantities of 10 miRNAs previously shown to be associated with AS reclassification. Logistic regression and Receiver Operating Characteristics curve analyses were performed to assess the predictive ability of miRNAs and DNA methylation biomarkers. Results We identified a 3-marker panel, consisting of miR-24, miR-30c and CRIP3 methylation, that was significant for prediction of patient reclassification (Odds ratio = 2.166, 95% confidence interval = 1.22–3.847) with a negative predictive value of 90.9%. Our 3-marker panel also demonstrated additive value to PSA for prediction of patient reclassification (c-statistic = 0.717, ROC bootstrapped 1000 iteration P = 0.041). Conclusion A urinary integrated panel of methylation and miRNA markers is a promising approach to identify AS patients at risk for reclassification. Our 3-marker panel, with its high negative predictive value, would be beneficial to identify and preclude AS patients with truly indolent cancer and to personalize monitoring strategies for AS patients.
📖 Papers frequently viewed together
8 Citations
References47
Newest
#1Laurence Klotz (Sunnybrook Health Sciences Centre)H-Index: 85
#2Andrew Loblaw (Sunnybrook Health Sciences Centre)H-Index: 35
Last. Masoom A. Haider (Sunnybrook Health Sciences Centre)H-Index: 40
view all 14 authors...
Abstract Background and objective This study aimed to determine, in men recently diagnosed with grade group 1 (GG1) prostate cancer, if magnetic resonance imaging (MRI) with targeted biopsy could identify a greater proportion of men with GG ≥2 cancer on their confirmatory biopsy compared with systematic biopsies. The study was registered with www.clinicaltrials.gov ( NCT01354171 ). Design, setting, and participants This study is a prospective, randomized, multicenter, open-label trial. Eligible ...
60 CitationsSource
#1Chuanan ZhuH-Index: 2
#2Xiumei HouH-Index: 2
Last. Wei WeiH-Index: 1
view all 5 authors...
: This study aimed to investigate the expression of miR-30c and miR-29b in prostate cancer (PCa) and its clinical significance. The expression of miR-30c and miR-29b was detected by RT-qPCR in 187 cases of PCa and their adjacent tissues. Combined with clinical information, the correlation between the expression of miR-29b and miR-30c and the clinical features of PCa was analyzed, and ROC curve was plotted. The expression of miR-30c and miR-29b detected by RT-qPCR showed that the expression of mi...
8 CitationsSource
#1Alberto Briganti (UniSR: Vita-Salute San Raffaele University)H-Index: 96
#2Nicola Fossati (UniSR: Vita-Salute San Raffaele University)H-Index: 36
Last. Hendrik Van Poppel (Katholieke Universiteit Leuven)H-Index: 82
view all 8 authors...
Abstract Active surveillance (AS) represents a well-recognized management option for many patients with low- and very low-risk prostate cancer (PCa). AS aims to reduce overtreatment whilst ensuring curative treatment for those in whom it is needed, without losing the window of curability. While long-term series have confirmed the safety of AS in carefully selected patients, this has resulted in new clinical questions. Can the inclusion criteria be expanded? Is there a role for biomarkers and mul...
58 CitationsSource
#1Veeru Kasivisvanathan (London North West Healthcare NHS Trust)H-Index: 4
#1Veeru Kasivisvanathan (Royal Free London NHS Foundation Trust)H-Index: 17
Last. Caroline M. Moore (London North West Healthcare NHS Trust)H-Index: 34
view all 41 authors...
Abstract Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography–guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to under...
836 CitationsSource
#1Richard S.C. Liu (U of T: University of Toronto)H-Index: 5
#2Ekaterina Olkhov-Mitsel (Lunenfeld-Tanenbaum Research Institute)H-Index: 11
Last. Bharati Bapat (U of T: University of Toronto)H-Index: 64
view all 11 authors...
Purpose: Conventional clinical variables cannot accurately differentiate indolent from aggressive prostate cancer in patients on active surveillance. We investigated promising circulating miRNA biomarkers to predict the reclassification of active surveillance cases.Materials and Methods: We collected serum samples from 2 independent active surveillance cohorts of 196 and 133 patients for the training and validation, respectively, of candidate miRNAs. All patients were treatment naive and diagnos...
11 CitationsSource
#1Rianne J. Hendriks (Radboud University Nijmegen)H-Index: 8
#2Marloes van der Leest (Radboud University Nijmegen)H-Index: 10
Last. Inge M. van Oort (Radboud University Nijmegen)H-Index: 31
view all 9 authors...
Background Prostate cancer (PCa) diagnostics would greatly benefit from more accurate, non-invasive techniques for the detection of clinically significant disease, leading to a reduction of over-diagnosis and over-treatment. The aim of this study was to determine the association between a novel urinary biomarker-based risk score (SelectMDx), multiparametric MRI (mpMRI) outcomes, and biopsy results for PCa detection. Methods This retrospective observational study used data from the validation stu...
37 CitationsSource
#1Zhang Jun (Fudan University)H-Index: 10
#2Wang Xilong (Fudan University)H-Index: 3
Last. Guowei Shi (Fudan University)H-Index: 7
view all 9 authors...
: Aberrant microRNA expression is associated with tumor development. The present study aimed to elucidate the role of miR-30c in the development of prostate cancer. Quantitative polymerase chain reaction was performed to compare miR-30c expression in LNCaP, DU145, PC-3 and RWPE-1 cell lines. Lentivirus expressing miR-30c was used to create stable overexpression cell lines to investigate the effects of miR-30c overexpression on cell proliferation, migration and invasion, which were determined in ...
8 CitationsSource
#1Hoin Kang (Catholic University of Korea)H-Index: 12
#2Jun Gi Rho (Ajou University)H-Index: 8
Last. Eun Kyung LeeH-Index: 28
view all 13 authors...
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by suppressing translation or facilitating mRNA decay. Differential expression of miRNAs is involved in the pathogenesis of several diseases including cancer. Here, we investigated the role of-miR-24-3p as a downregulated miRNA in metastatic cancer. miR-24-3p was decreased in metastatic cancer and lower expression of miR-24-3p was related to poor survival of cancer patients. Consistently, ectopic expression of ...
13 CitationsSource
One of the major challenges in prostate cancer (PCa) treatment is distinguishing insignificant PCa from those forms that need active treatment. We evaluated the impact of PSA isoforms on risk stratification in patients with low-risk PCa as well as in active surveillance (AS) candidates who underwent radical prostatectomy. A total of 112 patients with biopsy confirmed Gleason score (GS) 6 PCa of four different international institutions were prospectively enrolled in the study. Blood withdrawal w...
15 CitationsSource
#1Jacob Fredsøe (Aarhus University Hospital)H-Index: 10
Last. Karina Dalsgaard Sørensen (Aarhus University Hospital)H-Index: 31
view all 8 authors...
Abstract Background Widespread use of prostate-specific antigen (PSA) testing for prostate cancer (PC) detection has led to extensive overdiagnosis and overtreatment. Urine-based microRNA (miRNA) biomarkers could be useful in PC diagnosis and prognosis. Objective To train and validate urine-based microRNA (miRNA) biomarkers that may assist in PC diagnosis and prognosis. Design, setting, and participants We profiled the expression levels of 92 miRNAs via reverse transcriptase–poymerase chain reac...
39 CitationsSource
Cited By8
Newest
#1Paolo GandelliniH-Index: 25
Last. Nadia ZaffaroniH-Index: 66
view all 16 authors...
Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profi...
Source
#1Jeremy ClarkH-Index: 52
#2Rachel HurstH-Index: 19
Last. Colin CooperH-Index: 21
view all 11 authors...
Prostate cancer (PCa) can be highly heterogeneous and multifocal, and accurate assessment of the volume, grade, and stage of PCa in situ is not a simple task. Urine has been investigated as a source of PCa biomarkers for over 70 years, and there is now strong evidence that analysis of urine could provide more accurate diagnosis and a better risk stratification that could aid clinical decisions regarding disease surveillance and treatment. Urine diagnostics is a developing area, moving towards mu...
Source
#1D. FiorellaH-Index: 2
#2J.L. MarencoH-Index: 2
Last. José Rubio-BrionesH-Index: 15
view all 9 authors...
Resumen Introduccion y objetivos Un porcentaje no despreciable de pacientes incluidos en programas de vigilancia activa (VA) para el cancer de prostata (CaP) de bajo y muy bajo riesgo son reclasificados en la biopsia confirmatoria o desarrollan progresion de la enfermedad durante el seguimiento. Nuestro objetivo es evaluar el papel del PCA3 y el SelectMDx, de manera individual y combinada, para predecir la progresion patologica (PP) en un programa habitual de VA. Materiales y metodos Estudio pro...
1 CitationsSource
#1D. FiorellaH-Index: 2
#2J.L. MarencoH-Index: 2
Last. José Rubio-BrionesH-Index: 15
view all 0 authors...
Abstract null null Introduction & objectives null A not negligible percentage of patients included in active surveillance (AS) for low and very low risk prostate cancer (PCa) are reclassified in the confirmatory biopsy or have disease progression during follow-up. Our aim is to evaluate the role of PCA3 and SelectMDx, in an individual and combined way, in the prediction of pathological progression (PP) in a standard AS program. null null null Materials & methods null Prospective and observationa...
1 CitationsSource
Prostate cancer (PCa) is the fifth cause of tumor-related deaths in man worldwide. Despite the considerable improvement in the clinical management of PCa, several limitations emerged both in the screening for early diagnosis and in the medical treatment. The use of prostate-specific antigen (PSA)-based screening resulted in patients’ overtreatment and the standard therapy of patients suffering from locally advanced/metastatic tumors (e.g., radical prostatectomy, radiotherapy, and androgen depriv...
1 CitationsSource
#1Marc A. Dall'Era (UC Davis: University of California, Davis)H-Index: 24
In the past two decades, new biomarkers for prostate cancer detection and risk prediction have become available for clinical use. While tissue-based gene expression assays offer molecular risk assessment after diagnoses, several serum- and urine-based ‘liquid’ biomarkers are available for the pre-biopsy setting which may also play a role for active surveillance (AS). The medical literature was queried utilizing PubMed (pubmed.ncbi.nlm.nih.gov) for all relevant original publications describing pr...
Source
Studies investigating microRNAs as potential biomarkers for cancer, immune-related diseases, or cardiac pathogenic diseases, among others, have exponentially increased in the last years. In particular, altered expression of specific miRNAs correlates with the occurrence of several diseases, making these molecules potential molecular tools for non-invasive diagnosis, prognosis, and response to therapy. Nonetheless, microRNAs are not in clinical use yet, due to inconsistencies in the literature re...
Source
#1Enchong ZhangH-Index: 3
#2Mo ZhangH-Index: 4
Last. Yongsheng Song (PRC: China Medical University (PRC))H-Index: 14
view all 7 authors...
Prostate cancer (PCa) is a deadly disease for men, and studies of all types of omics data are necessary to promote precision medicine. The maturity of sequencing technology, the improvements of computer processing power, and the progress achieved in omics analysis methods have improved research efficiency and saved research costs. The occurrence and development of PCa is due to multisystem and multilevel pathological changes. Although omics research at a single level is important, this approach ...
1 CitationsSource
#1Maria FrantziH-Index: 14
#2Enrique Gómez-Gómez (Sofia University)H-Index: 10
Last. Harald Mischak (UCO: University of Córdoba (Spain))
view all 3 authors...
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies worldwide and is associated with high mortality. Broad screening through prostate-specific antigen analysis, along with an...
Source
1 CitationsSource