Abstract
BackgroundmiRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer.MethodsTaqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation.ResultsA 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen–nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094–0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24–0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08–0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033).ConclusionA 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.
Highlights
MiRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in formalin-fixed paraffin-embedded (FFPE) tissue
An initial comparison compared miRNAs induced in the three muscle invasive bladder cancer (MIBC) cell lines (T24, J82 and UMUC3) exposed to 0.2% and 1% O2
A hypoxia-associated miRNA signature was derived that predicted benefit from CON in patients with MIBC recruited in the Phase 3 Bladder Carbogen Nicotinamide (BCON) trial with trends for positive tests for interactions
Summary
MiRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. Different radiosensitising approaches are used, and as high levels of tumour hypoxia are associated with a poor prognosis irrespective of the treatment approach,[5] a predictive hypoxia biomarker would help select patients for RT with hypoxia-modifying therapy rather than chemo-radiotherapy.[2,6] Work from our group showed that necrosis, CA9, hypoxia-inducible factor (HIF)-1α and a 24-gene mRNA signature predict benefit for giving CON with RT in BCON.[3,7,8,9] The presence of tumour hypoxia is an adverse prognostic feature irrespective of treatment, and we showed that high 24-gene signature scores associated with a poor prognosis in patients with MIBC who did not receive RT.[9] The BCON trial randomised patients to RT alone or with hypoxia-modifying carbogen and nicotinamide (RT+CON) and showed that the combined treatment improved the 3-year overall survival rate by 13%.1,3 BC2001 randomised patients to RT alone or with chemotherapy (5 fluorouracil and mitomycin C) and showed that the combined treatment improved the 2-year locoregional disease-free survival rate by 13%.1,4 Different radiosensitising approaches are used, and as high levels of tumour hypoxia are associated with a poor prognosis irrespective of the treatment approach,[5] a predictive hypoxia biomarker would help select patients for RT with hypoxia-modifying therapy rather than chemo-radiotherapy.[2,6] Work from our group showed that necrosis, CA9, hypoxia-inducible factor (HIF)-1α and a 24-gene mRNA signature predict benefit for giving CON with RT in BCON.[3,7,8,9] The presence of tumour hypoxia is an adverse prognostic feature irrespective of treatment, and we showed that high 24-gene signature scores associated with a poor prognosis in patients with MIBC who did not receive RT.[9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
