scholarly journals Interactions between Germline and Somatic Mutated Genes in Aggressive Prostate Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Tarun Karthik Kumar Mamidi ◽  
Jiande Wu ◽  
Chindo Hicks
Keyword(s):  
Prostate Cancer ◽  
Somatic Mutations ◽  
Association Studies ◽  
Gene Signature ◽  
Tumor Formation ◽  
Biological Pathways ◽  
The Cancer Genome Atlas ◽  
Molecular Networks ◽  
Genome Wide Association Studies ◽  
Somatic Variation

Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the USA. Advances in high-throughput genotyping and next generation sequencing technologies have enabled discovery of germline genetic susceptibility variants and somatic mutations acquired during tumor formation. Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic variation and their role in aggressive PCa remain largely unexplored. Here we investigated the possible oncogenic interactions and cooperation between genes containing germline variation from genome-wide association studies (GWAS) and genes containing somatic mutations from tumor genomes of 305 men with aggressive tumors and 52 control samples from The Cancer Genome Atlas (TCGA). Network and pathway analysis were performed to identify molecular networks and biological pathways enriched for germline and somatic mutations. The analysis revealed 90 functionally related genes containing both germline and somatic mutations. Transcriptome analysis revealed a 61-gene signature containing both germline and somatic mutations. Network analysis revealed molecular networks of functionally related genes and biological pathways including P53, STAT3, NKX3-1, KLK3, and Androgen receptor signaling pathways enriched for germline and somatic mutations. The results show that integrative analysis is a powerful approach to uncovering the possible oncogenic interactions and cooperation between germline and somatic mutations and understanding the broader biological context in which they operate in aggressive PCa.

scholarly journals Elucidation of the Genomic-Epigenomic Interaction Landscape of Aggressive Prostate Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Tarun Karthik Kumar Mamidi ◽  
Jiande Wu ◽  
Chindo Hicks
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Association Studies ◽  
Unmet Need ◽  
The Cancer Genome Atlas ◽  
Intermediate Phenotype ◽  
Molecular Networks ◽  
Signalling Pathways ◽  
Genome Wide Association Studies ◽  
Aberrant Dna Methylation

Background. Majority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa. Methods. We addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype. Results. The investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa. Conclusions. The study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.

scholarly journals An Integrative Genomics Approach for Associating Genome-Wide Association Studies Information With Localized and Metastatic Prostate Cancer Phenotypes

2017 ◽  
Vol 12 ◽  
pp. 117727191769581 ◽  
Author(s):  
Chindo Hicks ◽  
Ritika Ramani ◽  
Oliver Sartor ◽  
Ritu Bhalla ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Susceptibility ◽  
Metastatic Prostate Cancer ◽  
Association Studies ◽  
Biological Pathways ◽  
Genome Wide Association ◽  
Molecular Networks ◽  
Genome Wide Association Studies ◽  
Disease States ◽  
Genome Wide

High-throughput genotyping has enabled discovery of genetic variants associated with an increased risk of developing prostate cancer using genome-wide association studies (GWAS). The goal of this study was to associate GWAS information of patients with primary organ–confined and metastatic prostate cancer using gene expression data and to identify molecular networks and biological pathways enriched for genetic susceptibility variants involved in the 2 disease states. The analysis revealed gene signatures for the 2 disease states and a gene signature distinguishing the 2 patient groups. In addition, the analysis revealed molecular networks and biological pathways enriched for genetic susceptibility variants. The discovered pathways include the androgen, apoptosis, and insulinlike growth factor signaling pathways. This analysis established putative functional bridges between GWAS discoveries and the biological pathways involved in primary organ–confined and metastatic prostate cancer.

scholarly journals Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 615
Author(s):  
Achala Fernando ◽  
Chamikara Liyanage ◽  
Afshin Moradi ◽  
Panchadsaram Janaththani ◽  
Jyotsna Batra
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Expression Profiles ◽  
Association Studies ◽  
Protein Isoforms ◽  
The Cancer Genome Atlas ◽  
Mass Spectrometry Analysis ◽  
Functional Domains ◽  
Homeodomain Protein ◽  
Genome Wide Association Studies

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.

scholarly journals Integrative Genomic Analysis for the Discovery of Biomarkers in Prostate Cancer

2014 ◽  
Vol 9 ◽  
pp. BMI.S13729 ◽  
Author(s):  
Chindo Hicks ◽  
Tejaswi Koganti ◽  
Shankar Giri ◽  
Memory Tekere ◽  
Ritika Ramani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Gene Expression Data ◽  
Genetic Variants ◽  
Association Studies ◽  
Biological Pathways ◽  
Great Success ◽  
Genome Wide Association Studies ◽  
Expression Data ◽  
Increased Risk

Genome-wide association studies (GWAS) have achieved great success in identifying single nucleotide polymorphisms (SNPs, herein called genetic variants) and genes associated with risk of developing prostate cancer. However, GWAS do not typically link the genetic variants to the disease state or inform the broader context in which the genetic variants operate. Here, we present a novel integrative genomics approach that combines GWAS information with gene expression data to infer the causal association between gene expression and the disease and to identify the network states and biological pathways enriched for genetic variants. We identified gene regulatory networks and biological pathways enriched for genetic variants, including the prostate cancer, IGF-1, JAK2, androgen, and prolactin signaling pathways. The integration of GWAS information with gene expression data provides insights about the broader context in which genetic variants associated with an increased risk of developing prostate cancer operate.

scholarly journals Functional annotation of risk loci identified through genome-wide association studies for prostate cancer

The Prostate ◽  
2010 ◽  
Vol 71 (9) ◽  
pp. 955-963 ◽  
Author(s):  
Yizhen Lu ◽  
Zheng Zhang ◽  
Hongjie Yu ◽  
S. Lily Zheng ◽  
William B. Isaacs ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Functional Annotation ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Exome-Wide Pan-Cancer Analysis of Germline Variants in 8,719 Individuals Finds Little Evidence of Rare Variant Associations

2021 ◽  
pp. 1-10
Author(s):  
Zoe Guan ◽  
Ronglai Shen ◽  
Colin B. Begg
Keyword(s):  
Rare Variant ◽  
Rare Variants ◽  
Association Studies ◽  
The Cancer Genome Atlas ◽  
Considerable Proportion ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Risk Variants ◽  
Cancer Types ◽  
Pan Cancer

<b><i>Background:</i></b> Many cancer types show considerable heritability, and extensive research has been done to identify germline susceptibility variants. Linkage studies have discovered many rare high-risk variants, and genome-wide association studies (GWAS) have discovered many common low-risk variants. However, it is believed that a considerable proportion of the heritability of cancer remains unexplained by known susceptibility variants. The “rare variant hypothesis” proposes that much of the missing heritability lies in rare variants that cannot reliably be detected by linkage analysis or GWAS. Until recently, high sequencing costs have precluded extensive surveys of rare variants, but technological advances have now made it possible to analyze rare variants on a much greater scale. <b><i>Objectives:</i></b> In this study, we investigated associations between rare variants and 14 cancer types. <b><i>Methods:</i></b> We ran association tests using whole-exome sequencing data from The Cancer Genome Atlas (TCGA) and validated the findings using data from the Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG). <b><i>Results:</i></b> We identified four significant associations in TCGA, only one of which was replicated in PCAWG (BRCA1 and ovarian cancer). <b><i>Conclusions:</i></b> Our results provide little evidence in favor of the rare variant hypothesis. Much larger sample sizes may be needed to detect undiscovered rare cancer variants.

scholarly journals Functional genomic approaches to improve crop plant heat stress tolerance

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1721 ◽  
Author(s):  
Baljeet Singh ◽  
Neha Salaria ◽  
Kajal Thakur ◽  
Sarvjeet Kukreja ◽  
Shristy Gautam ◽  
...  
Keyword(s):  
Heat Stress ◽  
Stress Tolerance ◽  
Association Studies ◽  
Subtractive Hybridization ◽  
Molecular Networks ◽  
Genome Wide Association Studies ◽  
Functional Genomic ◽  
Genome Wide ◽  
Signalling Network ◽  
Heat Stress Tolerance

Heat stress as a yield limiting issue has become a major threat for food security as global warming progresses. Being sessile, plants cannot avoid heat stress. They respond to heat stress by activating complex molecular networks, such as signal transduction, metabolite production and expressions of heat stress-associated genes. Some plants have developed an intricate signalling network to respond and adapt it. Heat stress tolerance is a polygenic trait, which is regulated by various genes, transcriptional factors, proteins and hormones. Therefore, to improve heat stress tolerance, a sound knowledge of various mechanisms involved in the response to heat stress is required. The classical breeding methods employed to enhance heat stress tolerance has had limited success. In this era of genomics, next generation sequencing techniques, availability of genome sequences and advanced biotechnological tools open several windows of opportunities to improve heat stress tolerance in crop plants. This review discusses the potential of various functional genomic approaches, such as genome wide association studies, microarray, and suppression subtractive hybridization, in the process of discovering novel genes related to heat stress, and their functional validation using both reverse and forward genetic approaches. This review also discusses how these functionally validated genes can be used to improve heat stress tolerance through plant breeding, transgenics and genome editing approaches.

scholarly journals Generalizability of Associations from Prostate Cancer Genome-Wide Association Studies in Multiple Populations

2009 ◽  
Vol 18 (4) ◽  
pp. 1285-1289 ◽  
Author(s):  
Kevin M. Waters ◽  
Loic Le Marchand ◽  
Laurence N. Kolonel ◽  
Kristine R. Monroe ◽  
Daniel O. Stram ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Association Studies ◽  
Cancer Genome ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Multiple Populations ◽  
Genome Wide

scholarly journals A health disparities study of MicroRNA-146a expression in prostate cancer samples derived from African American and European American patients

2020 ◽  
Vol 10 (2) ◽  
pp. 1
Author(s):  
Monet Stevenson ◽  
Narendra Narendra Banerjee ◽  
Narendra Banerjee ◽  
Kuldeep Rawat ◽  
Lin Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Association Studies ◽  
Single Gene ◽  
Micro Rna ◽  
Genome Wide Association Studies ◽  
Racial Groups ◽  
Protein Coding ◽  
Rna Molecules ◽  
Prostate Carcinogenesis

Considering the prevalence of prostate cancer all over the world, it is desired to have tools, technologies, and biomarkers which help in early detection of the disease and discriminate different races and ethnic groups. Genetic information from the single gene analysis and genome-wide association studies have identified few biomarkers, however, the drivers of prostate cancer remain unknown in the majority of prostate cancer patients. In those cases where genetic association has been identified, the genes confer only a modest risk of this cancer, hence, making them less relevant for risk counseling and disease management. There is a need for additional biomarkers for diagnosis and prognosis of prostate cancer. MicroRNAs are a class of non-protein coding RNA molecules that are frequently dysregulated in different cancers including prostate cancer and show promise as diagnostic biomarkers and targets for therapy. Here we describe the role of micro RNA 146a (miR-146a) which may serve as a diagnostic and prognostic marker for prostate cancer, as indicated from the data presented in this report. Also, a pilot study indicated differential expression of miR-146a in prostate cancer cell lines and tissues from different racial groups. Reduced expression of miR-146a was observed in African American tumor tissues compared to those from European Whites This report provides a novel insight into understanding the prostate carcinogenesis.

scholarly journals 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ryo Takata ◽  
Atsushi Takahashi ◽  
Masashi Fujita ◽  
Yukihide Momozawa ◽  
Edward J. Saunders ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
European Population ◽  
Genome Wide Association ◽  
High Risk Population ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Genome Wide

Abstract Genome-wide association studies (GWAS) have identified ~170 genetic loci associated with prostate cancer (PCa) risk, but most of them were identified in European populations. We here performed a GWAS and replication study using a large Japanese cohort (9,906 cases and 83,943 male controls) to identify novel susceptibility loci associated with PCa risk. We found 12 novel loci for PCa including rs1125927 (TMEM17, P = 3.95 × 10−16), rs73862213 (GATA2, P = 5.87 × 10−23), rs77911174 (ZMIZ1, P = 5.28 × 10−20), and rs138708 (SUN2, P = 1.13 × 10−15), seven of which had crucially low minor allele frequency in European population. Furthermore, we stratified the polygenic risk for Japanese PCa patients by using 82 SNPs, which were significantly associated with Japanese PCa risk in our study, and found that early onset cases and cases with family history of PCa were enriched in the genetically high-risk population. Our study provides important insight into genetic mechanisms of PCa and facilitates PCa risk stratification in Japanese population.

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