Predictive Biomarkers of Dicycloplatin Resistance or Susceptibility in Prostate Cancer.

Minglu Liu,Jun Liu,Guoqing Zhang,Chelong Lu,Shunchang Jiao,Xiaoyu Zhou,Jing Zhang

doi:10.3389/fgene.2021.669605

Minglu Liu, Jun Liu + Show 5 more

Open Access

https://doi.org/10.3389/fgene.2021.669605

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Abstract

BackgroundProstate cancer (PCa) is among the leading causes of cancer mortality. Dicycloplatin is a newer generation platinum-based drug that has less side effects than cisplatin and carboplatin. However, its effects in PCa is mixed due to lack of appropriate stratifying biomarkers. Aiming to search for such biomarkers, here, we analyze a group of PCa patients with different responses to dicycloplatin.MethodsWe carried out whole-exome sequencing on cell-free DNA (cfDNA) and matched leukocyte DNA from 16 PCa patients before treatment with dicycloplatin. We then compared the clinical characteristics, somatic mutations, copy number variants (CNVs), and mutational signatures between the dicycloplatin-sensitive (nine patients) and dicycloplatin-resistant (seven patients) groups and tested the identified mutations, CNV, and their combinations as marker of dicycloplatin response.ResultsThe mutation frequency of seven genes (SP8, HNRNPCL1, FRG1, RBM25, MUC16, ASTE1, and TMBIM4) and CNV rate of four genes (CTAGE4, GAGE2E, GAGE2C, and HORMAD1) were higher in the resistant group than in the sensitive group, while the CNV rate in six genes (CDSN, DPCR1, MUC22, TMSB4Y, VARS, and HISTCH2AC) were lower in the resistant group than in the sensitive group. A combination of simultaneous mutation in two genes (SP8/HNRNPCL1 or SP8/FRG1) and deletion of GAGE2C together were found capable to predict dicycloplatin resistance with 100% sensitivity and 100% specificity.ConclusionWe successfully used cfDNA to monitor mutational profiles of PCa and designed an effective composite marker to select patients for dicycloplatin treatment based on their mutational profile.

Highlights

Prostate cancer (PCa) is one of the most common cancers in men worldwide and has the second highest mortality (Siegel et al, 2020)
Nine of the patients were sensitive to the treatment, including six with partial response (PR) and three with complete response
The remaining seven patients were resistant to the treatment, including six with progressive disease (PD) and one with stable disease (SD)

Summary

Introduction

Prostate cancer (PCa) is one of the most common cancers in men worldwide and has the second highest mortality (Siegel et al, 2020). Predictive Biomarkers of Dicycloplatin in PCa can improve the survival time and clinical benefits for early stage PCa. about 10–20% of patients will inevitably develop into drug resistance within 5 years during the course of treatment, leading to castration-resistant prostate cancer (Kirby et al, 2011). Platinum-based chemotherapies, such as cisplatin and carboplatin, are attracting more and more attention in the treatment of cancer (Apps et al, 2015). The clinical benefits from these drug therapies are still low, they can prolong patients’ overall survival for only 3–6 months (Fortin et al, 2013) Their clinical application is limited by severe adverse effects, including ototoxicity, neurotoxicity, and myelosuppression (Rossi et al, 2012). Aiming to search for such biomarkers, here, we analyze a group of PCa patients with different responses to dicycloplatin

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