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American Journal of Clinical and Experimental Urology logoLink to American Journal of Clinical and Experimental Urology
. 2019 Dec 15;7(6):352–377.

Genetic alterations of interleukin-17 and related genes in human prostate cancer

Ruoxin Lan 2, Kun Zhang 3, Tianhua Niu 4, Zongbing You 1,2,5,6,7,8
PMCID: PMC6971475  PMID: 31970232

Abstract

Interleukin-17 (IL-17) has been shown to promote development of hormone-naïve prostate cancer (HNPC) and castration-resistant prostate cancer (CRPC) as well as lymph node metastasis in mouse models. Gene alterations of IL-17 family of cytokines and their downstream genes in human prostate cancer have not been investigated. We studied 7 datasets archived in cBioPortal and queried gene alterations in a total of 1303 cases of human prostate cancers. 35 genes were examined, including IL-17 family of cytokines and receptors, IL-17-downstream genes, and genes related to IL-17-downstream genes. We found that 34/35 (97%) genes had significantly more alterations in metastatic prostate cancer (with alteration rates ranging from 3.42% to 13.01%) than primary prostate cancer (with alteration rates ranging from 0.40% to 2.96%). 15/35 (43%) genes had significantly more alterations in primary CRPC than primary HNPC. 34/35 (97%) genes had significantly more alterations in metastatic CRPC than primary HNPC. Only three genes (S100A7, S100A8, and S100A9) had significantly more alterations in metastatic CRPC than primary CRPC. The gene alterations were mostly gene amplifications (97%), while gene deep deletions, missense mutations, and truncating mutations were very rare. 7/35 (20%) genes had significantly more alterations in primary neuroendocrine prostate cancer (NEPC) than primary adenocarcinoma (AC). 23/35 (66%) genes had significantly more alterations in metastatic NEPC than metastatic AC. Only three genes (S100A7, S100A8, and S100A9) had significantly more alterations in metastatic NEPC than metastatic AC with neuroendocrine features. Most of the gene alterations in metastatic NEPC were gene amplifications (80%), while gene deep deletions, missense mutations, and truncating mutations were very rare. Our findings suggest that gene amplifications of IL-17 and related genes are more frequently found in metastatic CRPC and NEPC than primary hormone-naïve prostate adenocarcinomas, implying that IL-17 and related genes may play important roles in the progression from HNPC to CRPC and from primary location to metastasis as well as in development of metastatic NEPC.

Keywords: Prostate cancer, metastasis, CRPC, IL-17, gene amplification

Introduction

Prostate cancer is the most common malignancy and the second most common cause of cancer-related deaths in American men; the American Cancer Society estimates that there are approximately 174,650 new cases and 31,620 deaths due to prostate cancer in 2019 [1]. Distant metastases are common findings in autopsies of prostate cancer patients. Hematogenous metastases were present in 35% of 1,589 patients with prostate cancer, with the most frequent involvement being the bone (90%), lungs (46%), liver (25%), pleura (21%), and adrenals (13%) [2]. Metastatic prostate cancers are usually treated with androgen deprivation therapy (ADT) and they often respond to ADT as they are hormone-naïve prostate cancer (HNPC). Eventually, almost all of them become insensitive to ADT even when the blood levels of androgens are at castration levels, hence they are called castration-resistant prostate cancer (CRPC). A small portion (approximately 0.5%-2%) of prostate cancer, so called neuroendocrine prostate cancer (NEPC), is small cell carcinoma, instead of adenocarcinoma (AC). NEPC does not express androgen receptor and is inherently CRPC [3]. Some adenocarcinomas (approximately 17% to 30%) may undergo focal neuroendocrine (NE) differentiation after ADT and present NE features [3]. The molecular and cellular mechanisms underlying the progression from primary prostate cancer to metastatic prostate cancer and from HNPC to CRPC have not been fully understood.

Interleukin-17 (IL-17) is a family of proinflammatory cytokines, including IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F [4]. There are five receptors for IL-17 cytokines, including IL-17 receptor A (IL-17RA), IL-17RB, IL-17RC, IL-17RD, and IL-17RE [4]. IL-17RA acts as a shared subunit and forms heterodimers with other four receptors [5]. Homodimers of IL-17A or IL-17F and heterodimer of IL-17A/IL-17F bind to IL-17RA/IL-17RC receptor complex. Homodimers of IL-17B or IL-17E bind to IL-17RA/IL-17RB receptor complex. IL-17C homodimer binds to IL-17RA/IL-17RE receptor complex. Recently, it has been reported that IL-17A, but not IL-17F or IL-17A/F, also binds to IL-17RA/IL-17RD receptor complex [6]. IL-17A and IL-17F are produced by T helper 17 (Th17) cells, γδ T cells, natural killer cells, and other immune cells [7]. Binding of IL-17A or IL-17F to IL-17RA/IL-17RC receptor complex recruits nuclear factor-κB (NF-κB) activator 1 (Act1) through SEFIR (similar expression to fibroblast growth factor genes, IL-17 receptors and Toll-IL-1R) domains of IL-17RA, IL-17RC, and Act1. Act1 acts as an E3 ubiquitin ligase to ubiquitinate tumor necrosis factor receptor-associated factor 6 (TRAF6) through lysine-63-linked ubiquitination [8]. Then, TRAF6 activates transforming growth factor-β-activated kinase 1 (TAK1) and subsequently IκB kinase (IKK) complex, resulting in activation of NF-κB pathway that initiates transcription of a variety of cytokines, chemokines, matrix metalloproteinases (MMP), and growth factors, such as IL-1α, IL-1β, IL-6, tumor necrosis factor α (TNFα), colony stimulating factor (CSF), C-X-C motif ligand 1 (CXCL1), CXCL2, CXCL5, CXCL8, C-C motif ligand 7 (CCL7), S100 Calcium Binding Protein A7 (S100A7), S100A8, S100A9, CCAAT Enhancer Binding Protein Beta (CEBPB), Prostaglandin-Endoperoxide Synthase-2 (PTGS2), MMP1, MMP2, MMP7, MMP9, and MMP13 [9-15]. IL-17 also induces expression of programmed cell death protein 1 (PD-1) ligand 1 (PD-L1), but not PD-L2 in a human prostate cancer LNCaP cell line [16].

IL-17 has been shown to promote development of colon cancer [17-20], skin cancer [21,22], breast cancer [23], prostate cancer [13,24], lung cancer [25,26], and pancreas cancer [27]. Using Il-17rc-null and phosphatase and tensin homolog (Pten)-null mouse models, we have demonstrated that Il-17rc knockout inhibits prostate cancer development [13]. IL-17 induces expression of MMP7 to cleave E-cadherin, thus activating β-catenin-mediated epithelial-to-mesenchymal transition, which subsequently enhances development of prostate cancer in Pten-null mice [14]. We have also shown that IL-17 promotes development of CRPC in Pten-null mice partially through increasing immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment [24]. Using an orthotopic allograft model in immunocompetent mice, we found that co-injection of recombinant IL-17A and mouse prostate cancer MPC3 cells slightly increased primary tumor growth, however, pelvic lymph node metastasis was significantly enhanced [28]. On the other hand, we found that Th17 inhibitor SR1001 and anti-mouse IL-17A antibody are able to partially inhibit formation of prostate cancer in Pten-null mice [29]. Recently, we have shown that Th17-polarized splenocytes promoted orthotopic allograft prostate tumor growth compared to the control splenocytes [30]. These studies suggest that Th17 cells and IL-17 cytokines secreted by Th17 cells may play important roles in development of primary prostate cancer, CRPC, and lymph node metastasis. The objective of this study was to analyze genetic alterations of IL-17 family of cytokines and related genes aforementioned in primary and metastatic prostate cancers, using publicly archived datasets and bioinformatics tools.

Materials and methods

Data sources

All of the data were obtained through cBioPortal for Cancer Genomics (www.cbioportal.org) [31,32]. cBioPortal has archived 20 datasets for gene alterations in human prostate cancers. We filtered through the datasets and excluded the datasets that potentially used overlapping original samples according to the linked publications. Seven datasets were included, which did not appear to have overlapping original samples (Table 1).

Table 1.

Data sources

Datasets‡ Author Year Included cases (N=1303) Excluded cases* (N=77)
MCTP Grasso [33] 2012 59 NA (n=60)
SU2C/PCF Dream Team Abida [34] 2019 427 Unknown (n=2)
Multi-Institute Beltran [35] 2016 81
Broad/Cornell Barbieri [36] 2012 112 NA (n=11)
Fred Hutchinson CRC Kumar [37] 2016 61 Not profiled (n=2)
SMMU Ren [38] 2017 65
TCGA TCGA data 498 Not profiled (n=2)
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‡

MCTP, Michigan Center for Translational Pathology; SU2C/PCF Dream Team, Stand Up to Cancer/Prostate Cancer Foundation Dream Team; Fred Hutchinson CRC, Fred Hutchinson Cancer Research Center; SMMU, Second Military Medical University (Shanghai); TCGA, The Cancer Genome Atlas.

*

Cases were excluded from analysis if the sample types were “Not available (NA)”, “Unknown”, or “Not profiled”; the number of cases excluded is shown.

The data of Michigan Center for Translational Pathology (MCTP) were generated by Dr. Arul Chinnaiyan’s and Dr. Scott Tomlins’ labs at the University of Michigan [33]; the data of Stand Up to Cancer/Prostate Cancer Foundation Dream Team (SU2C/PCF Dream Team) were generated by researchers at Dana-Farber Cancer Institute, Karmanos Cancer Institute, Memorial Sloan Kettering Cancer Center, Royal Marsden, University of Michigan, University of Washington, and Weill Cornell Medicine [34]; the data of Multi-Institute were generated by researchers at Weill Cornell Medicine [35]; the data of Broad/Cornell were generated by Dr. Levi Garraway’s lab at Broad Institute and Dr. Mark Rubin’s lab at Weill Cornell Medicine [36]; the data of Fred Hutchinson Cancer Research Center were generated by researchers at the University of Washington and Fred Hutchinson Cancer Research Center [37]; the data of the Second Military Medical University (Shanghai) (SMMU) were generated by researchers at Shanghai Changhai Hospital and Fudan University Cancer Center [38]; the data of The Cancer Genome Atlas (TCGA) (https://www.cancer.gov/tcga) were a public databank managed by the National Cancer Institute, National Institutes of Health. A total of 1303 cases of prostate cancer samples (N=1303) were included, while 77 cases were excluded from analysis because the sample types were “Not available (NA)”, “Unknown”, or “Not profiled” (Table 1).

Bioinformatics analysis

We used cBioPortal query tools to find genetic alterations of 35 IL-17 and related genes (Figure 1). These genes were chosen because they are IL-17 family of cytokines and receptors, IL-17-downstream genes, and related to IL-17-regulated genes (e.g., PD-1 and PD-L2 are related to PD-L1 that is regulated by IL-17 [16]). The bioinformatics analysis procedures are briefly described here: first, we chose “Prostate” organ type on the main page of cBioPortal; second, we chose the dataset named “Metastatic Prostate Adenocarcinoma (MCTP, Nature 2012)” and clicked the round button on the right side; third, we typed in gene names (e.g., IL17A) in the query box on right top corner of the page; fourth, we clicked “Charts” below the query box and clicked “Deselect all”; fifth, we chose “Sample Type” and we could see a pie chart on this page where we chose the portion named “metastatic” and clicked “Query” on the right side of query box; sixth, we moved the mouse on the “2.1%” on the right side of “IL17A”, which showed “altered/profiled 1/48”. That means the number of overall IL17A gene alterations in metastatic prostate cancers was 1, and the number of total cases was 48. We used Object Query Language (OQL) to do queries of the 35 genes. The gene alterations were categorized into copy number alterations (amplifications and deep deletions) and mutations (missense mutations and truncating mutations) according to cBioPortal (Figure 1). Prostate cancer sample types were categorized into primary prostate cancer (including both HNPC and CRPC), metastatic prostate cancer (including both HNPC and CRPC), primary HNPC, primary CRPC, metastatic HNPC (not included in analysis because there was only one case), metastatic CRPC, primary adenocarcinoma (AC), primary NEPC, metastatic AC, metastatic NEPC, primary AC with NE feature (not included in analysis because there was only one case), and metastatic AC with NE feature. We identified and calculated the numbers and percentages of overall gene alterations and individual categories of gene alterations after pooling the query results from the 7 datasets.

Figure 1.

Figure 1

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Representative illustration of cBioPortal query results. Metastatic prostate cancer samples from the SU2C/PCF Dream Team dataset were queried for overall gene alterations including missense mutations, truncating mutations, amplifications, and deep deletions (color bar-coded). 35 IL-17 and related genes were analyzed using cBioPortal query tools and the percentages of overall gene alterations are shown.

Statistical analysis

R software package [R version 3.5.2 (2018-12-20), R Core Team (2018); R: A language and environment for statistical computing, R Foundation for Statistical Computing, Vienna, Austria. https://www.r-project.org/] was used to perform Fisher’s exact test between two sample types. P<0.05 was considered statistically significant.

Results

Human prostate cancer samples

Data from a total of 1303 human prostate cancer samples (N=1303) were included in the analysis, while 77 samples were excluded (N=77) (Table 1). The samples were categorized into primary prostate cancer (N=742), metastatic prostate cancer (N=584), primary HNPC (N=684), primary CRPC (N=56), metastatic HNPC (N=1), metastatic CRPC (N=583), primary AC (N=724), primary NEPC (N=16), metastatic AC (N=461), metastatic NEPC (N=45), primary AC with NE feature (N=1), and metastatic AC with NE feature (N=12).

Overall gene alterations

Thirty-four of the 35 IL-17 and related genes studied had significantly higher rates of gene alterations in metastatic primary cancers (including both HNPC and CRPC) compared to primary prostate cancers (including both HNPC and CRPC) (Table 2). IL17C is the only gene that the gene alterations showed no significant difference. The alteration rate range was from 3.42% to 13.01%, with the top alterations in S100A7 (13.01%), S100A8 (12.50%), S100A9 (12.33%), and PTGS2 (10.27%) in metastatic prostate cancers (Table 2). Significantly higher rates of gene alterations were found in S100A7, S100A8, and S100A9 genes, but not in other genes, in metastatic CRPC, compared to primary CRPC (Table 3). However, significantly higher rates of gene alterations were found in 15 of the 35 genes in primary CRPC, compared to primary HNPC (Table 4). Further, significantly higher rates of gene alterations were found in 34 of the 35 genes in metastatic CRPC, compared to primary HNPC (Table 5).

Table 2.

Overall gene alterations in metastatic vs primary prostate cancer

Genes* Metastatic (N=584) Primary (N=742) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 23 3.94% 6 0.81% 1.86E-04
IL17B 36 6.16% 11 1.48% 7.10E-06
IL17C 48 8.22% 56 7.55% 6.81E-01
IL17D 31 5.31% 20 2.70% 2.05E-02
IL25 26 4.45% 5 0.67% 8.63E-06
IL17F 23 3.94% 3 0.40% 2.88E-06
IL17RA 24 4.11% 8 1.08% 4.46E-04
IL17RB 26 4.45% 11 1.48% 1.27E-03
IL17RC 42 7.19% 22 2.96% 4.35E-04
IL17RD 32 5.48% 9 1.21% 8.58E-06
IL17RE 43 7.36% 19 2.56% 6.13E-05
IL1A 20 3.42% 9 1.21% 7.58E-03
IL1B 22 3.77% 8 1.08% 1.30E-03
IL6 49 8.39% 13 1.75% 1.11E-08
TNF 28 4.79% 9 1.21% 1.38E-04
CSF3 31 5.31% 15 2.02% 1.36E-03
CCL7 30 5.14% 8 1.08% 1.60E-05
CXCL1 37 6.34% 6 0.81% 1.41E-08
CXCL2 31 5.31% 6 0.81% 6.97E-07
CXCL5 34 5.82% 7 0.94% 4.26E-07
CXCL8 35 5.99% 11 1.48% 1.22E-05
S100A7 76 13.01% 9 1.21% <2.2e-16
S100A8 73 12.50% 11 1.48% <2.2e-16
S100A9 72 12.33% 9 1.21% <2.2e-16
CEBPB 36 6.16% 9 1.21% 7.87E-07
PTGS2 60 10.27% 12 1.62% 3.08E-12
MMP1 38 6.51% 9 1.21% 2.34E-07
MMP2 25 4.28% 14 1.89% 1.33E-02
MMP3 38 6.51% 9 1.21% 2.34E-07
MMP7 34 5.82% 11 1.48% 2.07E-05
MMP9 42 7.19% 14 1.89% 2.85E-06
MMP13 38 6.51% 10 1.35% 7.77E-07
PDCD1 38 6.51% 15 2.02% 5.18E-05
CD274 36 6.16% 11 1.48% 7.10E-06
PDCD1LG2 36 6.16% 12 1.62% 1.13E-05
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*

IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene alterations in metastatic than primary prostate cancer.

Table 3.

Overall gene alterations in metastatic CRPC vs primary CRPC

Genes* Metastatic CRPC (N=583) Primary CPRC (N=56) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 23 3.95% 3 5.36% 4.90E-01
IL17B 36 6.17% 5 8.93% 3.92E-01
IL17C 48 8.23% 1 1.79% 1.11E-01
IL17D 31 5.32% 4 7.14% 5.36E-01
IL25 26 4.46% 4 7.14% 3.24E-01
IL17F 23 3.95% 2 3.57% 1.00E+00
IL17RA 24 4.12% 1 1.79% 7.16E-01
IL17RB 26 4.46% 5 8.93% 1.80E-01
IL17RC 42 7.20% 4 7.14% 1.00E+00
IL17RD 32 5.49% 5 8.93% 3.61E-01
IL17RE 43 7.38% 3 5.36% 7.88E-01
IL1A 20 3.43% 2 3.57% 1.00E+00
IL1B 22 3.77% 2 3.57% 1.00E+00
IL6 49 8.40% 2 3.57% 3.00E-01
TNF 28 4.80% 4 7.14% 5.14E-01
CSF3 31 5.32% 3 5.36% 1.00E+00
CCL7 30 5.15% 3 5.36% 1.00E+00
CXCL1 37 6.35% 3 5.36% 1.00E+00
CXCL2 31 5.32% 3 5.36% 1.00E+00
CXCL5 34 5.83% 3 5.36% 1.00E+00
CXCL8 35 6.00% 5 8.93% 3.83E-01
S100A7 76 13.04% 2 3.57% 3.35E-02
S100A8 73 12.52% 2 3.57% 4.92E-02
S100A9 72 12.35% 2 3.57% 4.92E-02
CEBPB 36 6.17% 4 7.14% 7.71E-01
PTGS2 60 10.29% 4 7.14% 6.41E-01
MMP1 38 6.52% 2 3.57% 5.66E-01
MMP2 25 4.29% 0 0.00% 1.55E-01
MMP3 38 6.52% 2 3.57% 5.66E-01
MMP7 34 5.83% 2 3.57% 7.61E-01
MMP9 42 7.20% 4 7.14% 1.00E+00
MMP13 38 6.52% 2 3.57% 5.66E-01
PDCD1 38 6.52% 1 1.79% 2.40E-01
CD274 36 6.17% 2 3.57% 7.65E-01
PDCD1LG2 36 6.17% 2 3.57% 7.65E-01
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*

IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene alterations in metastatic CRPC than primary CRPC.

Table 4.

Overall gene alterations in primary CRPC vs primary HNPC

Genes* Primary CRPC (N=56) Primary HNPC (N=684) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 3 5.36% 3 0.44% 6.98E-03
IL17B 5 8.93% 6 0.88% 6.77E-04
IL17C 1 1.79% 55 8.04% 1.13E-01
IL17D 4 7.14% 16 2.34% 5.73E-02
IL25 4 7.14% 1 0.15% 1.40E-04
IL17F 2 3.57% 1 0.15% 1.61E-02
IL17RA 1 1.79% 7 1.02% 4.69E-01
IL17RB 5 8.93% 6 0.88% 6.77E-04
IL17RC 4 7.14% 18 2.63% 7.72E-02
IL17RD 5 8.93% 4 0.58% 2.08E-04
IL17RE 3 5.36% 16 2.34% 1.68E-01
IL1A 2 3.57% 7 1.02% 1.44E-01
IL1B 2 3.57% 6 0.88% 1.17E-01
IL6 2 3.57% 11 1.61% 2.58E-01
TNF 4 7.14% 5 0.73% 2.79E-03
CSF3 3 5.36% 12 1.75% 9.75E-02
CCL7 3 5.36% 5 0.73% 1.75E-02
CXCL1 3 5.36% 3 0.44% 6.98E-03
CXCL2 3 5.36% 3 0.44% 6.98E-03
CXCL5 3 5.36% 4 0.58% 1.16E-02
CXCL8 5 8.93% 6 0.88% 6.77E-04
S100A7 2 3.57% 7 1.02% 1.44E-01
S100A8 2 3.57% 9 1.32% 2.00E-01
S100A9 2 3.57% 7 1.02% 1.44E-01
CEBPB 4 7.14% 5 0.73% 2.79E-03
PTGS2 4 7.14% 8 1.17% 9.23E-03
MMP1 2 3.57% 7 1.02% 1.44E-01
MMP2 0 0.00% 14 2.05% 6.16E-01
MMP3 2 3.57% 7 1.02% 1.44E-01
MMP7 2 3.57% 9 1.32% 2.00E-01
MMP9 4 7.14% 10 1.46% 1.67E-02
MMP13 2 3.57% 8 1.17% 1.71E-01
PDCD1 1 1.79% 14 2.05% 1.00E+00
CD274 2 3.57% 9 1.32% 2.00E-01
PDCD1LG2 2 3.57% 10 1.46% 2.28E-01
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*

IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene alterations in primary CRPC than primary HNPC.

Table 5.

Overall gene alterations in metastatic CRPC vs primary HNPC

Genes* Metastatic CRPC (N=583) Primary HNPC (N=684) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 23 3.95% 3 0.44% 8.75E-06
IL17B 36 6.17% 6 0.88% 9.91E-08
IL17C 48 8.23% 55 8.04% 9.18E-01
IL17D 31 5.32% 16 2.34% 6.74E-03
IL25 26 4.46% 1 0.15% 1.94E-08
IL17F 23 3.95% 1 0.15% 1.90E-07
IL17RA 24 4.12% 7 1.02% 4.02E-04
IL17RB 26 4.46% 6 0.88% 4.61E-05
IL17RC 42 7.20% 18 2.63% 1.62E-04
IL17RD 32 5.49% 4 0.58% 6.71E-08
IL17RE 43 7.38% 16 2.34% 2.39E-05
IL1A 20 3.43% 7 1.02% 3.28E-03
IL1B 22 3.77% 6 0.88% 7.68E-04
IL6 49 8.40% 11 1.61% 1.32E-08
TNF 28 4.80% 5 0.73% 4.02E-06
CSF3 31 5.32% 12 1.75% 5.23E-04
CCL7 30 5.15% 5 0.73% 1.12E-06
CXCL1 37 6.35% 3 0.44% 3.33E-10
CXCL2 31 5.32% 3 0.44% 4.18E-08
CXCL5 34 5.83% 4 0.58% 1.69E-08
CXCL8 35 6.00% 6 0.88% 1.86E-07
S100A7 76 13.04% 7 1.02% <2.2e-16
S100A8 73 12.52% 9 1.32% <2.2e-16
S100A9 72 12.35% 7 1.02% <2.2e-16
CEBPB 36 6.17% 5 0.73% 2.19E-08
PTGS2 60 10.29% 8 1.17% 1.75E-13
MMP1 38 6.52% 7 1.02% 1.19E-07
MMP2 25 4.29% 14 2.05% 2.28E-02
MMP3 38 6.52% 7 1.02% 1.19E-07
MMP7 34 5.83% 9 1.32% 1.34E-05
MMP9 42 7.20% 10 1.46% 2.33E-07
MMP13 38 6.52% 8 1.17% 2.51E-07
PDCD1 38 6.52% 14 2.05% 8.80E-05
CD274 36 6.17% 9 1.32% 2.55E-06
PDCD1LG2 36 6.17% 10 1.46% 7.09E-06
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene alterations in metastatic CRPC than primary HNPC.

Individual categories of gene alterations

We further analyzed the gene alterations by dividing them into four categories, namely, amplifications, deep deletions, missense mutations, and truncating mutations according to the default classification of cBioPortal. We found that 34 of the 35 IL-17 and related genes studied had significantly higher rates of gene amplifications in metastatic primary cancers (including both HNPC and CRPC) compared to primary prostate cancers (including both HNPC and CRPC) (Table 6). IL17C is the only gene that the gene amplifications showed no significant difference. The rate range was from 1.37% to 13.01%, with the top amplifications in S100A7 (13.01%), S100A8 (12.33%), S100A9 (12.33%), and PTGS2 (9.08%) in metastatic prostate cancers (Table 6). Gene deep deletions were significantly higher in MMP1 (2.23%), MMP3 (2.23%), PDCD1 (3.60%), CD274 (3.60%), and PDCD1LG2 (3.60%) in metastatic prostate cancers, compared to primary prostate cancers (Table 7). In contrast, gene deep deletions were significantly higher in CSF3 (0.94%) in primary prostate cancers, compared to metastatic prostate cancers (Table 7). Gene missense mutations were significantly higher in IL17RD (1.03%) and IL17RE (0.86%) in metastatic prostate cancers, compared to primary prostate cancers (Table 8). However, gene truncating mutations were very rare and there was no significant difference between metastatic and primary prostate cancers (Table 9).

Table 6.

Gene amplifications in metastatic vs primary prostate cancer

Genes* Metastatic (N=584) Primary (N=742) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 22 3.77% 2 0.27% 1.87E-06
IL17B 34 5.82% 9 1.21% 2.62E-06
IL17C 8 1.37% 6 0.81% 4.19E-01
IL17D 25 4.28% 8 1.08% 2.59E-04
IL25 24 4.11% 4 0.54% 6.93E-06
IL17F 23 3.94% 2 0.27% 9.36E-07
IL17RA 13 2.23% 1 0.13% 1.82E-04
IL17RB 20 3.42% 3 0.40% 2.41E-05
IL17RC 37 6.34% 6 0.81% 1.41E-08
IL17RD 21 3.60% 5 0.67% 1.80E-04
IL17RE 36 6.16% 5 0.67% 5.20E-09
IL1A 14 2.40% 2 0.27% 4.88E-04
IL1B 14 2.40% 2 0.27% 4.88E-04
IL6 47 8.05% 10 1.35% 1.68E-09
TNF 26 4.45% 6 0.81% 1.71E-05
CSF3 31 5.31% 8 1.08% 9.07E-06
CCL7 27 4.62% 3 0.40% 1.62E-07
CXCL1 36 6.16% 4 0.54% 9.29E-10
CXCL2 30 5.14% 4 0.54% 1.29E-07
CXCL5 32 5.48% 5 0.67% 8.43E-08
CXCL8 33 5.65% 8 1.08% 1.59E-06
S100A7 76 13.01% 9 1.21% <2.2e-16
S100A8 72 12.33% 8 1.08% <2.2e-16
S100A9 72 12.33% 9 1.21% <2.2e-16
CEBPB 35 5.99% 8 1.08% 4.51E-07
PTGS2 53 9.08% 6 0.81% 8.75E-14
MMP1 23 3.94% 3 0.40% 2.88E-06
MMP2 8 1.37% 1 0.13% 1.29E-02
MMP3 23 3.94% 3 0.40% 2.88E-06
MMP7 24 4.11% 4 0.54% 6.93E-06
MMP9 33 5.65% 8 1.08% 1.59E-06
MMP13 23 3.94% 3 0.40% 2.88E-06
PDCD1 16 2.74% 8 1.08% 3.59E-02
CD274 14 2.40% 1 0.13% 8.44E-05
PDCD1LG2 14 2.40% 1 0.13% 8.44E-05
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene amplifications in metastatic than primary prostate cancer.

Table 7.

Gene deep deletions in metastatic vs primary prostate cancer

Genes* Metastatic (N=584) Primary (N=742) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 0 0.00% 1 0.13% 1.00E+00
IL17B 1 0.17% 1 0.13% 1.00E+00
IL17C 39 6.68% 50 6.74% 1.00E+00
IL17D 6 1.03% 12 1.62% 4.75E-01
IL25 2 0.34% 1 0.13% 5.86E-01
IL17F 0 0.00% 1 0.13% 1.00E+00
IL17RA 7 1.20% 3 0.40% 1.17E-01
IL17RB 5 0.86% 5 0.67% 7.57E-01
IL17RC 4 0.68% 14 1.89% 9.17E-02
IL17RD 5 0.86% 3 0.40% 3.11E-01
IL17RE 4 0.68% 14 1.89% 9.17E-02
IL1A 5 0.86% 6 0.81% 1.00E+00
IL1B 5 0.86% 6 0.81% 1.00E+00
IL6 1 0.17% 2 0.27% 1.00E+00
TNF 1 0.17% 2 0.27% 1.00E+00
CSF3 0 0.00% 7 0.94% 2.01E-02
CCL7 3 0.51% 4 0.54% 1.00E+00
CXCL1 1 0.17% 2 0.27% 1.00E+00
CXCL2 1 0.17% 2 0.27% 1.00E+00
CXCL5 1 0.17% 2 0.27% 1.00E+00
CXCL8 1 0.17% 2 0.27% 1.00E+00
S100A7 0 0.00% 0 0.00% 1.00E+00
S100A8 0 0.00% 1 0.13% 1.00E+00
S100A9 0 0.00% 0 0.00% 1.00E+00
CEBPB 0 0.00% 0 0.00% 1.00E+00
PTGS2 3 0.51% 2 0.27% 6.60E-01
MMP1 13 2.23% 5 0.67% 1.74E-02
MMP2 15 2.57% 12 1.62% 2.44E-01
MMP3 13 2.23% 5 0.67% 1.74E-02
MMP7 10 1.71% 6 0.81% 2.04E-01
MMP9 3 0.51% 2 0.27% 6.60E-01
MMP13 12 2.05% 6 0.81% 5.83E-02
PDCD1 21 3.60% 6 0.81% 5.65E-04
CD274 21 3.60% 10 1.35% 9.50E-03
PDCD1LG2 21 3.60% 10 1.35% 9.50E-03
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene deep deletions in metastatic than primary prostate cancer and green indicates significantly more gene deep deletions in primary than metastatic prostate cancer.

Table 8.

Gene missense mutations in metastatic vs primary prostate cancer

Genes* Metastatic (N=584) Primary (N=742) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 1 0.17% 3 0.40% 6.35E-01
IL17B 1 0.17% 1 0.13% 1.00E+00
IL17C 2 0.34% 0 0.00% 1.94E-01
IL17D 0 0.00% 0 0.00% 1.00E+00
IL25 0 0.00% 1 0.13% 1.00E+00
IL17F 0 0.00% 0 0.00% 1.00E+00
IL17RA 5 0.86% 3 0.40% 3.11E-01
IL17RB 0 0.00% 2 0.27% 5.07E-01
IL17RC 1 0.17% 2 0.27% 1.00E+00
IL17RD 6 1.03% 1 0.13% 4.84E-02
IL17RE 5 0.86% 0 0.00% 1.64E-02
IL1A 0 0.00% 1 0.13% 1.00E+00
IL1B 3 0.51% 0 0.00% 8.52E-02
IL6 1 0.17% 1 0.13% 1.00E+00
TNF 1 0.17% 1 0.13% 1.00E+00
CSF3 0 0.00% 0 0.00% 1.00E+00
CCL7 0 0.00% 1 0.13% 1.00E+00
CXCL1 0 0.00% 0 0.00% 1.00E+00
CXCL2 0 0.00% 0 0.00% 1.00E+00
CXCL5 1 0.17% 0 0.00% 4.40E-01
CXCL8 1 0.17% 1 0.13% 1.00E+00
S100A7 0 0.00% 0 0.00% 1.00E+00
S100A8 1 0.17% 2 0.27% 1.00E+00
S100A9 0 0.00% 0 0.00% 1.00E+00
CEBPB 0 0.00% 0 0.00% 1.00E+00
PTGS2 2 0.34% 4 0.54% 7.00E-01
MMP1 2 0.34% 1 0.13% 5.86E-01
MMP2 2 0.34% 1 0.13% 5.86E-01
MMP3 2 0.34% 1 0.13% 5.86E-01
MMP7 0 0.00% 1 0.13% 1.00E+00
MMP9 5 0.86% 4 0.54% 5.18E-01
MMP13 1 0.17% 1 0.13% 1.00E+00
PDCD1 1 0.17% 1 0.13% 1.00E+00
CD274 1 0.17% 0 0.00% 4.40E-01
PDCD1LG2 1 0.17% 1 0.13% 1.00E+00
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene missense mutations in metastatic than primary prostate cancer.

Table 9.

Gene truncating mutations in metastatic vs primary prostate cancer

Genes* Metastatic (N=584) Primary (N=742) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 0 0.00% 0 0.00% 1.00E+00
IL17B 0 0.00% 0 0.00% 1.00E+00
IL17C 0 0.00% 0 0.00% 1.00E+00
IL17D 0 0.00% 0 0.00% 1.00E+00
IL25 0 0.00% 0 0.00% 1.00E+00
IL17F 0 0.00% 0 0.00% 1.00E+00
IL17RA 0 0.00% 1 0.13% 1.00E+00
IL17RB 1 0.17% 1 0.13% 1.00E+00
IL17RC 0 0.00% 0 0.00% 1.00E+00
IL17RD 0 0.00% 0 0.00% 1.00E+00
IL17RE 0 0.00% 0 0.00% 1.00E+00
IL1A 1 0.17% 0 0.00% 4.40E-01
IL1B 0 0.00% 0 0.00% 1.00E+00
IL6 0 0.00% 0 0.00% 1.00E+00
TNF 0 0.00% 0 0.00% 1.00E+00
CSF3 0 0.00% 0 0.00% 1.00E+00
CCL7 0 0.00% 0 0.00% 1.00E+00
CXCL1 0 0.00% 0 0.00% 1.00E+00
CXCL2 0 0.00% 0 0.00% 1.00E+00
CXCL5 0 0.00% 0 0.00% 1.00E+00
CXCL8 0 0.00% 0 0.00% 1.00E+00
S100A7 0 0.00% 0 0.00% 1.00E+00
S100A8 0 0.00% 0 0.00% 1.00E+00
S100A9 0 0.00% 0 0.00% 1.00E+00
CEBPB 1 0.17% 0 0.00% 4.40E-01
PTGS2 2 0.34% 0 0.00% 1.94E-01
MMP1 0 0.00% 0 0.00% 1.00E+00
MMP2 0 0.00% 0 0.00% 1.00E+00
MMP3 0 0.00% 0 0.00% 1.00E+00
MMP7 0 0.00% 0 0.00% 1.00E+00
MMP9 1 0.17% 0 0.00% 4.40E-01
MMP13 2 0.34% 0 0.00% 1.94E-01
PDCD1 0 0.00% 0 0.00% 1.00E+00
CD274 0 0.00% 0 0.00% 1.00E+00
PDCD1LG2 0 0.00% 0 0.00% 1.00E+00
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Gene alterations in NEPC

Since NEPC is inherently CRPC, we singled out this prostate cancer type and compared it against AC. We found that 7 of the 35 genes (namely, IL17B, IL25, IL17RB, TNF, CXCL8, CEBPB, and MMP9) had significantly more overall gene alterations (12.50%) in primary NEPC, compared to primary AC (Table 10). More dramatically, 23 of the 35 genes had significantly more overall gene alterations (ranging from 11.11% to 33.33%) in metastatic NEPC, compared to metastatic AC (ranging from 2.17% to 11.93%) (Table 11). S100A7 (28.89%), S100A8 (28.89%), S100A9 (28.89%), CEBPB (28.89%), PTGS2 (28.89%), and MMP9 (33.33%) were the genes with top alteration rates in metastatic NEPC. S100A7 (28.89%), S100A8 (28.89%) and S100A9 (28.89%) were also the genes with higher rates of gene alterations in metastatic NEPC, compared to metastatic AC with NE feature (Table 12). When comparing between metastatic AC with NE feature and metastatic AC, there were some genes with more or less gene alterations, but the differences were not statistically significant (Table 13). Further analysis of each individual categories of gene alterations showed that 28 of the 35 genes had significantly higher rates of gene amplifications in metastatic NEPC, compared to metastatic AC (Table 14). Gene deep deletions (Table 15), gene missense mutations (Table 16), and gene truncating mutations (Table 17) were very rare and there were no significant differences between metastatic NEPC and metastatic AC, except that MMP9 had significantly higher rate of gene missense mutations in metastatic NEPC than metastatic AC (Table 16).

Table 10.

Overall gene alterations in primary NEPC vs primary AC

Genes* Primary NEPC (N=16) Primary AC (N=724) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 1 6.25% 5 0.69% 1.23E-01
IL17B 2 12.50% 8 1.10% 1.78E-02
IL17C 0 0.00% 56 7.73% 6.25E-01
IL17D 0 0.00% 20 2.76% 1.00E+00
IL25 2 12.50% 3 0.41% 4.22E-03
IL17F 1 6.25% 2 0.28% 6.36E-02
IL17RA 0 0.00% 8 1.10% 1.00E+00
IL17RB 2 12.50% 9 1.24% 2.15E-02
IL17RC 1 6.25% 20 2.76% 3.72E-01
IL17RD 1 6.25% 8 1.10% 1.80E-01
IL17RE 1 6.25% 18 2.49% 3.43E-01
IL1A 1 6.25% 8 1.10% 1.80E-01
IL1B 1 6.25% 7 0.97% 1.61E-01
IL6 0 0.00% 13 1.80% 1.00E+00
TNF 2 12.50% 7 0.97% 1.45E-02
CSF3 1 6.25% 14 1.93% 2.82E-01
CCL7 1 6.25% 7 0.97% 1.61E-01
CXCL1 0 0.00% 6 0.83% 1.00E+00
CXCL2 0 0.00% 6 0.83% 1.00E+00
CXCL5 0 0.00% 7 0.97% 1.00E+00
CXCL8 2 12.50% 9 1.24% 2.15E-02
S100A7 0 0.00% 9 1.24% 1.00E+00
S100A8 0 0.00% 11 1.52% 1.00E+00
S100A9 0 0.00% 9 1.24% 1.00E+00
CEBPB 2 12.50% 7 0.97% 1.45E-02
PTGS2 0 0.00% 11 1.52% 1.00E+00
MMP1 1 6.25% 8 1.10% 1.80E-01
MMP2 0 0.00% 14 1.93% 1.00E+00
MMP3 1 6.25% 8 1.10% 1.80E-01
MMP7 1 6.25% 10 1.38% 2.15E-01
MMP9 2 12.50% 12 1.66% 3.43E-02
MMP13 1 6.25% 9 1.24% 1.97E-01
PDCD1 1 6.25% 14 1.93% 2.82E-01
CD274 0 0.00% 11 1.52% 1.00E+00
PDCD1LG2 0 0.00% 12 1.66% 1.00E+00
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene alterations in primary NEPC than primary AC.

Table 11.

Overall gene alterations in metastatic NEPC vs metastatic AC

Genes* Metastatic NEPC (N=45) Metastatic AC (N=461) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 10 22.22% 11 2.39% 1.95E-06
IL17B 9 20.00% 24 5.21% 1.19E-03
IL17C 2 4.44% 33 7.16% 7.58E-01
IL17D 8 17.78% 22 4.77% 2.75E-03
IL25 9 20.00% 15 3.25% 7.50E-05
IL17F 10 22.22% 10 2.17% 1.09E-06
IL17RA 3 6.67% 16 3.47% 2.34E-01
IL17RB 6 13.33% 17 3.69% 1.12E-02
IL17RC 8 17.78% 31 6.72% 1.54E-02
IL17RD 7 15.56% 20 4.34% 6.24E-03
IL17RE 10 22.22% 30 6.51% 1.29E-03
IL1A 5 11.11% 11 2.39% 9.25E-03
IL1B 6 13.33% 13 2.82% 3.97E-03
IL6 9 20.00% 39 8.46% 2.73E-02
TNF 12 26.67% 14 3.04% 2.19E-07
CSF3 9 20.00% 22 4.77% 7.15E-04
CCL7 10 22.22% 19 4.12% 6.45E-05
CXCL1 5 11.11% 30 6.51% 2.24E-01
CXCL2 5 11.11% 25 5.42% 1.73E-01
CXCL5 5 11.11% 27 5.86% 1.90E-01
CXCL8 5 11.11% 28 6.07% 2.00E-01
S100A7 13 28.89% 55 11.93% 4.39E-03
S100A8 13 28.89% 52 11.28% 3.63E-03
S100A9 13 28.89% 52 11.28% 3.63E-03
CEBPB 13 28.89% 22 4.77% 1.37E-06
PTGS2 13 28.89% 42 9.11% 3.64E-04
MMP1 6 13.33% 30 6.51% 1.19E-01
MMP2 1 2.22% 19 4.12% 1.00E+00
MMP3 6 13.33% 30 6.51% 1.19E-01
MMP7 6 13.33% 26 5.64% 5.40E-02
MMP9 15 33.33% 26 5.64% 2.02E-07
MMP13 6 13.33% 29 6.29% 1.13E-01
PDCD1 5 11.11% 26 5.64% 1.81E-01
CD274 9 20.00% 22 4.77% 7.15E-04
PDCD1LG2 9 20.00% 23 4.99% 9.28E-04
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene alterations in metastatic NEPC than metastatic AC.

Table 12.

Overall gene alterations in metastatic NEPC vs metastatic AC with NE feature

Genes* Metastatic NEPC (N=45) Metastatic AC with NE feature (N=12) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 10 22.22% 0 0.00% 9.97E-02
IL17B 9 20.00% 1 8.33% 6.71E-01
IL17C 2 4.44% 1 8.33% 5.15E-01
IL17D 8 17.78% 1 8.33% 6.67E-01
IL25 9 20.00% 1 8.33% 6.71E-01
IL17F 10 22.22% 0 0.00% 9.97E-02
IL17RA 3 6.67% 1 8.33% 1.00E+00
IL17RB 6 13.33% 1 8.33% 1.00E+00
IL17RC 8 17.78% 2 16.67% 1.00E+00
IL17RD 7 15.56% 2 16.67% 1.00E+00
IL17RE 10 22.22% 2 16.67% 1.00E+00
IL1A 5 11.11% 1 8.33% 1.00E+00
IL1B 6 13.33% 1 8.33% 1.00E+00
IL6 9 20.00% 1 8.33% 6.71E-01
TNF 12 26.67% 0 0.00% 5.28E-02
CSF3 9 20.00% 1 8.33% 6.71E-01
CCL7 10 22.22% 1 8.33% 4.26E-01
CXCL1 5 11.11% 0 0.00% 5.73E-01
CXCL2 5 11.11% 0 0.00% 5.73E-01
CXCL5 5 11.11% 0 0.00% 5.73E-01
CXCL8 5 11.11% 0 0.00% 5.73E-01
S100A7 13 28.89% 0 0.00% 4.98E-02
S100A8 13 28.89% 0 0.00% 4.98E-02
S100A9 13 28.89% 0 0.00% 4.98E-02
CEBPB 13 28.89% 1 8.33% 2.58E-01
PTGS2 13 28.89% 3 25.00% 1.00E+00
MMP1 6 13.33% 1 8.33% 1.00E+00
MMP2 1 2.22% 2 16.67% 1.09E-01
MMP3 6 13.33% 1 8.33% 1.00E+00
MMP7 6 13.33% 1 8.33% 1.00E+00
MMP9 15 33.33% 1 8.33% 1.48E-01
MMP13 6 13.33% 1 8.33% 1.00E+00
PDCD1 5 11.11% 1 8.33% 1.00E+00
CD274 9 20.00% 2 16.67% 1.00E+00
PDCD1LG2 9 20.00% 2 16.67% 1.00E+00
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene alterations in metastatic NEPC than metastatic AC with NE feature.

Table 13.

Overall gene alterations in metastatic AC with NE feature vs metastatic AC

Genes* Metastatic AC with NE feature (N=12) Metastatic AC (N=461) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 0 0.00% 11 2.39% 1.00E+00
IL17B 1 8.33% 24 5.21% 4.83E-01
IL17C 1 8.33% 33 7.16% 5.96E-01
IL17D 1 8.33% 22 4.77% 4.54E-01
IL25 1 8.33% 15 3.25% 3.42E-01
IL17F 0 0.00% 10 2.17% 1.00E+00
IL17RA 1 8.33% 16 3.47% 3.59E-01
IL17RB 1 8.33% 17 3.69% 3.76E-01
IL17RC 2 16.67% 31 6.72% 2.01E-01
IL17RD 2 16.67% 20 4.34% 1.03E-01
IL17RE 2 16.67% 30 6.51% 1.92E-01
IL1A 1 8.33% 11 2.39% 2.68E-01
IL1B 1 8.33% 13 2.82% 3.06E-01
IL6 1 8.33% 39 8.46% 1.00E+00
TNF 0 0.00% 14 3.04% 1.00E+00
CSF3 1 8.33% 22 4.77% 4.54E-01
CCL7 1 8.33% 19 4.12% 4.08E-01
CXCL1 0 0.00% 30 6.51% 1.00E+00
CXCL2 0 0.00% 25 5.42% 1.00E+00
CXCL5 0 0.00% 27 5.86% 1.00E+00
CXCL8 0 0.00% 28 6.07% 1.00E+00
S100A7 0 0.00% 55 11.93% 3.76E-01
S100A8 0 0.00% 52 11.28% 3.78E-01
S100A9 0 0.00% 52 11.28% 3.78E-01
CEBPB 1 8.33% 22 4.77% 4.54E-01
PTGS2 3 25.00% 42 9.11% 9.62E-02
MMP1 1 8.33% 30 6.51% 5.61E-01
MMP2 2 16.67% 19 4.12% 9.48E-02
MMP3 1 8.33% 30 6.51% 5.61E-01
MMP7 1 8.33% 26 5.64% 5.10E-01
MMP9 1 8.33% 26 5.64% 5.10E-01
MMP13 1 8.33% 29 6.29% 5.49E-01
PDCD1 1 8.33% 26 5.64% 5.10E-01
CD274 2 16.67% 22 4.77% 1.19E-01
PDCD1LG2 2 16.67% 23 4.99% 1.28E-01
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Purple indicates more gene alterations in metastatic AC with NE feature than metastatic AC and blue indicates more gene alterations in metastatic AC than metastatic AC with NE feature, but without statistical significance.

Table 14.

Gene amplifications in metastatic NEPC vs metastatic AC

Genes* Metastatic NEPC (N=45) Metastatic AC (N=461) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 10 22.22% 10 2.17% 1.09E-06
IL17B 9 20.00% 22 4.77% 7.15E-04
IL17C 2 4.44% 6 1.30% 1.54E-01
IL17D 7 15.56% 18 3.90% 3.88E-03
IL25 9 20.00% 15 3.25% 7.50E-05
IL17F 10 22.22% 10 2.17% 1.09E-06
IL17RA 3 6.67% 8 1.74% 6.54E-02
IL17RB 6 13.33% 13 2.82% 3.97E-03
IL17RC 8 17.78% 26 5.64% 6.45E-03
IL17RD 6 13.33% 13 2.82% 3.97E-03
IL17RE 8 17.78% 25 5.42% 5.29E-03
IL1A 5 11.11% 7 1.52% 2.21E-03
IL1B 5 11.11% 7 1.52% 2.21E-03
IL6 9 20.00% 37 8.03% 1.38E-02
TNF 12 26.67% 12 2.60% 6.98E-08
CSF3 9 20.00% 22 4.77% 7.15E-04
CCL7 10 22.22% 16 3.47% 2.09E-05
CXCL1 5 11.11% 29 6.29% 2.12E-01
CXCL2 5 11.11% 24 5.21% 1.66E-01
CXCL5 5 11.11% 25 5.42% 1.73E-01
CXCL8 5 11.11% 27 5.86% 1.90E-01
S100A7 13 28.89% 55 11.93% 4.39E-03
S100A8 13 28.89% 52 11.28% 3.63E-03
S100A9 13 28.89% 52 11.28% 3.63E-03
CEBPB 13 28.89% 21 4.56% 9.18E-07
PTGS2 12 26.67% 37 8.03% 4.58E-04
MMP1 6 13.33% 16 3.47% 8.87E-03
MMP2 1 2.22% 6 1.30% 4.81E-01
MMP3 6 13.33% 16 3.47% 8.87E-03
MMP7 6 13.33% 17 3.69% 1.12E-02
MMP9 13 28.89% 20 4.34% 6.04E-07
MMP13 6 13.33% 16 3.47% 8.87E-03
PDCD1 4 8.89% 12 2.60% 4.50E-02
CD274 8 17.78% 5 1.08% 1.95E-06
PDCD1LG2 8 17.78% 5 1.08% 1.95E-06
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IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene amplifications in metastatic NEPC than metastatic AC.

Table 15.

Gene deep deletions in metastatic NEPC vs metastatic AC

Genes* Metastatic NEPC (N=45) Metastatic AC (N=461) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 0 0.00% 0 0.00% 1.00E+00
IL17B 0 0.00% 1 0.22% 1.00E+00
IL17C 0 0.00% 26 5.64% 1.54E-01
IL17D 1 2.22% 4 0.87% 3.74E-01
IL25 0 0.00% 0 0.00% 1.00E+00
IL17F 0 0.00% 0 0.00% 1.00E+00
IL17RA 0 0.00% 6 1.30% 1.00E+00
IL17RB 0 0.00% 3 0.65% 1.00E+00
IL17RC 0 0.00% 4 0.87% 1.00E+00
IL17RD 0 0.00% 4 0.87% 1.00E+00
IL17RE 0 0.00% 4 0.87% 1.00E+00
IL1A 0 0.00% 4 0.87% 1.00E+00
IL1B 0 0.00% 4 0.87% 1.00E+00
IL6 0 0.00% 1 0.22% 1.00E+00
TNF 0 0.00% 1 0.22% 1.00E+00
CSF3 0 0.00% 0 0.00% 1.00E+00
CCL7 0 0.00% 3 0.65% 1.00E+00
CXCL1 0 0.00% 1 0.22% 1.00E+00
CXCL2 0 0.00% 1 0.22% 1.00E+00
CXCL5 0 0.00% 1 0.22% 1.00E+00
CXCL8 0 0.00% 1 0.22% 1.00E+00
S100A7 0 0.00% 0 0.00% 1.00E+00
S100A8 0 0.00% 0 0.00% 1.00E+00
S100A9 0 0.00% 0 0.00% 1.00E+00
CEBPB 0 0.00% 0 0.00% 1.00E+00
PTGS2 1 2.22% 1 0.22% 1.70E-01
MMP1 0 0.00% 12 2.60% 6.13E-01
MMP2 0 0.00% 11 2.39% 6.10E-01
MMP3 0 0.00% 12 2.60% 6.13E-01
MMP7 0 0.00% 9 1.95% 1.00E+00
MMP9 0 0.00% 3 0.65% 1.00E+00
MMP13 0 0.00% 11 2.39% 6.10E-01
PDCD1 1 2.22% 13 2.82% 1.00E+00
CD274 1 2.22% 17 3.69% 1.00E+00
PDCD1LG2 1 2.22% 17 3.69% 1.00E+00
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*

IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Table 16.

Gene missense mutations in metastatic NEPC vs metastatic AC

Genes* Metastatic NEPC (N=45) Metastatic AC (N=461) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 0 0.00% 1 0.22% 1.00E+00
IL17B 0 0.00% 1 0.22% 1.00E+00
IL17C 1 2.22% 1 0.22% 1.70E-01
IL17D 0 0.00% 0 0.00% 1.00E+00
IL25 0 0.00% 0 0.00% 1.00E+00
IL17F 0 0.00% 0 0.00% 1.00E+00
IL17RA 0 0.00% 2 0.43% 1.00E+00
IL17RB 0 0.00% 0 0.00% 1.00E+00
IL17RC 0 0.00% 1 0.22% 1.00E+00
IL17RD 1 2.22% 3 0.65% 3.12E-01
IL17RE 2 4.44% 3 0.65% 6.51E-02
IL1A 0 0.00% 0 0.00% 1.00E+00
IL1B 1 2.22% 2 0.43% 2.44E-01
IL6 0 0.00% 1 0.22% 1.00E+00
TNF 0 0.00% 1 0.22% 1.00E+00
CSF3 0 0.00% 0 0.00% 1.00E+00
CCL7 0 0.00% 0 0.00% 1.00E+00
CXCL1 0 0.00% 0 0.00% 1.00E+00
CXCL2 0 0.00% 0 0.00% 1.00E+00
CXCL5 0 0.00% 1 0.22% 1.00E+00
CXCL8 0 0.00% 0 0.00% 1.00E+00
S100A7 0 0.00% 0 0.00% 1.00E+00
S100A8 0 0.00% 0 0.00% 1.00E+00
S100A9 0 0.00% 0 0.00% 1.00E+00
CEBPB 0 0.00% 0 0.00% 1.00E+00
PTGS2 0 0.00% 2 0.43% 1.00E+00
MMP1 0 0.00% 2 0.43% 1.00E+00
MMP2 0 0.00% 2 0.43% 1.00E+00
MMP3 0 0.00% 2 0.43% 1.00E+00
MMP7 0 0.00% 0 0.00% 1.00E+00
MMP9 2 4.44% 2 0.43% 4.14E-02
MMP13 0 0.00% 1 0.22% 1.00E+00
PDCD1 0 0.00% 1 0.22% 1.00E+00
CD274 0 0.00% 0 0.00% 1.00E+00
PDCD1LG2 0 0.00% 1 0.22% 1.00E+00
Open in a new tab
*

IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Red indicates significantly more gene missense mutations in metastatic NEPC than metastatic AC.

Table 17.

Gene truncating mutations in metastatic NEPC vs metastatic AC

Genes* Metastatic NEPC (N=45) Metastatic AC (N=461) P-value (Fisher’s exact)
Number Percent Number Percent
IL17A 0 0.00% 0 0.00% 1.00E+00
IL17B 0 0.00% 0 0.00% 1.00E+00
IL17C 0 0.00% 0 0.00% 1.00E+00
IL17D 0 0.00% 0 0.00% 1.00E+00
IL25 0 0.00% 0 0.00% 1.00E+00
IL17F 0 0.00% 0 0.00% 1.00E+00
IL17RA 0 0.00% 0 0.00% 1.00E+00
IL17RB 0 0.00% 1 0.22% 1.00E+00
IL17RC 0 0.00% 0 0.00% 1.00E+00
IL17RD 0 0.00% 0 0.00% 1.00E+00
IL17RE 0 0.00% 0 0.00% 1.00E+00
IL1A 0 0.00% 0 0.00% 1.00E+00
IL1B 0 0.00% 0 0.00% 1.00E+00
IL6 0 0.00% 0 0.00% 1.00E+00
TNF 0 0.00% 0 0.00% 1.00E+00
CSF3 0 0.00% 0 0.00% 1.00E+00
CCL7 0 0.00% 0 0.00% 1.00E+00
CXCL1 0 0.00% 0 0.00% 1.00E+00
CXCL2 0 0.00% 0 0.00% 1.00E+00
CXCL5 0 0.00% 0 0.00% 1.00E+00
CXCL8 0 0.00% 0 0.00% 1.00E+00
S100A7 0 0.00% 0 0.00% 1.00E+00
S100A8 0 0.00% 0 0.00% 1.00E+00
S100A9 0 0.00% 0 0.00% 1.00E+00
CEBPB 0 0.00% 1 0.22% 1.00E+00
PTGS2 0 0.00% 2 0.43% 1.00E+00
MMP1 0 0.00% 0 0.00% 1.00E+00
MMP2 0 0.00% 0 0.00% 1.00E+00
MMP3 0 0.00% 0 0.00% 1.00E+00
MMP7 0 0.00% 0 0.00% 1.00E+00
MMP9 0 0.00% 1 0.22% 1.00E+00
MMP13 0 0.00% 1 0.22% 1.00E+00
PDCD1 0 0.00% 0 0.00% 1.00E+00
CD274 0 0.00% 0 0.00% 1.00E+00
PDCD1LG2 0 0.00% 0 0.00% 1.00E+00
Open in a new tab
*

IL17A, also named interleukin-17A, IL17; IL17B, also named interleukin-17B, IL-20; IL17C, also named interleukin-17C, CX2; IL17D, also named interleukin-17D, IL-27; IL25, also named interleukin-25, IL17E; IL17F, also named interleukin-17F, IL-17F; IL17RA, also named interleukin-17 Receptor A, IL-17RA; IL17RB, also named interleukin-17 Receptor B, IL-17RB; IL17RC, also named interleukin-17 Receptor C, IL-17RL; IL17RD, also named interleukin-17 Receptor D, IL-17RD; IL17RE, also named interleukin-17 Receptor E, IL-17RE; IL1A, also named interleukin-1 Alpha, IL1F1; IL1B, also named interleukin-1 Beta, IL-1 Beta; IL6, also named interleukin-6, IL-6; TNF, also named Tumor Necrosis Factor, TNFA; CSF3, also named Colony Stimulating Factor-3, GCSF; CCL7, also named C-C Motif Chemokine Ligand-7, SCYA6; CXCL1, also named C-X-C Motif Chemokine Ligand-1, NAP-3; CXCL2, also named C-X-C Motif Chemokine Ligand-2, MIP2A; CXCL5, also named C-X-C Motif Chemokine Ligand-5, SCYB5; CXCL8, also named C-X-C Motif Chemokine Ligand-8, GCP-1; S100A7, also named S100 Calcium Binding Protein A7, PSOR1; S100A8, also named S100 Calcium Binding Protein A8, CAGA; S100A9, also named S100 Calcium Binding Protein A9, MRP-14; CEBPB, also named CCAAT Enhancer Binding Protein Beta, TCF5; PTGS2, also named Prostaglandin-Endoperoxide Synthase-2, PGHS-2; MMP1, also named Matrix Metallopeptidase-1, CLG; MMP2, also named Matrix Metallopeptidase-2, CLG4A; MMP3, also named Matrix Metallopeptidase-3, STMY1; MMP7, also named Matrix Metallopeptidase-7, MMP-7; MMP9, also named Matrix Metallopeptidase-9, CLG4B; MMP13, also named Matrix Metallopeptidase-13, MMP-13; PDCD1, also named Programmed Cell Death 1, PD1; CD274, also named CD274 Molecule, PD-L1; PDCD1LG2, also named Programmed Cell Death 1 Ligand 2, PD-L2.

Discussion

In the present study, we included 1303 cases of human prostate cancers in 7 datasets archived in cBioPortal and queried gene alterations in 35 IL-17 and related genes. We found that 34/35 (97%) genes had significantly more alterations in metastatic prostate cancer (with alteration rates ranging from 3.42% to 13.01%) than primary prostate cancer (with alteration rates ranging from 0.40% to 2.96%). 15/35 (43%) genes had significantly more alterations in primary CRPC than primary HNPC. 34/35 (97%) genes had significantly more alterations in metastatic CRPC than primary HNPC. Only three genes (S100A7, S100A8, and S100A9) had significantly more alterations in metastatic CRPC than primary CRPC. The gene alterations were mostly gene amplifications (97%), while gene deep deletions, missense mutations, and truncating mutations were very rare. 7/35 (20%) genes had significantly more alterations in primary NEPC than primary AC. 23/35 (66%) genes had significantly more alterations in metastatic NEPC (ranging from 11.11% to 33.33%) than metastatic AC (ranging from 2.17% to 11.93%). Only three genes (S100A7, S100A8, and S100A9) had significantly more alterations in metastatic NEPC than metastatic AC with neuroendocrine features. Most of the gene alterations in metastatic NEPC were gene amplifications (80%), while gene deep deletions, missense mutations, and truncating mutations were very rare. A prominent trend is that gene amplifications are more frequently found in metastatic CRPC and NEPC than primary hormone-naïve prostate adenocarcinomas (Figure 2).

Figure 2.

Figure 2

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Trend of gene alterations in prostate cancers. A. Overall gene alterations. B. Individual gene alterations including amplifications (Amp), deep deletions (DD), missense mutations (MM), and truncating mutations (TM). Each bar represents a gene; gene names (from left to right) within each color-coded block are the same as shown in Figure 1 or Table 2 (from top to bottom). HNPC, hormone-naïve prostate cancer; CRPC, castration-resistant prostate cancer; PC, prostate cancer including HNPC and CRPC; AC, adenocarcinoma; NEPC, neuroendocrine prostate cancer; NE, neuroendocrine feature.

Three S100 family members (S100A7, S100A8, and S100A9) are among the genes with the highest gene amplifications (12-13% in metastatic prostate cancers and 28.89% in metastatic NEPC, respectively). S100 proteins comprise a family of 23 different members characterized by high homology, low-molecular weight, and two calcium-binding EF-hands, as well as tissue-specific expression [39]. S100A7/8/9 are induced by IL-17 to recruit neutrophils that protect against infections [40] or exacerbate psoriasis [41]. S100A7 protein expression was found to be increased in prostate cancer compared to normal prostate, and S100A7 promotes survival and invasiveness of prostate cancer cells [42]. S100A8 and S100A9 were found to be up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, and S100A9 serum levels were significantly elevated in prostate cancer patients compared with patients with benign prostatic hypertrophy or healthy individuals [43]. Gene amplifications of S100A7/8/9 genes in metastatic CRPC/NEPC may lead to overexpression of them at mRNA and protein levels, which remains to be determined. It is not known if S100A7/8/9 proteins play any roles in the progression from HNPC to CRPC/NEPC and from the primary tumor to metastatic tumor, which warrants future studies.

One potential caveat of the present study is that we cannot completely rule out the possibility of redundant samples among different datasets. For example, we are not sure if any of the sample data from the five U.S. datasets were also deposited into the TCGA dataset. We checked the patient identification (ID) numbers and sample IDs and could not find any overlapping numbers, however, we did not know if the IDs were separately assigned in different datasets. We had to use different datasets because TCGA dataset contains only primary adenocarcinomas. The five U.S. datasets might also share some samples, but we did not find any identical patient IDs. Since more gene amplifications are found in metastatic CRPC/NEPC that mostly (N=415) came from SU2C/PCF Dream Team, we think that the gene alteration rates might not be dramatically affected even if there were a few overlapping cases. Another caveat is that we did not include all IL-17-downstream genes, which may miss some genes that may be more important than the ones studied. The choice of these genes is arbitrarily based on our previous research work and we include only the well-known IL-17-downstream genes.

In summary, our findings suggest that gene amplifications of IL-17 and related genes are more frequently found in metastatic CRPC and NEPC than primary hormone-naïve prostate adenocarcinomas, implying that IL-17 and related genes may play important roles in the progression from HNPC to CRPC and from primary location to metastasis as well as in development of metastatic NEPC. Future studies shall determine if expression at mRNA and protein levels of these genes is increased in metastatic CRPC and NEPC and if the genes function to promote prostate cancer progression.

Acknowledgements

This work is part of Mr. Ruoxin Lan’s thesis required to obtain a Master’s Degree. All of the research activities were conducted at VA and Tulane University and all intellectual property rights belong to the U.S. institutions. The results shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. Dr. Zongbing You was partially supported by a Merit Review Award (I01BX004158) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research & Development Service. Dr. Zongbing You is a Research Physiologist employed by the Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA-629. Dr. Kun Zhang was partially supported by Research Centers in Minority Institutions (RCMI) funded by National Institutes of Health (2U54MD007595). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views or policies of the Department of Veterans Affairs, National Institutes of Health, or the United States government.

Disclosure of conflict of interest

None.

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