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Prostate Cancer Genetics and the Emergence of Targeted Therapies Based...
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Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 30960

Special Issue Editors

Dr. Liesel M. FitzGerald

E-Mail Website
Guest Editor
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7005, Australia
Interests: cancer; genetics; prostate cancer; predictive and prognostic biomarker research
Dr. Csilla Sipeky

E-Mail Website
Guest Editor
University of Turku, Institute of Biomedicine, 20520 Turku, Finland
Interests: prostate cancer; clinically actionable biomarker; precision medicine; pharmacogenomics

Special Issue Information

Dear Colleagues,

Our understanding of the genetic basis of prostate cancer has increased considerably over the last decade. Two very recent studies have shown that approximately 30% of familial relative risk is explained by common variants, discovered through genome-wide association studies and fine-mapping efforts. While these results are significant, the true clinical utility of these variants is yet to be revealed in terms of patient stratification, especially with respect to distinguishing patients at risk for aggressive or fatal disease. In an effort to uncover some of the ‘missing heritability’ of prostate cancer, next-generation sequencing methodologies are being used for rare variant discovery, which promises to identify more functionally relevant risk variants. Combined with patient stratification, this approach can also be used to discover rare variants associated with aggressive or fatal prostate cancer. Furthermore, molecular profiling of rare variants at both the germline and somatic level, including circulating tumour cells, can identify biomarkers that predict patient response to targeted therapies (i.e., pharmacogenomics). For example, early trials are showing great promise for the poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic castrate-resistant patients with DNA repair gene mutations. In this Special Issue of Genes, we extend an invitation for reviews, mini-reviews and original research articles that focus on the discovery of rare prostate cancer variants, particularly those that can be used to distinguish clinically-relevant disease or predict therapeutic efficacies and outcomes.

Dr. Liesel M. FitzGerald
Dr. Csilla Sipeky
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Prostate cancer
  • Genetics
  • Common and rare variants
  • Germline and somatic variants
  • Outcomes
  • Molecular profiling
  • Therapy
  • Pharmacogenomics

Published Papers (7 papers)

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Research

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17 pages, 2475 KiB  
Article
Pathway Analysis of Genes Identified through Post-GWAS to Underpin Prostate Cancer Aetiology
by Samaneh Farashi, Thomas Kryza and Jyotsna Batra
Genes 2020, 11(5), 526; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11050526 - 08 May 2020
Cited by 2 | Viewed by 3781
Abstract
Understanding the functional role of risk regions identified by genome-wide association studies (GWAS) has made considerable recent progress and is referred to as the post-GWAS era. Annotation of functional variants to the genes, including cis or trans and understanding their biological pathway/gene network [...] Read more.
Understanding the functional role of risk regions identified by genome-wide association studies (GWAS) has made considerable recent progress and is referred to as the post-GWAS era. Annotation of functional variants to the genes, including cis or trans and understanding their biological pathway/gene network enrichments, is expected to give rich dividends by elucidating the mechanisms underlying prostate cancer. To this aim, we compiled and analysed currently available post-GWAS data that is validated through further studies in prostate cancer, to investigate molecular biological pathways enriched for assigned functional genes. In total, about 100 canonical pathways were significantly, at false discovery rate (FDR) < 0.05), enriched in assigned genes using different algorithms. The results have highlighted some well-known cancer signalling pathways, antigen presentation processes and enrichment in cell growth and development gene networks, suggesting risk loci may exert their functional effect on prostate cancer by acting through multiple gene sets and pathways. Additional upstream analysis of the involved genes identified critical transcription factors such as HDAC1 and STAT5A. We also investigated the common genes between post-GWAS and three well-annotated gene expression datasets to endeavour to uncover the main genes involved in prostate cancer development/progression. Post-GWAS generated knowledge of gene networks and pathways, although continuously evolving, if analysed further and targeted appropriately, will have an important impact on clinical management of the disease. Full article
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
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13 pages, 1355 KiB  
Article
Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer
by Tommi Rantapero, Tiina Wahlfors, Anna Kähler, Christina Hultman, Johan Lindberg, Teuvo L. J. Tammela, Matti Nykter, Johanna Schleutker and Fredrik Wiklund
Genes 2020, 11(3), 314; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11030314 - 14 Mar 2020
Cited by 17 | Viewed by 4783
Abstract
Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal [...] Read more.
Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with CHEK2 (4.1%) and ATM (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed (p = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness. Full article
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
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10 pages, 446 KiB  
Article
Gene‒Prostate-Specific-Antigen-Guided Personalized Screening for Prostate Cancer
by Teng-Kai Yang, Pi-Chun Chuang, Amy Ming-Fang Yen, Hsiu-Hsi Chen and Sam Li-Sheng Chen
Genes 2019, 10(9), 641; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10090641 - 24 Aug 2019
Cited by 2 | Viewed by 2397
Abstract
(1) Background: A simulation approach for prostate cancer (PrCa) with a prostate-specific antigen (PSA) test incorporating genetic information provides a new avenue for the development of personalized screening for PrCa. Going by the evidence-based principle, we use the simulation method to evaluate the [...] Read more.
(1) Background: A simulation approach for prostate cancer (PrCa) with a prostate-specific antigen (PSA) test incorporating genetic information provides a new avenue for the development of personalized screening for PrCa. Going by the evidence-based principle, we use the simulation method to evaluate the effectiveness of mortality reduction resulting from PSA screening and its utilization using a personalized screening regime as opposed to a universal screening program. (2) Methods: A six-state (normal, over-detected, low-grade, and high-grade PrCa in pre-clinical phase, and low-grade and high-grade PrCa in clinical phase) Markov model with genetic and PSA information was developed after a systematic review of genetic variant studies and dose-dependent PSA studies. This gene‒PSA-guided model was used for personalized risk assessment and risk stratification. A computer-based simulated randomized controlled trial was designed to estimate the reduction of mortality achieved by three different screening methods, personalized screening, universal screening, and a non-screening group. (3) Results: The effectiveness of PrCa mortality reduction for a personalized screening program compared to a non-screening group (22% (9%‒33%)) was similar to that noted in the universal screening group (20% (7%‒21%). However, a personalized screening program could dispense with 26% of unnecessary PSA testing, and avoid over-detection by 2%. (4) Conclusions: Gene‒PSA-guided personalized screening for PrCa leads to fewer unnecessary PSA tests without compromising the benefits of mortality reduction (as happens with the universal screening program). Full article
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
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14 pages, 2434 KiB  
Article
Single-Nucleotide Polymorphisms Sequencing Identifies Candidate Functional Variants at Prostate Cancer Risk Loci
by Peng Zhang, Lori S. Tillmans, Stephen N. Thibodeau and Liang Wang
Genes 2019, 10(7), 547; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10070547 - 18 Jul 2019
Cited by 7 | Viewed by 3583
Abstract
Genome-wide association studies have identified over 150 risk loci that increase prostate cancer risk. However, few causal variants and their regulatory mechanisms have been characterized. In this study, we utilized our previously developed single-nucleotide polymorphisms sequencing (SNPs-seq) technology to test allele-dependent protein binding [...] Read more.
Genome-wide association studies have identified over 150 risk loci that increase prostate cancer risk. However, few causal variants and their regulatory mechanisms have been characterized. In this study, we utilized our previously developed single-nucleotide polymorphisms sequencing (SNPs-seq) technology to test allele-dependent protein binding at 903 SNP sites covering 28 genomic regions. All selected SNPs have shown significant cis-association with at least one nearby gene. After preparing nuclear extract using LNCaP cell line, we first mixed the extract with dsDNA oligo pool for protein–DNA binding incubation. We then performed sequencing analysis on protein-bound oligos. SNPs-seq analysis showed protein-binding differences (>1.5-fold) between reference and variant alleles in 380 (42%) of 903 SNPs with androgen treatment and 403 (45%) of 903 SNPs without treatment. From these significant SNPs, we performed a database search and further narrowed down to 74 promising SNPs. To validate this initial finding, we performed electrophoretic mobility shift assay in two SNPs (rs12246440 and rs7077275) at CTBP2 locus and one SNP (rs113082846) at NCOA4 locus. This analysis showed that all three SNPs demonstrated allele-dependent protein-binding differences that were consistent with the SNPs-seq. Finally, clinical association analysis of the two candidate genes showed that CTBP2 was upregulated, while NCOA4 was downregulated in prostate cancer (p < 0.02). Lower expression of CTBP2 was associated with poor recurrence-free survival in prostate cancer. Utilizing our experimental data along with bioinformatic tools provides a strategy for identifying candidate functional elements at prostate cancer susceptibility loci to help guide subsequent laboratory studies. Full article
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
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Review

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28 pages, 1128 KiB  
Review
The Impact of African Ancestry on Prostate Cancer Disparities in the Era of Precision Medicine
by Deyana D. Lewis and Cheryl D. Cropp
Genes 2020, 11(12), 1471; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121471 - 08 Dec 2020
Cited by 17 | Viewed by 4290
Abstract
Prostate cancer disproportionately affects men of African ancestry at nearly twice the rate of men of European ancestry despite the advancement of treatment strategies and prevention. In this review, we discuss the underlying causes of these disparities including genetics, environmental/behavioral, and social determinants [...] Read more.
Prostate cancer disproportionately affects men of African ancestry at nearly twice the rate of men of European ancestry despite the advancement of treatment strategies and prevention. In this review, we discuss the underlying causes of these disparities including genetics, environmental/behavioral, and social determinants of health while highlighting the implications and challenges that contribute to the stark underrepresentation of men of African ancestry in clinical trials and genetic research studies. Reducing prostate cancer disparities through the development of personalized medicine approaches based on genetics will require a holistic understanding of the complex interplay of non-genetic factors that disproportionately exacerbate the observed disparity between men of African and European ancestries. Full article
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
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23 pages, 264 KiB  
Review
Pharmacogenomic Biomarkers in Docetaxel Treatment of Prostate Cancer: From Discovery to Implementation
by Reka Varnai, Leena M. Koskinen, Laura E. Mäntylä, Istvan Szabo, Liesel M. FitzGerald and Csilla Sipeky
Genes 2019, 10(8), 599; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10080599 - 08 Aug 2019
Cited by 16 | Viewed by 3505
Abstract
Prostate cancer is the fifth leading cause of male cancer death worldwide. Although docetaxel chemotherapy has been used for more than fifteen years to treat metastatic castration resistant prostate cancer, the high inter-individual variability of treatment efficacy and toxicity is still not well [...] Read more.
Prostate cancer is the fifth leading cause of male cancer death worldwide. Although docetaxel chemotherapy has been used for more than fifteen years to treat metastatic castration resistant prostate cancer, the high inter-individual variability of treatment efficacy and toxicity is still not well understood. Since prostate cancer has a high heritability, inherited biomarkers of the genomic signature may be appropriate tools to guide treatment. In this review, we provide an extensive overview and discuss the current state of the art of pharmacogenomic biomarkers modulating docetaxel treatment of prostate cancer. This includes (1) research studies with a focus on germline genomic biomarkers, (2) clinical trials including a range of genetic signatures, and (3) their implementation in treatment guidelines. Based on this work, we suggest that one of the most promising approaches to improve clinical predictive capacity of pharmacogenomic biomarkers in docetaxel treatment of prostate cancer is the use of compound, multigene pharmacogenomic panels defined by specific clinical outcome measures. In conclusion, we discuss the challenges of integrating prostate cancer pharmacogenomic biomarkers into the clinic and the strategies that can be employed to allow a more comprehensive, evidence-based approach to facilitate their clinical integration. Expanding the integration of pharmacogenetic markers in prostate cancer treatment procedures will enhance precision medicine and ultimately improve patient outcomes. Full article
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
19 pages, 1166 KiB  
Review
PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development
by Verneri Virtanen, Kreetta Paunu, Johanna K. Ahlskog, Reka Varnai, Csilla Sipeky and Maria Sundvall
Genes 2019, 10(8), 565; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10080565 - 26 Jul 2019
Cited by 47 | Viewed by 8062
Abstract
Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to [...] Read more.
Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono-and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors. Full article
(This article belongs to the Special Issue Prostate Cancer Genetics and the Emergence of Targeted Therapies Based on Molecular Profiling)
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