Genetic Prostate Cancer Research Articles

Genetics of prostate cancer and its utility in treatment and screening.

Prostate cancer heritability is attributed to a combination of rare, moderate to highly penetrant genetic variants as well as commonly occurring variants conferring modest risks [single nucleotide polymorphisms (SNPs)]. Some of the former type of variants (e.g., BRCA2 mutations) predispose particularly to aggressive prostate cancer and confer poorer prognoses compared to men who do not carry mutations. Molecularly targeted treatments such as PARP inhibitors have improved outcomes in men carrying somatic and/or germline DNA repair gene mutations. Ongoing clinical trials are exploring other molecular targeted approaches based on prostate cancer somatic alterations. Genome wide association studies have identified >250 loci that associate with prostate cancer risk. Multi-ancestry analyses have identified shared as well as population specific risk SNPs. Prostate cancer risk SNPs can be used to estimate a polygenic risk score (PRS) to determine an individual's genetic risk of prostate cancer. The odds ratio of prostate cancer development in men whose PRS lies in the top 1% of the risk profile ranges from 9 to 11. Ongoing studies are investigating the utility of a prostate cancer PRS to target population screening to those at highest risk. With the advent of personalized medicine and development of DNA sequencing technologies, access to clinical genetic testing is increasing, and oncology guidelines from bodies such as NCCN and ESMO have been updated to provide criteria for germline testing of "at risk" healthy men as well as those with prostate cancer. Both germline and somatic prostate cancer research have significantly evolved in the past decade and will lead to further development of precision medicine approaches to prostate cancer treatment as well as potentially developing precision population screening models.

Polygenic risk score for genetic evaluation of prostate cancer risk in Asian populations: A narrative review.

Decreasing costs of genetic testing and interest in disease inheritance has changed the landscape of cancer prediction in prostate cancer (PCa), and guidelines now include genetic testing for high-risk groups. Familial and hereditary PCa comprises approximately 20% and 5% of all PCa, respectively. Multifaceted disorders like PCa are caused by a combinatory effect of rare genes of high penetrance and smaller genetic variants of relatively lower effect size. Polygenic risk score (PRS) is a novel tool utilizing PCa-associated single nucleotide polymorphisms (SNPs) identified from genome-wide association study (GWAS) to generate an additive estimate of an individual's lifetime genetic risk for cancer. However, most PRS are developed based on GWAS collected from mainly European populations and do not address ethnic differences in PCa genetics. This review highlights the attempts to generate a PRS tailored to Asian males including data from Korea, China, and Japan, and discuss the clinical implications for prediction of early onset and aggressive PCa.

Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer

Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer

Prostate cancer genetics and biology:
 literature review

Prostate cancer genetics and biology:
 literature review

Prostate cancer genetics
 and biology

Relevance: Despite a high survival with localized
 prostate cancer, metastatic prostate cancer remains
 virtually incurable even after intensive multimodal therapy. Death in advanced stages of the disease is caused
 by the lack of therapeutic regimens able to produce a
 long-term tumor reaction due to its extreme genetic and
 cellular heterogeneity. According to epidemiological
 studies, a family history of prostate cancer significantly
 increases the risk. Clinical diagnosis is often based on a
 single biopsy made to determine the molecular status of
 a particular cancer case. Pathological and genomic heterogeneity can lead to bias in diagnosis. Therefore, the
 use of genetic research technologies is highly relevant.
 The purpose wasto justify the use of genetic profiling technologies for patients with prostate cancer.
 Results: Many cases lack an understanding of the
 multifactorial impact of current treatment methods
 on the patient’s immune system. Combination therapy efficacy and tolerability depend on the choice of an
 optimal treatment regimen. Approaches to prioritizing
 the types of combination therapy should be developed.
 Cancer genome affects the disease course and progression. Simulation of these interactions in a genetic model
 allows predicting the treatment outcome and effectiveness.
 Conclusions: The conducted systematic review
 shows that a deep understanding of prostate cancer biology and genetics and genetic profiling can save and
 improve the lives of many patients with serious diseases.

Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling.

SummaryAnti-androgens are a common therapy in prostate cancer (PCa) targeting androgen receptor (AR) signaling. However, these therapies fail due to selection of highly aggressive AR-negative cancer cells that have no therapeutic options available. We demonstrate that elevating endogenous ceramide levels with administration of exogenous ceramide nanoliposomes (CNLs) was efficacious in AR-negative cell lines with limited efficacy in AR-positive cells. This effect is mediated through reduced de novo sphingolipid synthesis in AR-positive cells. We show that anti-androgens elevate de novo generation of sphingolipids via SPTSSB, a rate-limiting mediator of sphingolipid generation. Moreover, pharmacological inhibition of AR increases the efficacy of CNL in AR-positive cells through de novo synthesis, while SPTSSB knockdown limited CNL's efficacy in AR-negative cells. Alluding to clinical relevance, SPTSSB is upregulated in patients with advanced PCa after anti-androgens treatment. These findings emphasize the relevance of AR regulation upon sphingolipid metabolism and the potential of CNL as a PCa therapeutic.

Alzheimer Gene BIN1 may Simultaneously Influence Dementia Risk and Androgen Deprivation Therapy Dosage in Prostate Cancer.

Androgen deprivation therapy (ADT) is extensively used in prostate cancer. Yet the risk of impaired cognition or Alzheimer disease (AD) in men with prostate cancer receiving ADT is uncertain. Some studies of prostate cancer and ADT suggest that the risk of AD is not increased. But other studies have found an increased risk of AD and cognitive impairment. As the uncertainty about ADT and dementia might relate to the genetics of prostate cancer and AD, the authors used the Cancer Genome Atlas (TCGA) to examine the relationship in men with prostate cancer between genes implicated in AD and genes implicated in prostate cancer. The authors examined the genomics of 492 prostate cancer cases in the Genomic Data Commons (GDC) TCGA Prostate Cancer (PRAD) data set. To access and analyze the data, 2 web-based interfaces were used: (1) the UCSC Xena browser, a web-based visual integration and exploration tool for TCGA data, including clinical and phenotypic annotations; and (2) cBioportal, a web-based interface that enables integrative analysis of complex cancer genomics and clinical profiles. Co-occurrence analysis indicates that alterations in the prostate cancer gene Speckle-type POZ protein (SPOP) significantly co-occur with alterations in the AD gene BIN1 (P<0.001). The presence of somatic mutations (deleterious and missense/in frame) in SPOP deranges BIN1 gene expression. SPOP/BIN1 RNA gene expression in 492 prostate cancer specimens is significantly correlated (P<0.001). Increased expression of SPOP in 492 prostate cancers is associated with reduced survival (P=0.00275). Men receiving pharmacologic therapy had a tumor with a significantly higher Gleason score (P=0.023). Gleason score and BIN1 RNA gene expression, unit log2 (fragments per kilobase of transcript per million mapped reads upper quartile [FPKM-UQ]+1), in 499 prostate cancer specimens were significantly inversely correlated (P<0.001). BIN1 forms part of a network that interacts with the MYC oncogene, activated at the earliest phases of prostate cancer and in its position on chr8q24 linked to disease aggressiveness. Dynamic regulation of the BIN1-Tau interaction is involved in AD. BIN1 loss in AD allows phosphorylated tau to be mis-sorted to synapses, which likely alters the integrity of the postsynapse, alongside reducing the functionally important release of physiological forms of tau. Alzheimer symptoms are usually preceded by a preclinical phase that may be 16 years long. The authors suggest that the ADT dosage reflects the severity of a process that is already underway. The severity is determined by the genetics of the tumor itself, at least in part by BIN1. ADT is not causing new cases of AD. The oncologist treats higher-grade prostate cancer with more ADT, which serves as a surrogate marker for disease severity. Our analysis of TCGA data does not support the idea that ADT causes AD or dementia.

Implementation of systematic germline genetic testing (GT) for metastatic prostate cancer (mPC) patients at the Puget Sound VA prostate oncology clinic.

1578 Background: There is increasing clinical relevance for GT in patients with mPC to evaluate the 2-fold possibilities of molecularly targeted therapies and implications for relatives. NCCN guidelines recommend GT for subsets of men, including those with mPC. While exciting, there are new logistical challenges around workflows for delivering GT services. We sought to address these challenges through a prospective pilot study designed to systematically deliver GT to all men with mPC receiving care at the Puget Sound VA prostate cancer (PUG-VA PC) Clinic. Our hypothesis was that systematic universal GT for men with mPC would identify similar prevalence rates of germline pathogenic/likely pathogenic variants (P/LPV) among veterans compared to previously reported cohorts. Methods: We conducted an IRB-approved, prospective trial testing feasibility of a systematic workflow to identify all veterans with mPC seen at PUG-VA PC Clinic between 11/2016-1/2020 to discuss and offer GT. A research coordinator pre-screened each clinic schedule to identify patients with mPC, notified the oncologist to discuss pretest education and GT with the patient at the appointment. Consenting patients provided a saliva sample same day in clinic for the CLIA-certified Color Genomics 30-gene cancer gene panel. Results were issued to patients and providers, and results were discussed by email and phone with a genetic counselor. Uptake of GT and prevalence of P/LPV was measured and compared to previously reported data from the retrospectively tested UW TAN cohort. χ2-test was performed. Results: 84% (190/227) of approached veterans with mPC consented and 80% (182/227) completed GT. 6.6% (12/182) of men were found to carry P/LPV in DNA repair genes: 3 in BRCA2, 2 in BRCA1, 4 in ATM, and 3 in CHEK2. Overall, 6.6% rate of P/LPV in DNA repair genes was comparable to the 8.8% previously reported in the UW TAN cohort (p = 0.69). Conclusions: Dedicated clinic-based strategies to offer and provide GT and services for veterans with mPC is feasible and results in high GT consent and uptake, especially with direct oncologist involvement. Proportion of consenting to proceed with GT was nearly identical to a referral-based specialty Prostate Cancer Genetics Clinic (Pouv, Sokolova, and Cheng, unpublished). The proportion of P/LPV in the PUG-VA PC population was comparable to a geographically similar retrospective cohort. Updated data, including detailed demographics and GT results, will be reported at final presentation.

8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

Genetic Testing in Prostate Cancer.

This review summarizes recent advances in prostate cancer (PCa) genetics. Upwards of 20% of metastatic castration-resistant prostate tumors (mCRPC) carry homologous recombination (HR) repair gene mutations, of which ~ 10% are germline (inherited). Another ~ 5% exhibit microsatellite instability (MSI-H) and/or mismatch repair deficiency (MMRd). Pembrolizumab is approved for tumors with MMRd, thus patients with mCRPC and MMRd are candidates for pembrolizumab. Emerging data indicate that platinum chemotherapy and poly ADP-ribose polymerase inhibitors (PARPi) are effective in PCa exhibiting HR deficiency. NCCN guidelines now recommend germline and somatic tumor testing in specific clinical scenarios due to treatment and family implications. Genetic testing in PCa patients may inform prognosis, treatment options, and have implications for family counseling. PARPi, platinum chemotherapy, and immune checkpoint inhibitors are promising targeted therapies for PCa with specific molecular features. Therapeutic advances, along with importance to relatives, are driving genetic testing in prostate cancer.

Co-occurrent Alterations of Alzheimer's Genes and Prostate Cancer Genes in Prostate Cancer.

Androgen deprivation therapy (ADT) is extensively employed in treatment of prostate cancer. Some studies have found increased risk of Alzheimer's disease and cognitive impairment in patients treated with ADT. Since the uncertainty about ADT and dementia might relate to the genetics of prostate cancer and Alzheimer's disease, we used the Cancer Genome Atlas (TCGA) to examine the relationship between genes implicated in Alzheimer's disease and genes implicated in prostate cancer in men with prostate cancer. The genomics of 492 prostate cancer cases in the Genomic Data Commons TCGA Prostate Cancer data set were examined. Alterations (mutation, amplification or deletion) in prostate cancer gene speckle-type POZ protein (SPOP) significantly co-occurred with alterations in Alzheimer's disease gene bridging integrator-1 (BIN1). Alterations in prostate cancer gene spectrin alpha 1 (SPTA1) significantly co-occurred with alterations in Alzheimer's disease gene CD2-associated protein (CD2AP) (p<0.001). The presence of somatic mutations (deleterious and missense/in frame) in SPOP disturbs BIN1 gene expression. SPOP and BIN1 RNA expression in 492 prostate cancer specimens was significantly positively correlated (p<0.001). Increased expression of SPOP in 492 cases of prostate cancer was associated with reduced survival (p=0.00275). BIN1 forms part of a network that interacts with the MYC oncogene, which is activated at the earliest phases of prostate cancer and is linked to disease aggressiveness. Men receiving ADT had tumor with a significantly higher Gleason score (p=0.023). Gleason score and BIN1 RNA expression in 499 prostate cancer specimens were significantly correlated (p<0.001). The severity of prostate cancer is determined by the genetics of the tumor itself, possibly at least in part by the interactions of SPOP/BIN1, MYC/BIN1 and SPTA1/CD2AP. Oncologists treats higher grade prostate cancer with more ADT, which serves as a surrogate marker for disease severity. A weakness of our study is that we did not examine Alzheimer's disease or dementia at all in patients with cancer, only co-occurrence of genetic alterations. Nevertheless, our analysis of TCGA data does not support the idea that ADT causes Alzheimer's disease or dementia.

Clonal evaluation of early onset prostate cancer by expression profiling of ERG, SPINK1, ETV1, and ETV4 on whole-mount radical prostatectomy tissue.

Expression profiles of erythroblast transformation-specific (ETS)-related gene fusions and serine protease inhibitor Kazal-type 1 (SPINK1) in early onset prostate cancer have not been thoroughly explored. We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55 years) and characterized the expression of ETS-related gene (ERG), SPINK1, ETS Variant 1 (ETV1), and ETV4 by dual immunohistochemistry and dual RNA in situ hybridization. Age, race, family history, preoperative prostate-specific antigen, biochemical recurrence, and pathological variables using whole-mount radical prostatectomy tissue were collected. A total of 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans were included in the analysis. Positive family history of prostate cancer was seen in 65 (43%) patients. Preoperative prostate-specific antigen ranged from 0.3 to 52.7 ng/mL (mean = 7.04). The follow-up period ranged from 1 to 123.7 months (mean = 30.3). Biochemical recurrence was encountered in 8 of 151 (5%). ERG overexpression was observed in 85 of 151 (56%) cases, followed by SPINK1 in 61 of 151 (40%), ETV1 in 9 of 149 (6%), and ETV4 in 4 of 141 (3%). There were 25 of 151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients (≤45 years old; 76% vs 49%, P = .002), Caucasian men (71% vs 41% P = .0007), organ-confined tumors (64% vs 33%, P = .0008), and tumors of Gleason Grade groups 1 and 2 (62% vs 26%, P = .009). SPINK1 overexpression was more in African American men (68% vs 26%, P = .00008), in tumors with high tumor volume (>20%) and with anterior located tumors. ETV1 and ETV4 demonstrated rare overexpression in these tumors, particularly in the higher-grade tumors. This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer.

Bringing Prostate Cancer Germline Genetics into Clinical Practice.

Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations. We searched PubMed® for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer Network®, Bureau of Labor Statistics and National Society of Genetic Counselors websites. A number of germline mutations in DNA damage repair genes ( BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes ( MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study ( ClinicalTrials.gov NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors. Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.

Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants.

Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.

Global Genetics Research in Prostate Cancer: A Text Mining and Computational Network Theory Approach.

Prostate cancer is the most common cancer type in men in Finland and second worldwide. In this paper, we analyze almost 150, 000 published papers about prostate cancer, authored by ten thousands of scientists worldwide, with an integrated text mining and computational network theory approach. We demonstrate how to integrate text mining with network analysis investigating research contributions of countries and collaborations within and between countries. Furthermore, we study the time evolution of individually and collectively studied genes. Finally, we investigate a collaboration network of Finland and compare studied genes with globally studied genes in prostate cancer genetics. Overall, our results provide a global overview of prostate cancer research in genetics. In addition, we present a specific discussion for Finland. Our results shed light on trends within the last 30 years and are useful for translational researchers within the full range from genetics to public health management and health policy.

Germline Genetics of Prostate Cancer: Time to Incorporate Genetics into Early Detection Tools.

Prostate cancer (PCa) remains the most common solid malignancy in men, and its prevalence makes understanding its heritability of paramount importance. To date, the most common factors used to estimate a man's risk of developing PCa are age, race, and family history. Despite recent advances in its utility in multiple malignancies (e.g., breast and colon cancer), genetic testing is still relatively underutilized in PCa. Multiple highly penetrant genes (HPGs) and single-nucleotide polymorphisms (SNPs) have been show to increase a patient's risk of developing PCa. Mutations in the former, like DNA damage repair genes, can confer a 2- to 3-fold increased risk of developing PCa and can increase the risk of aggressive disease. Similarly, PCa-risk SNPs can be used to create risk scores (e.g., genetic or polygenic risk scores) that can be used to further stratify an individual's disease susceptibility. Specifically, these genetic risk scores can provide more specific estimates of a man's lifetime risk ranging up to >6-fold higher risk of PCa. It is becoming increasingly evident that in addition to the standard family history and race information, it is necessary to obtain genetic testing (including an assessment of HPG mutation status and genetic risk score) to provide a full risk assessment. The additional information derived thereby will improve current practices in PCa screening by risk-stratifying patients before initial prostate-specific antigen testing, determining a patient's frequency of visits, and even help identify potentially at-risk family members.

Two prostate cancer‑associated polymorphisms in the 3'UTR of IGF1R influences prostate cancer susceptibility by affecting miRNA binding.

Prostate cancer (PCa) is a common malignant cancer in men worldwide. Numerous genetic variations have been associated with PCa, but their biological function remains unclear. Single nucleotide polymorphisms (SNPs) inside 3'untranslated region (UTR) affect gene expression, with one essential mechanism being regulation by micro (mi)RNAs. Based on data from genome‑wide association study of the Consortium for Chinese Consortium for Prostate Cancer Genetics, rs1815009 and rs2684788 inside 3'UTR of insulin‑like growth factor1 receptor (IGF1R) presented significant genotype distribution between PCa and control samples. In the current study, targeting miRNAs were predicted using TargetScan and miRanda. The prediction was confirmed using a thermodynamic model for miRNA‑target interaction and luciferase reporter assays for miRNA binding inside IGF1R 3'UTR. Furthermore, data from public databases and miRNA overexpression further supported miRNAs function. The results suggested that miR‑133a and miR‑133b may bind near rs1815009, and miR‑455 near rs2684788, within IGF1R 3'UTR. Compared with normal tissues, miR‑133a, miR‑133b and miR‑455 exhibited significantly lower expression in PCa tissues in the public datasets analyzed. The results of the present study revealed an association between rs1815009, rs2684788 and PCa risk, which involves altered miRNA regulation and contributes to cancer susceptibility.

Genetics and biology of prostate cancer.

Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels. Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological advances focused on disease detection and management. These advances, along with an improved understanding of the adaptive responses to conventional cancer therapies, anti-androgen therapy, and immunotherapy, are catalyzing development of more effective therapeutic strategies for advanced disease. In particular, knowledge of the heterotypic interactions between and coevolution of cancer and host cells in the tumor microenvironment has illuminated novel therapeutic combinations with a strong potential for more durable therapeutic responses and eventual cures for advanced disease. Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.

RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells.

The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene.

CD24 is a genetic modifier for risk and progression of prostate cancer.

CD24 plays an oncogenic role in the onset and progression of various human cancers, including prostate cancer. In the present study, we identified two linkage disequilibrium blocks with four recombination hotspot motifs in human CD24 locus. To elucidate whether genetic variants of CD24 are associated with susceptibility to prostate cancer and its disease status, we conducted a case-control association study with two P170 C/T and P-534 A/C polymorphisms of CD24 in 590 patients with prostate cancer and 590 healthy controls. A significant increased risk of prostate cancer was found in men with the P170T/T genotype over the P170C/C genotype (odd ratio = 1.74, 95% confidence interval = 1.16-2.63, P = 0.008), and in men with the P-534C/C genotype over the P-534A/A genotype (odd ratio = 1.47, 95% CI = 1.18-2.26, P = 0.003). Cochran-Armitage trend analysis showed that the P170T allele was significantly correlated with an increased risk of prostate cancer progression (P = 0.029, trend between genotypes and stages) and this observation was also validated in an independent sample cohort. Next, we found that tumors with P170T or P-534C alleles had more twofold increased protein expressions of CD24 as compared to those with P170C or P-534A alleles, respectively. Likewise, tumors with a combination of P170T/T and P-534C/C genotypes were associated with a high mRNA level of CD24. Our data suggest a significant association of CD24 genetic variants with prostate cancer onset and progression, which provides new insight into molecular genetics of prostate cancer; however, these findings need to be validated in multiple independent cohorts. © 2016 Wiley Periodicals, Inc.