TY - JOUR
T1 - The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer
AU - Hansen, Emma Kirstine Bollmann
AU - Fredsøe, Jacob Hesselvig
AU - Okholm, Trine Line Hauge
AU - Ulhøi, Benedicte Parm
AU - Klingenberg, Søren
AU - Jensen, Jørgen Bjerggaard
AU - Kjems, Jørgen
AU - Bouchelouche, Kirsten
AU - Borre, Michael
AU - Damgaard, Christian Kroun
AU - Pedersen, Jakob Skou
AU - Kristensen, Lasse Sommer
AU - Sørensen, Karina Dalsgaard
PY - 2022/1
Y1 - 2022/1
N2 - Background: Circular RNAs (circRNAs) constitute a largely unexplored source for biomarker discovery in prostate cancer (PC). Here, we characterize the biomarker potential of circRNAs in PC, where the need for novel diagnostic and prognostic tools to facilitate more personalized management is pressing. Methods: We profiled the transcriptomic landscape of circRNAs in PC by total RNA sequencing of 31 adjacent-normal and 143 tumor samples from localized (radical prostatectomy (RP)) and metastatic PC patients (cohort 1, training). Diagnostic and prognostic potential was evaluated in cohort 1, and 39 top circRNA candidates were selected for validation in two additional PC cohorts (cohort 2, n = 111; RP cohort 3, n = 191) by NanoString-based expression analysis. Biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier, univariate, and multivariate Cox regression analyses. The circRNA candidates were further detected in extracellular vesicle (EV)-enriched plasma samples from PC patients and controls (cohort 4, n = 54). Results: Expression of circABCC4, circFAT3, circATRNL1, and circITGA7 was highly cancer-specific (area under the curve 0.71–0.86), while low circITGA7 expression was significantly (P < 0.05) associated with BCR in univariate analysis in two RP cohorts. Moreover, we successfully trained and validated a novel 5-circRNA prognostic signature (circKMD1A/circTULP4/circZNF532/circSUMF1/circMKLN1) significantly associated with BCR beyond routine clinicopathological variables (RP cohort 1: P = 0.02, hazard ratio = 2.1; RP cohort 3: P < 0.001, hazard ratio = 2.1). Lastly, we provide proof-of-principle for detection of candidate circRNAs in EV-enriched plasma samples from PC patients. Conclusions: circRNAs hold great biomarker potential in PC and display both high cancer specificity and association to disease progression.
AB - Background: Circular RNAs (circRNAs) constitute a largely unexplored source for biomarker discovery in prostate cancer (PC). Here, we characterize the biomarker potential of circRNAs in PC, where the need for novel diagnostic and prognostic tools to facilitate more personalized management is pressing. Methods: We profiled the transcriptomic landscape of circRNAs in PC by total RNA sequencing of 31 adjacent-normal and 143 tumor samples from localized (radical prostatectomy (RP)) and metastatic PC patients (cohort 1, training). Diagnostic and prognostic potential was evaluated in cohort 1, and 39 top circRNA candidates were selected for validation in two additional PC cohorts (cohort 2, n = 111; RP cohort 3, n = 191) by NanoString-based expression analysis. Biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier, univariate, and multivariate Cox regression analyses. The circRNA candidates were further detected in extracellular vesicle (EV)-enriched plasma samples from PC patients and controls (cohort 4, n = 54). Results: Expression of circABCC4, circFAT3, circATRNL1, and circITGA7 was highly cancer-specific (area under the curve 0.71–0.86), while low circITGA7 expression was significantly (P < 0.05) associated with BCR in univariate analysis in two RP cohorts. Moreover, we successfully trained and validated a novel 5-circRNA prognostic signature (circKMD1A/circTULP4/circZNF532/circSUMF1/circMKLN1) significantly associated with BCR beyond routine clinicopathological variables (RP cohort 1: P = 0.02, hazard ratio = 2.1; RP cohort 3: P < 0.001, hazard ratio = 2.1). Lastly, we provide proof-of-principle for detection of candidate circRNAs in EV-enriched plasma samples from PC patients. Conclusions: circRNAs hold great biomarker potential in PC and display both high cancer specificity and association to disease progression.
KW - Biomarker
KW - Cancer
KW - Prostate
KW - circRNA
KW - Prostatic Neoplasms/genetics
KW - Prognosis
KW - Humans
KW - Male
KW - Prostatectomy
KW - Neoplasm Recurrence, Local/diagnosis
KW - RNA, Circular
KW - Biomarkers, Tumor/genetics
U2 - 10.1186/s13073-021-01009-3
DO - 10.1186/s13073-021-01009-3
M3 - Journal article
C2 - 35078526
SN - 1756-994X
VL - 14
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 8
ER -