Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis.

Pai-Chi Teng,Deng-Neng Chen,Yo-Liang Lai,Wei-Chung Cheng,Shu-Pin Huang,Ting-Yi Lin,Shu-Chi Wang,Chia-Hsin Liu,Hsin-Chih Yeh,Chih-Pin Chuu,Yi-Chun Cho,Chia-Yang Li

doi:10.3390/ijms222111771

Abstract

In the recent decade, the importance of DNA damage repair (DDR) and its clinical application have been firmly recognized in prostate cancer (PC). For example, olaparib was just approved in May 2020 to treat metastatic castration-resistant PC with homologous recombination repair-mutated genes; however, not all patients can benefit from olaparib, and the treatment response depends on patient-specific mutations. This highlights the need to understand the detailed DDR biology further and develop DDR-based biomarkers. In this study, we establish a four-gene panel of which the expression is significantly associated with overall survival (OS) and progression-free survival (PFS) in PC patients from the TCGA-PRAD database. This panel includes DNTT, EXO1, NEIL3, and EME2 genes. Patients with higher expression of the four identified genes have significantly worse OS and PFS. This significance also exists in a multivariate Cox regression model adjusting for age, PSA, TNM stages, and Gleason scores. Moreover, the expression of the four-gene panel is highly correlated with aggressiveness based on well-known PAM50 and PCS subtyping classifiers. Using publicly available databases, we successfully validate the four-gene panel as having the potential to serve as a prognostic and predictive biomarker for PC specifically based on DDR biology.

Highlights

Prostate cancer (PC) is the second most commonly diagnosed cancer in men with an estimate of 1.4 million new cases, causing approximate 374,000 deaths worldwide in 2020 [1]
NotablyL, othweerre were only threereMf 1 (i.e., prostate cancer (PC) withredf istant metastasries)f patients in thisrsetfudy becauseHailglhtehre PC tissues we1r3e.8obtained from1p.2r1imary PC by ra1d5i8cal prostatecto0m.03y4.8As shownAigne T(yaebalre) 2, the patient1s.0w5ith higher fou0r.-9g5ene expression1.w15ere independe0n.3tl6y67associated with poorer overall survival (OS) (Cox HR = 13.8, 95% CI = 1.21 to 158, p = 0.0348) and progression-free survival (PFS) (Cox HR = 2.3P2S, A95(%ngC/Im=L1) .36 to 3.95, p0.=990.0020)
We examined the expression of our four-gene panel based on these two well-known PC classifiers using data from an independent cohort [23]

Summary

Introduction

Prostate cancer (PC) is the second most commonly diagnosed cancer in men with an estimate of 1.4 million new cases, causing approximate 374,000 deaths worldwide in 2020 [1]. Other treatment options for advanced PC include taxanes, antibody–drug conjugates, radium-223, DNA damage repair (DDR) inhibitors, etc [6]. Olaparib, a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, was approved in 2020 as the first targeted therapy against a specific molecular phenotype of mCRPC with certain DDR gene mutations [7,8]. Many studies have reported both somatic and germline mutations of DDR pathways in PC. The Cancer Genome Atlas (TCGA) dataset revealed the inactivation of DDR genes including BRCA1, BRCA2, CDK12, ATM, FANCD2, and RAD51C in 19% of tissues collected from 333 localized PC patients who underwent radical prostatectomy [9]. A systemic review by Lang et al summarized 11,648 records from 80 studies and demonstrated that the median prevalence rates for somatic and germline mutations of DDR genes were 10.7% and 18.6%, respectively [10]. BRCA2, ATM, and PALB2 genes had higher mutation rates of ≥4% [10], while in mCRPC, 19.3% of aberrations in BRCA2, BRCA1, and ATM genes were found in bone or soft tissue tumor biopsies that were substantially more frequently compared to those in primary PC tissues [11]

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Results