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NRG1 Genetic Variant Influences the Efficacy of Androgen-Deprivation

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NRG1 Genetic Variant Influences the Efficacy of Androgen-Deprivation biomedicines Article NRG1 Genetic Variant Influences the Efficacy of Androgen-Deprivation Therapy in Men with Prostate Cancer Shu-Pin Huang 1,2,3,4,†, Yei-Tsung Chen 5,† , Lih-Chyang Chen 6, Cheng-Hsueh Lee 1,2, Chao-Yuan Huang 7, Chia-Cheng Yu 8,9,10, Victor C. Lin 11,12, Te-Ling Lu 13 and Bo-Ying Bao 13,14,15,* 1 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; [email protected] (S.-P.H.); [email protected] (C.-H.L.) 2 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan 3 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan 4 Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan 5 Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; [email protected] 6 Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan; [email protected] 7 Department of Urology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan; [email protected] 8 Department of Surgery, Division of Urology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; [email protected] 9 Department of Urology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan 10 Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung 907, Taiwan 11 Department of Urology, E-Da Hospital, Kaohsiung 824, Taiwan; [email protected] 12 School of Medicine for International Students, I-Shou University, Kaohsiung 840, Taiwan 13 Department of Pharmacy, China Medical University, Taichung 404, Taiwan; [email protected] Citation: Huang, S.-P.; Chen, Y.-T.; 14 Sex Hormone Research Center, China Medical University Hospital, Taichung 404, Taiwan Chen, L.-C.; Lee, C.-H.; Huang, C.-Y.; 15 Department of Nursing, Asia University, Taichung 413, Taiwan Yu, C.-C.; Lin, V.C.; Lu, T.-L.; Bao, * Correspondence: [email protected]; Tel.: +886-4-22053366 (ext. 5126) B.-Y. NRG1 Genetic Variant Influences † These authors contributed equally to this work. the Efficacy of Androgen-Deprivation Abstract: Neuregulins (NRGs) activate receptor tyrosine kinases of the ErbB family, and play essential Therapy in Men with Prostate Cancer. Biomedicines 2021, 9, 528. https:// roles in the proliferation, survival, and differentiation of normal and malignant tissue cells. We doi.org/10.3390/biomedicines9050528 hypothesized that genetic variants of NRG signalling pathway genes may influence treatment out- comes in prostate cancer. To test this hypothesis, we performed a comprehensive analysis to evaluate Academic Editor: Francesco Ceci the associations of 459 single-nucleotide polymorphisms in 19 NRG pathway genes with cancer- specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in 630 patients with Received: 20 April 2021 prostate cancer receiving androgen-deprivation therapy (ADT). After multivariate Cox regression Accepted: 6 May 2021 and multiple testing correction, we found that NRG1 rs144160282 C > T is significantly associated Published: 10 May 2021 with worsening CSS, OS, and PFS during ADT. Further analysis showed that low expression of NRG1 is closely related to prostate cancer, as indicated by a high Gleason score, an advanced stage, and Publisher’s Note: MDPI stays neutral a shorter PFS rate. Meta-analysis of 16 gene expression datasets of 1,081 prostate cancer samples with regard to jurisdictional claims in and 294 adjacent normal samples indicate lower NRG1 expression in the former compared with the published maps and institutional affil- latter (p < 0.001). These results suggest that NRG1 rs144160282 might be a prognostic predictor of the iations. efficacy of ADT. Further studies are required to confirm the significance of NRG1 as a biomarker and therapeutic target for prostate cancer. Keywords: androgen-deprivation therapy; neuregulin; meta-analysis; prostate cancer; survival Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Attribution (CC BY) license (https:// Prostate cancer is one of the major causes of mortality worldwide with an estimated creativecommons.org/licenses/by/ 1.4 million new cases and 0.38 million deaths in 2020 [1]. Since the critical role of an- 4.0/). drogens in stimulating prostate cancer growth was established, androgen deprivation Biomedicines 2021, 9, 528. https://doi.org/10.3390/biomedicines9050528 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 528 2 of 11 therapy (ADT) has become the most common concomitant therapy for prostate cancer [2]. Although most patients with prostate cancer initially respond to ADT, the duration of this response is highly variable. Once patients experience disease progression despite hormonal manipulation, the median survival period of patients with castration-resistant prostate cancer (CRPC) is 15–36 months depending on the tumour characteristics [3]. Currently, several clinicopathological factors, such as prostate-specific antigen (PSA), Gleason score, and cancer stage, have been concluded as predictors for the efficacy of ADT, but patient prognosis remains heterogeneous. Previously conducted epidemiological studies on twins suggest that prostate cancer is an inherited disease, with approximately 42% of its risk attributed to genetic factors [4]. To date, genome-wide association studies (GWAS) have identified more than 100 prostate cancer susceptibility loci [5]. However, these loci explain only 33% of the familial risk of prostate cancer, suggesting that a significant proportion of prostate cancer heritability remains undiscovered. Compared to GWAS, a hypothesis- driven pathway-based approach is advantageous as it avoids stringent multiple testing corrections and false negative results. Neuregulins (NRGs) are a subclass of the epidermal growth factor family, and are also known as heregulins, because they were initially identified while searching for Erb-B2 recep- tor tyrosine kinase 2 (ERBB2/HER2/NEU) activators [6]. Four NRG genes (NRG1-4) can be coded for more than 30 different protein isoforms using distinct promoters and alternative splicing [7]. NRGs principally act as ligands by binding to ERBB3/HER3 and ERBB4/HER4, and lead to the stimulation of diverse pathways, including mitogen-activated protein ki- nase (MAPK), protein kinase C, signal transducer and activator of transcription, and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt serine/threonine kinase (AKT) signalling pathways, resulting in the regulation of cell proliferation and development in multiple organs [8]. Recent genetic studies have shown that several germline variants of NRG genes are associated with the risks of developing thyroid and breast cancers [9,10]. An intronic variant of NRG1 was also found to be associated with non-small cell lung cancer survival [11]. Moreover, a polymorphism in NRG3 might lead to better overall survival in patients with stage IV epithelial ovarian cancer who are receiving first-line treatment [12]. However, the roles of genetic variants within the NRG signalling pathway in prostate cancer are unclear, and investigations into their functions may provide insight into the etiology and prognostic significance of the disease. Since the NRG signalling pathway is considered to reflect the underlying biological processes of cancer development and progression, it is anticipated that single-nucleotide polymorphisms (SNPs) in NRG pathway genes may influence the response to cancer therapy. Therefore, we performed a pathway-based survival analysis to evaluate SNPs within the NRG pathway in a cohort of patients with prostate cancer treated with ADT. 2. Materials and Methods 2.1. Patient Response Evaluation This study included 630 patients with prostate cancer who had been treated with ADT in three medical centres in Taiwan: National Taiwan University Hospital, Kaohsiung Medical University Hospital, and Kaohsiung Veterans General Hospital, as described previously [13,14]. The study was approved by the institutional review board of Kaohsiung Medical University Hospital (KMU-HIRB-2013132) in compliance with the Good Clinical Practice guidelines, and written informed consent was obtained from all participants. Clinicopathological information was collected from the patients’ medical records. Cancer- specific survival (CSS) was defined as the time from the initiation of ADT to the last follow- up or cancer-related death. Overall survival (OS) was defined as the time from the initiation of ADT to death attributable to any disease. Progression-free survival (PFS) was defined as the time from the initiation of ADT to disease progression or cancer-related death. Biomedicines 2021, 9, 528 3 of 11 2.2. SNP Selection and Genotyping Haplotype-tagging SNPs (htSNPs) covering 19 NRG pathway genes, including NRG1- 4; ERBB4; PI3K catalytic subunits alpha, beta, and delta (PIK3CA, PIK3CB, and PIK3CD); the mechanistic target of rapamycin kinase (MTOR); AKT1-3; BCL2 associated agonist of cell death (BAD); glycogen synthase kinase 3 beta (GSK3B); cyclin dependent kinase inhibitors 1A and 1B (CDKN1A and CDKN1B); eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1); and ribosomal protein S6 kinases B1 and B2 (RPS6KB1 and RPS6KB2) and their five kb flanking regions were selected using the 1000 Genomes
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