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A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231751 | GEO | 2023/07/11

REPOSITORIES: GEO

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A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus [RNA-Seq]

Project description:To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer (PCa) risk region is a particularly strong expression quantitative trait locus (eQTL) for IRX4 transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (47bp/21bp) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP PCa cells (homozygous for the short allele), a single copy knock-in of the long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, H3K27 acetylation, and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional PCa risk loci. We estimated that at least 5% of PCa risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.

2023-07-11 | GSE231747 | GEO

A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ATAC-Seq]

2023-07-11 | GSE231750 | GEO

A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ChIP-Seq]

2023-07-11 | GSE231748 | GEO

A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus

Project description:A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus

| PRJNA967606 | ENA

A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus [RNA-Seq]

Project description:A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus [RNA-Seq]

| PRJNA967618 | ENA

A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ChIP-Seq]

Project description:A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ChIP-Seq]

| PRJNA967617 | ENA

A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ATAC-Seq]

Project description:A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ATAC-Seq]

| PRJNA967620 | ENA

A single nucleotide polymorphism in <i>CYP1B1</i> leads to differential prostate cancer risk and telomere length.

Project description:BACKGROUND: Cytochrome P450 1B1 (CYP1B1) is a key enzyme in its oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Functionally relevant genetic variants within CYP1B1 may affect the telomere length and subsequently lead to prostate carcinogenesis. METHODS: We evaluated 8 CYP1B1 tag single nucleotide polymorphisms (SNPs) in 1015 men with prostate cancer (PCa) and 1052 cancer-free controls, and calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate their association with risk of PCa. The influence of CYP1B1 SNPs on the relative telomere lengths was then appraised in peripheral blood leukocytes using real-time PCR. RESULTS:CYP1B1 rs1056836 variant was associated with decreased risk of PCa [odds ratio (OR): 0.80; 95% confidence interval (CI): 0.68-0.99, P = 0.041]. Longer telomere length showed a significantly higher proportion of the CYP1B1 rs1056836 CG/GG genotypes, compared with that of the CC genotype (OR: 1.60, 95% CI: 1.04-2.45). CONCLUSION: Our findings suggest that genetic variants within CYP1B1 may confer genetic susceptibility to PCa by altering telomere length.

| S-EPMC5771334 | biostudies-literature

Prostate Cancer Risk-Associated Single-Nucleotide Polymorphism Affects Prostate-Specific Antigen Glycosylation and Its Function.

Project description:BackgroundGenetic association studies have reported single-nucleotide polymorphisms (SNPs) at chromosome 19q13.3 to be associated with prostate cancer (PCa) risk. Recently, the rs61752561 SNP (Asp84Asn substitution) in exon 3 of the kallikrein-related peptidase 3 (KLK3) gene encoding prostate-specific antigen (PSA) was reported to be strongly associated with PCa risk (P = 2.3 × 10-8). However, the biological contribution of the rs61752561 SNP to PCa risk has not been elucidated.MethodsRecombinant PSA protein variants were generated to assess the SNP-mediated biochemical changes by stability and substrate activity assays. PC3 cell-PSA overexpression models were established to evaluate the effect of the SNP on PCa pathogenesis. Genotype-specific correlation of the SNP with total PSA (tPSA) concentrations and free/total (F/T) PSA ratio were determined from serum samples.ResultsFunctional analysis showed that the rs61752561 SNP affects PSA stability and structural conformation and creates an extra glycosylation site. This PSA variant had reduced enzymatic activity and the ability to stimulate proliferation and migration of PCa cells. Interestingly, the minor allele is associated with lower tPSA concentrations and high F/T PSA ratio in serum samples, indicating that the amino acid substitution may affect PSA immunoreactivity to the antibodies used in the clinical immunoassays.ConclusionsThe rs61752561 SNP appears to have a potential role in PCa pathogenesis by changing the glycosylation, protein stability, and PSA activity and may also affect the clinically measured F/T PSA ratio. Accounting for these effects on tPSA concentration and F/T PSA ratio may help to improve the accuracy of the current PSA test.

| S-EPMC6643286 | biostudies-literature

Association of single nucleotide polymorphism rs6983267 with the risk of prostate cancer.

Project description:Many studies have investigated the association between single nucleotide polymorphism (SNP) rs6983267 and the risk of prostate cancer. However, results of these studies are inconsistent. Therefore, we summarised available data and performed a meta-analysis to determine this association. Relevant articles were identified by searching the PubMed, Web of Science and Embase database. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random effects model. We used dominant model (GG + TG vs TT), recessive model (GG vs TG + TT) and additive model (GG +TT vs TG) to determine the association between the rs6983267 polymorphism and risk of prostate cancer. Summary, 9 studies involving 8726 participants were included in this meta-analysis. Overall, though no association was observed between the rs6983267 polymorphism and risk of prostate cancer, subgroup analysis according to ethnicity showed a significant association between the rs6983267 polymorphism and risk of prostate cancer among white European men [recessive model: GG vs TG + TT, OR=1.21, (95% CI: 1.03, 1.42), P=0.02]. Our results indicate that the GG genotype of the rs6983267 polymorphism will increase individual susceptibility to prostate cancer in white European men.

| S-EPMC5041923 | biostudies-literature

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