Genome-Wide Scan for Genetic Variants Associated with Early Onset Prostate Cancer
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ABSTRACT:
PROVIDER: PRJNA338514 | ENA |
REPOSITORIES: ENA
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Project description:<p>This is a genome-wide association scan of 931 early-onset prostate cancer cases of European ancestry. The samples were selected from prostate cancer studies at the University of Michigan. Controls were previously genotyped individuals selected from the Cancer Genetics Markers of Susceptibility (CGEMS) and Illumina's iControlDB database.</p>
| phs001185 | dbGaP
Project description:Prostate cancer is the most common non-skin cancer and the second leading cause of cancer related mortality for men in the United States. There is strong empirical and epidemiological evidence supporting a stronger role of genetics in early-onset prostate cancer. We performed a genome-wide association scan for early-onset prostate cancer. Novel aspects of this study include the focus on early-onset disease (defined as men with prostate cancer diagnosed before age 56 years) and use of publically available control genotype data from previous genome-wide association studies. We found genome-wide significant (p<5×10(-8)) evidence for variants at 8q24 and 11p15 and strong supportive evidence for a number of previously reported loci. We found little evidence for individual or systematic inflated association findings resulting from using public controls, demonstrating the utility of using public control data in large-scale genetic association studies of common variants. Taken together, these results demonstrate the importance of established common genetic variants for early-onset prostate cancer and the power of including early-onset prostate cancer cases in genetic association studies.
| S-EPMC3989171 | biostudies-literature
Project description:Prostate cancer (PrCa) manifests substantial variation in incidence rates among distinct populations. African American (AA) men are more likely to be diagnosed with and die from PrCa than European American (EA) men. Despite ongoing advancements in identifying polygenic risk variants from large genome-wide association study (GWAS) cohorts, the genetic mechanisms underlying the higher prevalence of PrCa in AA men remain unclear. A systematic approach that does not rely on extensive cohorts to identify causal regulatory variants contributing to PrCa development is still lacking. Here, by employing a sequence-based deep learning model of prostate regulatory enhancers, we identified ~2,000 essential SNPs (eSNPs) with increased alternative allele frequency in AA and which potentially affect the enhancer function leading to greater PrCa susceptibility. The identified eSNPs potentially mediate PrCa development through two complementary mechanisms: alternative alleles with increased enhancer activity are associated with immune system suppression, while those with decreased enhancer activity are linked to differentiation processes. Interestingly, the eSNPs disrupt the binding of key prostate transcription factors including FOX, AR and HOX families, collectively contributing to PrCa predisposition. Together these eSNPs can be used to assess polygenic risk score that is more effective than previous GWAS-based risk scores in distinguishing individuals with PrCa from the control.
2025-08-19 | GSE276748 | GEO
Project description:Genome-Wide Scan for Genetic Variants Associated with Early Onset Prostate Cancer
| PRJNA338515 | ENA
Project description:The hereditary spastics paraplegias (HSPs) are a group of over 80 neurogenetic disorders that share the feature of progressive lower limb spasticity. Bi-allelic loss-of-function variants in the RINT1 gene have been implicated in acute liver failure in the pediatric population, and were recently described to lead to a complex form of HSP in three children with early-onset spastic paraplegia, ataxia, optic nerve hypoplasia with significant vision impairment, dysmorphic features, and a thin corpus callosum. We read the article by Launay et al. with great interest and would like to add a fourth case due to novel biallelic RINT1 variants presenting with a largely ‘pure’ form of HSP including one missense variant and one splice site variant identifier by whole genome sequencing.
2025-08-31 | GSE270806 | GEO
Project description:Early Onset Malignancies Initiative
| PRJNA597501 | ENA
Project description:Early Onset Malignancies Initiative
| PRJNA597502 | ENA
Project description:The spliced variant forms of androgen receptor (AR-Vs) have been identified recently in castration-resistant prostate cancer (CRPC) cell lines and clinical samples. Here we identified the cistrome and transcriptome landscape of AR-Vs in CRPC cell lines and determine the clinical significance of AR variants regulated gene.The AR variants binding sites can be identified in 22Rv1 cell line in the absence of androgen. Knocking down full-length AR (AR-FL) doesn't affect AR-Vs binding sites in genome-wide. A set of genes were identified to be regulated uniquely by AR-Vs, but not by AR-FL in androgen-depleted condition. Integrated analysis showed that some genes may be modulated by AR-Vs directly. Unsupervised clustering analysis demonstrated that AR variants gene signature can separate not only the benign and malignant prostate tissue, but also the localized prostate cancer and metastatic CRPC specimens. Some genes modulated uniquely by AR variants were also identified to correlate with the Gleason Pattern of prostate cancer and PSA failure. We conclude that AR spliced variants bind to DNA independent of full-length AR, and can modulate a unique set of genes which is not regulated by full-length AR in the absence of androgen. AR variants gene signature correlate with CRPC and prostate cnacer disease progress. Androgen receptor (AR) binding sites in human prostate cancer 22Rv1 cell lines were studied using ChIP-seq. ChIP enriched and input DNA were sequenced using Illumina HiSeq 2000.
2014-09-10 | E-GEOD-58478 | biostudies-arrayexpress
Project description:Background: Numerous germline genetic variants are associated with prostate cancer risk, but their biological role is not well understood. One possibility is that these variants influence gene expression in prostate tissue. We therefore examined the association of prostate cancer risk variants with the expression of genes nearby and genome-wide. Methods: We generated mRNA expression data for 20,254 genes with the Affymetrix GeneChip Human Gene 1.0 ST microarray from normal prostate (N=160) and prostate tumor (N=264) tissue from participants of the Physicians’ Health Study and Health Professionals Follow-up Study. With linear models, we tested the association of 39 risk variants with nearby genes and all genes, and the association of each variant with canonical pathways using a global test. Results: In addition to confirming previously reported associations, we detected several new significant (p<0.05) associations of variants with the expression of nearby genes including C2orf43, ITGA6, MLPH, CHMP2B, BMPR1B, and MTL5. Genome-wide, four genes (MSMB, NUDT11, NEFM, KLHL33) were significantly associated after accounting for multiple comparisons for each SNP (p<2.5x10-6). Many more genes had a false discovery rate <10%, including SRD5A1 and PSCA, and we observed significant associations with pathways in tumor tissue. Conclusions: The risk variants were associated with several genes, including promising prostate cancer candidates and lipid metabolism pathways, suggesting mechanisms for their impact on disease. These genes should be further explored in biological and epidemiological studies. Impact: Determining the biological role of these variants can lead to improved understanding of prostate cancer etiology and identify new targets for chemoprevention.
2014-12-01 | GSE62872 | GEO
Project description:Novel Bi-Allelic Variants in RINT1 Presenting As Early-Onset Pure Hereditary Spastic Paraplegia
| PRJNA1128538 | ENA