Publications by authors named "Jyotsna Batra"

116 Publications

Identifying Complex lncRNA/Pseudogene-miRNA-mRNA Crosstalk in Hormone-Dependent Cancers.

Biology (Basel) 2021 Oct 9;10(10). Epub 2021 Oct 9.

Centre for Genomics and Personalised Health, School of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD 4000, Australia.

The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs and other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other's expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long-non-coding RNA-associated ceRNA networks. Here, we identify an extended ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of five hormone-dependent (HD) cancers, i.e., prostate, breast, colon, rectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across five HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene-associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding the shared molecular pathogenesis in a group of related diseases.
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http://dx.doi.org/10.3390/biology10101014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533463PMC
October 2021

Integrative Transcriptome-Wide Analyses Uncover Novel Risk-Associated MicroRNAs in Hormone-Dependent Cancers.

Front Genet 2021 26;12:716236. Epub 2021 Aug 26.

Centre for Genomics and Personalised Health, School of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD, Australia.

Background: Hormone-dependent cancers (HDC) are among the leading causes of death worldwide among both men and women. Some of the established risk factors of HDC include unhealthy lifestyles, environmental factors, and genetic influences. Numerous studies have been conducted to understand gene-cancer associations. Transcriptome-wide association studies (TWAS) integrate data from genome-wide association studies (GWAS) and gene expression (expression quantitative trait loci - eQTL) to yield meaningful information on biological pathways associated with complex traits/diseases. Recently, TWAS have enabled the identification of novel associations between HDC risk and protein-coding genes.

Methods: In the present study, we performed a TWAS analysis using the summary data-based Mendelian randomization (SMR)-heterogeneity in dependent instruments (HEIDI) method to identify microRNAs (miRNAs), a group of non-coding RNAs (ncRNAs) associated with HDC risk. We obtained eQTL and GWAS summary statistics from the ncRNA-eQTL database and the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) GWAS Catalog.

Results: We identified 13 TWAS-significant miRNAs at regions (±1 Mb) associated with HDC risk (two, five, one, two, and three miRNAs for prostate, breast, ovarian, colorectal, and endometrial cancers, respectively). Among them, eight novel miRNAs were recognized in HDC risk. Eight protein-coding genes targeted by TWAS-identified miRNAs (, , , , , , , and ) are associated with HDC functions and signaling pathways.

Conclusion: Overall, identifying risk-associated miRNAs across a group of related cancers may help to understand cancer biology and provide novel insights into cancer genetic mechanisms. This customized approach can be applied to identify significant miRNAs in any trait/disease of interest.
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http://dx.doi.org/10.3389/fgene.2021.716236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427606PMC
August 2021

Design and Characterization of a Cell-Penetrating Peptide Derived from the SOX2 Transcription Factor.

Int J Mol Sci 2021 Aug 28;22(17). Epub 2021 Aug 28.

Curtin Medical School, Curtin Health Innovation Research Institute and Curtin Institute for Computation, Curtin University, GPO Box U1987, Perth, WA 6845, Australia.

SOX2 is an oncogenic transcription factor overexpressed in nearly half of the basal-like triple-negative breast cancers associated with very poor outcomes. Targeting and inhibiting SOX2 is clinically relevant as high SOX2 mRNA levels are positively correlated with decreased overall survival and progression-free survival in patients affected with breast cancer. Given its key role as a master regulator of cell proliferation, SOX2 represents an important scaffold for the engineering of dominant-negative synthetic DNA-binding domains (DBDs) that act by blocking or interfering with the oncogenic activity of the endogenous transcription factor in cancer cells. We have synthesized an interference peptide (iPep) encompassing a truncated 24 amino acid long C-terminus of SOX2 containing a potential SOX-specific nuclear localization sequence, and the determinants of the binding of SOX2 to the DNA and to its transcription factor binding partners. We found that the resulting peptide (SOX2-iPep) possessed intrinsic cell penetration and promising nuclear localization into breast cancer cells, and decreased cellular proliferation of SOX2 overexpressing cell lines. The novel SOX2-iPep was found to exhibit a random coil conformation predominantly in solution. Molecular dynamics simulations were used to characterize the interactions of both the SOX2 transcription factor and the SOX2-iPep with FGF4-enhancer DNA in the presence of the POU domain of the partner transcription factor OCT4. Predictions of the free energy of binding revealed that the iPep largely retained the binding affinity for DNA of parental SOX2. This work will enable the future engineering of novel dominant interference peptides to transport different therapeutic cargo molecules such as anti-cancer drugs into cells.
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http://dx.doi.org/10.3390/ijms22179354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431565PMC
August 2021

Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism.

Cancers (Basel) 2021 Jul 17;13(14). Epub 2021 Jul 17.

School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4000, Australia.

Background: Emerging evidence has revealed that genetic variations in microRNA (miRNA) binding sites called miRSNPs can alter miRNA binding in an allele-specific manner and impart prostate cancer (PCa) risk. Two miRSNPs, rs1530865 (G > C) and rs2357637 (C > A), in the 3' untranslated region of pyruvate dehydrogenase kinase 1 (PDK1) have been previously reported to be associated with PCa risk. However, these results have not been functionally validated.

Methods: In silico analysis was used to predict miRNA-PDK1 interactions and was tested using PDK1 knockdown, miRNA overexpression and reporter gene assay.

Results: PDK1 expression was found to be upregulated in PCa metastasis. Further, our results show that PDK1 suppression reduced the migration, invasion, and glycolysis of PCa cells. Computational predictions showed that miR-3916, miR-3125 and miR-3928 had a higher binding affinity for the C allele than the G allele for the rs1530865 miRSNP which was validated by reporter gene assays. Similarly, miR-2116 and miR-889 had a higher affinity for the A than C allele of the rs2357637 miRSNP. Overexpression of miR-3916 and miR-3125 decreased PDK1 protein levels in cells expressing the rs1530865 SNP C allele, and miR-2116 reduced in cells with the rs2357637 SNP A allele.

Conclusions: The present study is the first to report the regulation of the PDK1 gene by miRNAs in an allele-dependent manner and highlights the role of PDK1 in metabolic adaption associated with PCa progression.
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http://dx.doi.org/10.3390/cancers13143582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304593PMC
July 2021

Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium.

Eur J Epidemiol 2021 Sep 18;36(9):913-925. Epub 2021 Jul 18.

Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, University of Quebec, 531 boul. des Prairies, Laval, QC, H7V 1B7, Canada.

While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.
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http://dx.doi.org/10.1007/s10654-021-00781-1DOI Listing
September 2021

Prostate cancer racial, socioeconomic, geographic disparities: targeting the genomic landscape and splicing events in search for diagnostic, prognostic and therapeutic targets.

Am J Cancer Res 2021 15;11(4):1012-1030. Epub 2021 Apr 15.

SAMRC/UP Precision Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield 0028, South Africa.

Prostate cancer (PCa) is one of the leading causes of deaths in men globally. This is a heterogeneous and complex disease that urgently warrants further insight into its pathology. Developed countries have thus far the highest PCa incidence rates, with comparatively low mortality rates. Even though PCa in the Asian population seems to have high incidence and mortality rates, the African countries are emerging as the focal center for this disease. It has also been reported that the Sub-Saharan (SSA) countries have both the highest incidence and mortality rates. To date, few studies have reported the link between PCa and African populations. Adequate evidence is still missing to fully comprehend this relationship. While it has been brought to attention that racial, geographical and socioeconomic status are contributing factors, men of African descent across the globe, irrespective of their geographical position have higher PCa incidence and mortality rates compared to their white counterparts. To date, hormone therapy is the mainstay treatment of PCa, while the dysregulation of androgen receptor (AR) signaling is a hallmark of PCa. One of the emerging problems with this therapeutic approach is resistance to antiandrogens, and that AR splice isoforms implicated in the progression of PCa lack the therapeutic ligand-binding domain (LBD) target. AR splice variants targeted therapy is emerging and in clinical trials. Leveraging PCa transcriptomics is key towards PCa precision medicine. The aim of this review is to outline the PCa epidemiology globally and in Africa, PCa associated risk factors, discuss AR signaling and PCa mechanisms, the role of dysregulated splicing in PCa as novel prognostic indicators and therapeutic targets.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085879PMC
April 2021

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Sci Rep 2021 04 29;11(1):9264. Epub 2021 Apr 29.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10) and 3145 (P < 1 × 10) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-85169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084951PMC
April 2021

Identification and Characterization of Alternatively Spliced Transcript Isoforms of in Prostate Cancer.

Genes (Basel) 2021 04 21;12(5). Epub 2021 Apr 21.

Faculty of Health, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane QLD 4059, Australia.

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management.
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http://dx.doi.org/10.3390/genes12050615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143155PMC
April 2021

Next-Generation Digital Histopathology of the Tumor Microenvironment.

Genes (Basel) 2021 04 7;12(4). Epub 2021 Apr 7.

TissueGnostics GmbH, 1020 Vienna, Austria.

Progress in cancer research is substantially dependent on innovative technologies that permit a concerted analysis of the tumor microenvironment and the cellular phenotypes resulting from somatic mutations and post-translational modifications. In view of a large number of genes, multiplied by differential splicing as well as post-translational protein modifications, the ability to identify and quantify the actual phenotypes of individual cell populations in situ, i.e., in their tissue environment, has become a prerequisite for understanding tumorigenesis and cancer progression. The need for quantitative analyses has led to a renaissance of optical instruments and imaging techniques. With the emergence of precision medicine, automated analysis of a constantly increasing number of cellular markers and their measurement in spatial context have become increasingly necessary to understand the molecular mechanisms that lead to different pathways of disease progression in individual patients. In this review, we summarize the joint effort that academia and industry have undertaken to establish methods and protocols for molecular profiling and immunophenotyping of cancer tissues for next-generation digital histopathology-which is characterized by the use of whole-slide imaging (brightfield, widefield fluorescence, confocal, multispectral, and/or multiplexing technologies) combined with state-of-the-art image cytometry and advanced methods for machine and deep learning.
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http://dx.doi.org/10.3390/genes12040538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068063PMC
April 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Hepatocyte nuclear factor 1 beta: A perspective in cancer.

Cancer Med 2021 03 13;10(5):1791-1804. Epub 2021 Feb 13.

Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Brisbane, QLD, Australia.

Hepatocyte nuclear factor 1 beta (HNF1 β/B) exists as a homeobox transcription factor having a vital role in the embryonic development of organs mainly liver, kidney and pancreas. Initially described as a gene causing maturity-onset diabetes of the young (MODY), HNF1β expression deregulation and single nucleotide polymorphisms in HNF1β have now been associated with several tumours including endometrial, prostate, ovarian, hepatocellular, renal and colorectal cancers. Its function has been studied either as homodimer or heterodimer with HNF1α. In this review, the role of HNF1B in different cancers will be discussed along with the role of its splice variants, and its emerging role as a potential biomarker in cancer.
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http://dx.doi.org/10.1002/cam4.3676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940219PMC
March 2021

SWATH-MS Based Proteomic Profiling of Prostate Cancer Cells Reveals Adaptive Molecular Mechanisms in Response to Anti-Androgen Therapy.

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Faculty of Health, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia.

Prostate cancer (PCa) is the second most common cancer affecting men worldwide. PCa shows a broad-spectrum heterogeneity in its biological and clinical behavior. Although androgen targeted therapy (ATT) has been the mainstay therapy for advanced PCa, it inevitably leads to treatment resistance and progression to castration resistant PCa (CRPC). Thus, greater understanding of the molecular basis of treatment resistance and CRPC progression is needed to improve treatments for this lethal phenotype. The current study interrogated both proteomics and transcriptomic alterations stimulated in AR antagonist/anti-androgen (Bicalutamide and Enzalutamide) treated androgen-dependent cell model (LNCaP) in comparison with androgen-independent/castration-resistant cell model (C4-2B). The analysis highlighted the activation of MYC and PSF/SFPQ oncogenic upstream regulators in response to the anti-androgen treatment. Moreover, the study revealed anti-androgen induced genes/proteins related to transcription/translation regulation, energy metabolism, cell communication and signaling cascades promoting tumor growth and proliferation. In addition, these molecules were found dysregulated in PCa clinical proteomic and transcriptomic datasets, suggesting their potential involvement in PCa progression. In conclusion, our study provides key molecular signatures and associated pathways that might contribute to CRPC progression despite treatment with anti-androgens. Such molecular signatures could be potential therapeutic targets to improve the efficacy of existing therapies and/or predictive/prognostic value in CRPC for treatment response.
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http://dx.doi.org/10.3390/cancers13040715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916382PMC
February 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

COVID-19: Targeting Proteases in Viral Invasion and Host Immune Response.

Front Mol Biosci 2020 9;7:215. Epub 2020 Oct 9.

School of Biomedical Sciences, Faculty of Health, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.

An acute respiratory disorder (COVID-19) that accelerated across the globe has been found to be caused by a novel strain of coronaviruses (SARS-CoV-2). The absence of a specific antiviral drug or vaccination has promoted the development of immediate therapeutic responses against SARS-CoV-2. As increased levels of plasma chemokines and, cytokines and an uncontrolled influx of inflammatory cells were observed in lethal cases, it was concluded that the severity of the infection corresponded with the imbalanced host immunity against the virus. Tracing back the knowledge acquired from SERS and MERS infections, clinical evidence suggested similar host immune reactions and host ACE2 receptor-derived invasion by SARS-CoV-2. Further studies revealed the integral role of proteases (TMPRSS2, cathepsins, plasmin, etc.) in viral entry and the immune system. This review aims to provide a brief review on the latest research progress in identifying the potential role of proteases in SARS-CoV-2 viral spread and infection and combines it with already known information on the role of different proteases in providing an immune response. It further proposes a multidisciplinary clinical approach to target proteases specifically, through a combinatorial administration of protease inhibitors. This predictive review may help in providing a perspective to gain deeper insights of the proteolytic web involved in SARS-CoV-2 viral invasion and host immune response.
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http://dx.doi.org/10.3389/fmolb.2020.00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581869PMC
October 2020

A Pilot Study on the Whole Exome Sequencing of Prostate Cancer in the Indian Phenotype Reveals Distinct Polymorphisms.

Front Genet 2020 25;11:874. Epub 2020 Aug 25.

Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India.

Prostate cancer (PCa) is the third most common cancer among men in India, and no next-generation sequencing (NGS) studies have been attempted earlier. Recent advances in NGS have heralded the discovery of biomarkers from Caucasian/European and Chinese ancestry, but not much is known about the Indian phenotype/variant of PCa. In a pilot study using the whole exome sequencing of benign/PCa patients, we identified characteristic mutations specific to the Indian sub-population. We observed a large number of mutations in DNA repair genes, helicases, TP53, and BRCA besides the variants of unknown significance with a possibly damaging rare variant (rs730881069/chr19:55154172C/TR136Q) in the TNNI3 gene that has been previously reported as a semi-conservative amino acid substitution. Our pilot study attempts to bring an understanding of PCa prognosis and recurrence for the Indian phenotype.
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http://dx.doi.org/10.3389/fgene.2020.00874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477354PMC
August 2020

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.

Cancer Epidemiol Biomarkers Prev 2020 09 24;29(9):1731-1738. Epub 2020 Jun 24.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.

Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.

Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.

Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483627PMC
September 2020

The effect of sample size on polygenic hazard models for prostate cancer.

Eur J Hum Genet 2020 10 8;28(10):1467-1475. Epub 2020 Jun 8.

Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.
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http://dx.doi.org/10.1038/s41431-020-0664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608255PMC
October 2020

Pathway Analysis of Genes Identified through Post-GWAS to Underpin Prostate Cancer Aetiology.

Genes (Basel) 2020 05 8;11(5). Epub 2020 May 8.

School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059, Australia.

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 or 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.
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http://dx.doi.org/10.3390/genes11050526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291227PMC
May 2020

A New Era of Prostate Cancer Precision Medicine.

Front Oncol 2019 26;9:1263. Epub 2019 Nov 26.

School of Biomedical Sciences, Queensland University of Technology, Institute of Health and Biomedical Innovation, Brisbane, QLD, Australia.

Prostate cancer is the second most common male cancer affecting Western society. Despite substantial advances in the exploration of prostate cancer biomarkers and treatment strategies, men are over diagnosed with inert prostate cancer, while there is also a substantial mortality from the invasive disease. Precision medicine is the management of treatment profiles across different cancers predicting therapies for individual cancer patients. With strategies including individual genomic profiling and targeting specific cancer pathways, precision medicine for prostate cancer has the potential to impose changes in clinical practices. Some of the recent advances in prostate cancer precision medicine comprise targeting gene fusions, genome editing tools, non-coding RNA biomarkers, and the promise of liquid tumor profiling. In this review, we will discuss these recent scientific advances to scale up these approaches and endeavors to overcome clinical barriers for prostate cancer precision medicine.
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http://dx.doi.org/10.3389/fonc.2019.01263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901987PMC
November 2019

Differential roles of protease isoforms in the tumor microenvironment.

Cancer Metastasis Rev 2019 09;38(3):389-415

School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.

Alternative splicing of precursor mRNA is a key mediator of gene expression regulation leading to greater diversity of the proteome in complex organisms. Systematic sequencing of the human genome and transcriptome has led to our understanding of how alternative splicing of critical genes leads to multiple pathological conditions such as cancer. For many years, proteases were known only for their roles as proteolytic enzymes, acting to regulate/process proteins associated with diverse cellular functions. However, the differential expression and altered function of various protease isoforms, such as (i) anti-apoptotic activities, (ii) mediating intercellular adhesion, and (iii) modifying the extracellular matrix, are evidence of their specific contribution towards shaping the tumor microenvironment. Revealing the alternative splicing of protease genes and characterization of their protein products/isoforms with distinct and opposing functions creates a platform to understand how protease isoforms contribute to specific cancer hallmarks. Here, in this review, we address cancer-specific isoforms produced by the alternative splicing of proteases and their distinctive roles in the tumor microenvironment.
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http://dx.doi.org/10.1007/s10555-019-09816-2DOI Listing
September 2019

Beyond the biomarker role: prostate-specific antigen (PSA) in the prostate cancer microenvironment.

Cancer Metastasis Rev 2019 09;38(3):333-346

School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.

The prostate-specific antigen (PSA) blood test is the accepted biomarker of tumor recurrence. PSA levels in serum correlate with disease progression, though its diagnostic accuracy is questionable. As a result, significant progress has been made in developing modified PSA tests such as PSA velocity, PSA density, 4Kscore, PSA glycoprofiling, Prostate Health Index, and the STHLM3 test. PSA, a serine protease, is secreted from the epithelial cells of the prostate. PSA has been suggested as a molecular target for prostate cancer therapy due to the fact that it is not only active in prostate tissue but also has a pivotal role on prostate cancer signaling pathways including proliferation, invasion, metastasis, angiogenesis, apoptosis, immune response, and tumor microenvironment regulation. Here, we summarize the current standing of PSA in prostate cancer progression as well as its utility in prostate cancer therapeutic approaches with an emphasis on the role of PSA in the tumor microenvironment.
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http://dx.doi.org/10.1007/s10555-019-09815-3DOI Listing
September 2019

The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer.

Mol Oncol 2020 01 28;14(1):105-128. Epub 2019 Nov 28.

Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Institute of Health & Biomedical Innovation, Queensland University of Technology, Woolloongabba, Australia.

Kallikrein-related peptidase 14 (KLK14) is one of the several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumor microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analyzed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic, and in vitro assays with the goal to identify substrates, related-signaling pathways, and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neoadjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression reoccurred in patients who developed castrate-resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14 substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14-regulated genes (Interleukin 32, midkine, SRY-Box 9), particularly an involvement of the mitogen-activated protein kinase 1 and interleukin 1 receptor pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumors. Additional work is necessary to determine the benefits and implications of targeting/cotargeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment.
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http://dx.doi.org/10.1002/1878-0261.12587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944120PMC
January 2020

Encapsulation and Controlled Release of Resveratrol Within Functionalized Mesoporous Silica Nanoparticles for Prostate Cancer Therapy.

Front Bioeng Biotechnol 2019 18;7:225. Epub 2019 Sep 18.

School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.

Resveratrol (RES) is a naturally existing polyphenol which exhibits anti-oxidant, anti-inflammatory, and anti-cancer properties. In recent years, RES has attracted attention for its synergistic effect with other anti-cancer drugs for the treatment of drug resistant cancers. However, RES faces the issues of poor pharmacokinetics, stability and low solubility which limits its clinical application. In present study, RES has been loaded onto uniformly sized (~60 nm) mesoporous silica nanoparticles (MSNs) to improve its anti-proliferative activity and sensitization of Docatexal in hypoxia induced drug resistance in prostate cancer. RES was efficiently encapsulated within phosphonate (negatively charged) and amine (positively charged) modified MSNs. The effect of surface functionalization was studied on the loading, release, anti-proliferative and cytotoxic potential of RES using prostate cancer cell line. At pH 7.4 both free and NH-MSNs loaded RES showed burst release which was plateaued with almost 90% of drug released in first 12 h. On the other hand, PO-MSNs showed significantly slower release kinetics with only 50% drug release in first 12 h at pH 7.4. At pH 5.5, however, both the PO-MSNs and NH-MSNs showed significant control over release (around 40% less release compared with free RES in 24 h). Phosphonate modified MSNs significantly enhanced the anti-proliferative potential of RES with an IC of 7.15 μM as compared to 14.86 μM of free RES whereas amine modified MSNs didn't affect proliferation with an IC value higher than free RES (20.45 μM). Furthermore, RES loaded onto PO-MSNs showed robust and dose dependent sensitization of Docatexal in hypoxic cell environment which was comparable to pure RES solution. This study provides an example of applicability of MSNs loaded with polyphenols such as RES as next generation anticancer formulations for treating drug resistant cancers such as prostate cancer.
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http://dx.doi.org/10.3389/fbioe.2019.00225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759778PMC
September 2019

Editorial: Establishing Genetic Pleiotropy to Identify Common Pharmacological Agents for Common Diseases.

Front Pharmacol 2019 13;10:1038. Epub 2019 Sep 13.

Molecular Cancer Epidemiology Laboratory, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

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http://dx.doi.org/10.3389/fphar.2019.01038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753863PMC
September 2019

Profiling MicroRNA Markers in Plasma: Looking into Better Approaches and Recommendations.

Methods Mol Biol 2019 ;2054:93-103

School of Biomedical Sciences, Institute of Health and Biomedical Innovation (IHBI), Translational Research Institute, Queensland University of Technology (QUT), Brisbane, QLD, Australia.

The revelation of stable microRNA (miRNA) species in body fluids has led to the speculation of disease-related alterations in miRNA expression levels as indicative of disease state making them attractive minimally invasive biomarkers for the diagnosis and prognosis of cancer and other diseases. Although miRNA expression profiling in body fluids holds great promise, working with low amounts of RNA in plasma and serum represents several challenges during purification, relative quantification, normalization, and data analysis. Here, we present an experimental protocol for miRNA profiling in plasma using plasma/serum-specific miRNA purification and RT-qPCR to identify potential miRNA biomarkers. We also discuss the challenges encountered during the miRNA profiling process and provide recommendations for robust purification and relative quantification of miRNAs in patient plasma samples.
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http://dx.doi.org/10.1007/978-1-4939-9769-5_5DOI Listing
June 2020

Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism.

Clin Chem 2019 09 17;65(9):1090-1101. Epub 2019 May 17.

School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia;

Background: Metabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.

Content: miRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.

Summary: In this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.
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http://dx.doi.org/10.1373/clinchem.2018.299651DOI Listing
September 2019
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