A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer

Abstract

Genetic variation at the 8q24 locus is linked with the greater susceptibility to prostate cancer in men of African ancestry. One such African ancestry specific rare variant, rs72725854 (A>G/T) (~6% allele frequency) has been associated with a~2-fold increase in prostate cancer risk. However, the functional relevance of this variant is unknown. Here we show that the variant rs72725854 is present in a prostate cancer-specific enhancer at 8q24 locus. Chromatin-conformation capture and dCas9 mediated enhancer blocking establish a direct regulatory link between this enhancer and lncRNAs PCAT1, PRNCR1 and PVT1. The risk allele ('T') is associated with higher expression of PCAT1, PVT1 and c-myc in prostate tumors. Further, enhancer with the risk allele gains response to androgen stimulation by recruiting the transcription factor SPDEF whereas, non-risk alleles remain non-responsive. Elevated expression of these lncRNAs and c-myc in risk allele carriers may explain their greater susceptibility to prostate cancer.

Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

“…However, the involvement of genetic variants impacting lncRNA genes and contributing to complex disease remains difficult to ascertain. Examples of prominent rare variants impacting lncRNA genes in disease have included prostate cancer (Walavalkar et al, 2020), HELLP syndrome (van Dijk et al, 2015), and limb malformation (Allou et al, 2021). By applying gene expression outlier analysis, we were able to identify rare variants that impact lncRNA genes and connect those effects to body mass index, a highly polygenic trait.…”

Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease

“…Many of these Chr8q24 risk signals are located a substantial distance from genes, however a number of plausible candidate variants within regulatory elements have been identified [ 173 , 174 ]. These are implicated in regulating the expression of multiple protein coding genes including the MYC proto-oncogene [ 175 , 176 , 177 , 178 ], POU5F1B transcriptional activator [ 165 , 179 ] and FAM84B gene [ 113 , 180 ], and long noncoding RNAs [ 181 ] including PVT1 [ 178 , 182 ], PCAT1 [ 178 , 183 ] and PRNCR1 [ 178 , 184 ]. This indicates that PrCa risk modulation by the Chr8q24 locus is likely to be influenced through a diverse and complex range of biological mechanisms.…”

“…Several of these PrCa risk loci contain genes heavily linked to prostate function, or whose expression is enriched in the prostate relative to other tissues [ 195 ]; however, the biological mechanisms underpinning the majority of PrCa risk loci identified through GWAS generally remain poorly characterised at present. Functional validation of a small number of candidate causal variants has been performed to date [ 169 , 175 , 178 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 ], whilst fine-mapping of association signals and in silico annotation procedures have also helped to narrow the pool of likely candidate causal variants and identify prospective target genes and biological mechanisms that may give rise to differential risk [ 173 , 206 , 207 , 208 , 209 ]. A related methodology, transcriptome wide association studies (TWAS), in which GWAS summary statistic datasets and SNP-gene expression data from a reference panel are integrated, for the purpose of imputing gene expression data into phenotyped datasets which lack directly measured expression data, has also been employed in order to identify prospective gene–trait associations and prioritise putative candidate genes at many GWAS loci [ 210 ].…”

Genetic Contributions to Prostate Cancer Disparities in Men of West African Descent

“…However, subsequent fine mapping of this region has identified several long non-coding RNAs. The African specific variant rs72725854 is located at the enhancer region, and the risk allele is associated with higher expression of non-coding RNAs and MYC gene ( 74 ). Han and colleagues conducted fine mapping of the 8q24 risk region to identify novel associations with common and rare variation in 9,531 (4853 cases and 4678 controls) men of African descent.…”