In vivo exploration of the functional activity of the non-coding 8q24 prostate cancer risk locus.
Ontology highlight
ABSTRACT:
SUBMITTER: Lamb DJ
PROVIDER: S-EPMC3739063 | biostudies-literature | 2010 Nov
REPOSITORIES: biostudies-literature
Publications
In vivo exploration of the functional activity of the non-coding 8q24 prostate cancer risk locus.
Lamb Dolores J DJ Tannour-Louet Mounia M
Asian journal of andrology 20100906 6
Similar Datasets
Project description:Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus.
| S-EPMC2884104 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified >100 independent susceptibility loci for prostate cancer, including the hot spot at 8q24. However, how genetic variants at this locus confer disease risk hasn't been fully characterized. Using circularized chromosome conformation capture (4C) coupled with next-generation sequencing and an enhancer at 8q24 as "bait", we identified genome-wide partners interacting with this enhancer in cell lines LNCaP and C4-2B. These 4C-identified regions are distributed in open nuclear compartments, featuring active histone marks (H3K4me1, H3K4me2 and H3K27Ac). Transcription factors NKX3-1, FOXA1 and AR (androgen receptor) tend to occupy these 4C regions. We identified genes located at the interacting regions, and found them linked to positive regulation of mesenchymal cell proliferation in LNCaP and C4-2B, and several pathways (TGF beta signaling pathway in LNCaP and p53 pathway in C4-2B). Common genes (e.g. MYC and POU5F1B) were identified in both prostate cancer cell lines. However, each cell line also had exclusive genes (e.g. ELAC2 and PTEN in LNCaP and BRCA2 and ZFHX3 in C4-2B). In addition, BCL-2 identified in C4-2B might contribute to the progression of androgen-refractory prostate cancer. Overall, our work reveals key genes and pathways involved in prostate cancer onset and progression.
| S-EPMC4776156 | biostudies-literature
Project description:Understanding the functional effects of the wide-range of aberrant genetic characteristics associated with the human chromosome 8q24 region in cancer remains daunting due to the complexity of the locus. The most logical target for study remains the MYC proto-oncogene, a prominent resident of 8q24 that was first identified more than a quarter of a century ago. However, many of the amplifications, translocation breakpoints, and viral integration sites associated with 8q24 are often found throughout regions surrounding large expanses of the MYC locus that include other transcripts. In addition, chr.8q24 is host to a number of single nucleotide polymorphisms associated with cancer risk. Yet, the lack of a direct correlation between cancer risk alleles and MYC expression has also raised the possibility that MYC is not always the target of these genetic associations. The 8q24 region has been described as a "gene desert" because of the paucity of functionally annotated genes located within this region. Here we review the evidence for the role of other loci within the 8q24 region, most of which are non-coding transcripts, either in concert with MYC or independent of MYC, as possible candidate gene targets in malignancy.
| S-EPMC3339310 | biostudies-literature
Project description:A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.
| S-EPMC1599913 | biostudies-literature
Project description:Prostate cancer is a common complex disease that disproportionately affects men of African descent. Recently, several different common variants on chromosome 8q24 have been shown to be associated with prostate cancer in multiple studies and ethnic groups. The objective of this study was to confirm the association of 8q24 markers with prostate cancer in African Americans. We genotyped 24 markers along 8q24 and 80 unlinked ancestry informative markers in a hospital-based case-control sample of 1057 African American men (490 prostate cancer cases and 567 controls). Association analyses of 8q24 markers with prostate cancer risk were adjusted for both global and local 8q24 admixture stratification using estimates from ancestry informative markers. We report that rs7008482, which maps to the 8q24.13 region, is an additional independent prostate cancer risk variant (P = 5 x 10(-4)), and we also replicate the association of rs16901979 with prostate cancer (P = 0.002). Other published risk variants in the region such as rs1447295 and rs6983267 showed a similar direction and magnitude of effect, but were not significant in our population. Both rs7008482 and rs16901979 independently predicted risk and remained significant (P < 0.001) after controlling for each other. Our data combined with additional replications of 8q24 markers provide compelling support for multiple regions of risk for prostate cancer on 8q24.
| S-EPMC2099580 | biostudies-literature
Project description:Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream.
| S-EPMC3140991 | biostudies-literature
Project description:Genome-wide association studies (GWAS) routinely identify risk variants in noncoding DNA, as exemplified by reports of multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer in five independent regions in a gene desert on 8q24. Two of these regions also have been associated with breast and colorectal cancer. These findings implicate functional variation within long-range cis-regulatory elements in disease etiology. We used an in vivo bacterial artificial chromosome (BAC) enhancer-trapping strategy in mice to scan a half-megabase of the 8q24 gene desert encompassing the prostate cancer-associated regions for long-range cis-regulatory elements. These BAC assays identified both prostate and mammary gland enhancer activities within the region. We demonstrate that the 8q24 cancer-associated variant rs6983267 lies within an in vivo prostate enhancer whose expression mimics that of the nearby MYC proto-oncogene. Additionally, we show that the cancer risk allele increases prostate enhancer activity in vivo relative to the non-risk allele. This allele-specific enhancer activity is detectable during early prostate development and throughout prostate maturation, raising the possibility that this SNP could assert its influence on prostate cancer risk before tumorigenesis occurs. Our study represents an efficient strategy to build experimentally on GWAS findings with an in vivo method for rapidly scanning large regions of noncoding DNA for functional cis-regulatory sequences harboring variation implicated in complex diseases.
| S-EPMC2928497 | biostudies-literature
Project description:We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. We identify a new association with prostate cancer risk on chromosome 8q24 (rs620861, P = 1.3 x 10(-10), heterozygote OR = 1.17, 95% CI 1.10-1.24; homozygote OR = 1.33, 95% CI 1.21-1.45). This defines a new locus associated with prostate cancer susceptibility on 8q24.
| S-EPMC3430510 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-04-11 | GSE45934 | GEO
Project description:Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.
| S-EPMC2717370 | biostudies-literature