Similar Datasets
Project description:Metastatic, castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer with a high mortality rate due to a current lack of treatment options. While much is already known about how mutations in protein-coding sequences across the genome affect prostate cancer, somatic mutations occurring in the 3’ untranslated regions (3’UTRs) of genes are largely unstudied. The 3’UTR is a genomic region that controls post-transcriptional gene expression through its recruitment of trans-acting factors such as RNA-binding proteins (RBPs) and microRNAs (miRNAs), which themselves are known to be oncogenes and tumor suppressors in many cases. To better understand the role of 3’UTR mutations across prostate cancer, we have created a database of 3’UTR somatic mutations in 185 patients with mCRPC, discovering 14,497 single-nucleotide mutations throughout the 3’UTRome. In order to functionally assay these variants, we have developed a novel pair of massively parallel reporter assays (MPRA) able to determine the effect of thousands of patient somatic mutations on post-transcriptional gene expression. In this two-pronged approach, we are able to measure whether each of 6,892 mutations found in recurrently mutated 3’UTRs affect mRNA stability, steady-state transcript level, and translation efficiency. This deep functional assessment of thousands of 3’UTR mutations allows us to uncover patterns in mutation functionality, including their association with RNA motifs and sequence conservation. Investigation into how the resultant gene expression changes from 3’UTR mutations affect prostate cancer pathogenesis, such as cancer growth or response to treatment, is also underway. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation efficiency, and cancer phenotypes, expanding the boundaries of functional cancer genomics and potentially uncovering novel therapeutic targets in previously unexplored regulatory regions.
2023-06-30 | GSE200303 | GEO
Project description:Metastatic, castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer with a high mortality rate due to a current lack of treatment options. While much is already known about how mutations in protein-coding sequences across the genome affect prostate cancer, somatic mutations occurring in the 3’ untranslated regions (3’UTRs) of genes are largely unstudied. The 3’UTR is a genomic region that controls post-transcriptional gene expression through its recruitment of trans-acting factors such as RNA-binding proteins (RBPs) and microRNAs (miRNAs), which themselves are known to be oncogenes and tumor suppressors in many cases. To better understand the role of 3’UTR mutations across prostate cancer, we have created a database of 3’UTR somatic mutations in 185 patients with mCRPC, discovering 14,497 single-nucleotide mutations throughout the 3’UTRome. In order to functionally assay these variants, we have developed a novel pair of massively parallel reporter assays (MPRA) able to determine the effect of thousands of patient somatic mutations on post-transcriptional gene expression. In this two-pronged approach, we are able to measure whether each of 6,892 mutations found in recurrently mutated 3’UTRs affect mRNA stability, steady-state transcript level, and translation efficiency. This deep functional assessment of thousands of 3’UTR mutations allows us to uncover patterns in mutation functionality, including their association with RNA motifs and sequence conservation. Investigation into how the resultant gene expression changes from 3’UTR mutations affect prostate cancer pathogenesis, such as cancer growth or response to treatment, is also underway. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation efficiency, and cancer phenotypes, expanding the boundaries of functional cancer genomics and potentially uncovering novel therapeutic targets in previously unexplored regulatory regions.
2023-06-30 | GSE217530 | GEO
Project description:Metastatic, castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer with a high mortality rate due to a current lack of treatment options. While much is already known about how mutations in protein-coding sequences across the genome affect prostate cancer, somatic mutations occurring in the 3’ untranslated regions (3’UTRs) of genes are largely unstudied. The 3’UTR is a genomic region that controls post-transcriptional gene expression through its recruitment of trans-acting factors such as RNA-binding proteins (RBPs) and microRNAs (miRNAs), which themselves are known to be oncogenes and tumor suppressors in many cases. To better understand the role of 3’UTR mutations across prostate cancer, we have created a database of 3’UTR somatic mutations in 185 patients with mCRPC, discovering 14,497 single-nucleotide mutations throughout the 3’UTRome. In order to functionally assay these variants, we have developed a novel pair of massively parallel reporter assays (MPRA) able to determine the effect of thousands of patient somatic mutations on post-transcriptional gene expression. In this two-pronged approach, we are able to measure whether each of 6,892 mutations found in recurrently mutated 3’UTRs affect mRNA stability, steady-state transcript level, and translation efficiency. This deep functional assessment of thousands of 3’UTR mutations allows us to uncover patterns in mutation functionality, including their association with RNA motifs and sequence conservation. Investigation into how the resultant gene expression changes from 3’UTR mutations affect prostate cancer pathogenesis, such as cancer growth or response to treatment, is also underway. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation efficiency, and cancer phenotypes, expanding the boundaries of functional cancer genomics and potentially uncovering novel therapeutic targets in previously unexplored regulatory regions.
2023-06-30 | GSE200302 | GEO
Project description:A genome-wide functional study of 3’UTR mutations in advanced prostate cancer
| PRJNA824026 | ENA
Project description:A genome-wide functional study of 3’UTR mutations in advanced prostate cancer [DNA-seq]
| PRJNA824032 | ENA
Project description:A genome-wide functional study of 3’UTR mutations in advanced prostate cancer [Polysome-Seq]
| PRJNA824033 | ENA
Project description:A genome-wide functional study of 3’UTR mutations in advanced prostate cancer [RNA-seq]
| PRJNA899485 | ENA
Project description:MicroRNAs (miRNAs) are involved in the regulation of gene expression via incomplete base pairing to sequence motifs at the three prime untranslated regions (3'-UTRs) of mRNAs and play critical roles in the etiology of cancers. Single nucleotide polymorphisms (SNPs) in the 3'-UTR miRNA-binding regions may influence the miRNA affinity. However, this biological mechanism in prostate cancer (PCa) remains unclear. Here, a three-stage genome-wide association study of 3'-UTR SNPs (n=33 117) is performed in 5515 Chinese men. Three genome-wide significant variants are discovered at 8p21.2 (rs1567669, rs4872176, and rs4872177), which are all located in a linkage disequilibrium region of the NKX3-1 gene. Phenome-wide association analysis using the FinnGen data reveals a specific association of rs1567669 with PCa over 2,264 disease endpoints. Expression quantitative trait locus analyses based on both Chinese PCa cohort and the GTEx database show that risk alleles of these SNPs are significantly associated with low expression of NKX3-1. Based on the MirSNP database, dual-luciferase reporter assays show that risk alleles of these SNPs downregulate the expression of NKX3-1 via increased miRNA binding. These results indicate that the SNPs at the 3'-UTR of NKX3-1 significantly downregulate NKX3-1 expression by influencing the affinity of miRNA and increase the PCa risk.
| S-EPMC9376745 | biostudies-literature
Project description:A pressing clinical issue in prostate cancer is to distinguish which men will have an indolent or aggressive course of disease. Clinical variables such as Gleason grade and stage are useful predictors of lethal cancer; however, the low predictive values of the common Gleason scores, changes in grading over time, and earlier diagnosis of patients due to screening limits their clinical utility. Identifying genetic variants associated with lethal prostate cancer could inform clinical decision making.We conducted a genome-wide association study, comparing lethal prostate cancer cases to cases surviving at least 10 years beyond their initial diagnosis. Genotyping was done with the Affymetrix 5.0 chip [?500,000 single nucleotide polymorphisms (SNP) and 1,483 copy number variants (CNV)] on DNA from participants in the Physicians' Health Study and Health Professionals Follow-up Study (196 lethal cases, 368 long-term survivors). After excluding SNPs and individuals based on quality control criteria, logistic regression assuming an additive model was done using the PLINK software.No SNP reached genome-wide significance (P ? 1 × 10(-7)); however, three independent SNPs had P < 1 × 10(-5). One top-ranked SNP replicated (P = 0.05) in an independent follow-up study. Although no CNV had genome-wide significance, 14 CNVs showed nominal association with prostate cancer mortality (P < 0.05).No variants were significantly associated at a genome-wide level with prostate cancer mortality. Common genetic determinants of lethal prostate cancer are likely to have odds ratios <2.0.Genetic markers identified could provide biological insight to improve therapy for men with potentially fatal cancer. Larger studies are necessary to detect the genetic causes of prostate cancer mortality.
| S-EPMC3197738 | biostudies-literature
Project description:BACKGROUND:Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS:We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). RESULTS:We observed no significant association between genetic variants and prostate cancer survival. CONCLUSIONS:Common genetic variants with large impact on prostate cancer survival were not observed in this study. IMPACT:Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.
| S-EPMC5674990 | biostudies-literature