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

Kaivalya Walavalkar,Rajat Mann,Anurag Kumar Singh,Matthew L Freedman,Ashwin Nair,Bharath Saravanan,Zubairul Islam,Dimple Notani,Ranveer Singh Jayani,Umer Farooq,Radhakrishnan Sabarinathan,Deepanshu Soota,Christopher A Haiman,Padubidri V Shivaprasad

doi:10.1038/s41467-020-17325-y

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.

Highlights

Genetic variation at the 8q24 locus is linked with the greater susceptibility to prostate cancer in men of African ancestry
We show that the 8q24 prostate cancer rare variant, rs72725854 is present in an enhancer and regulates multiple lncRNAs genes namely, PCAT1, PRNCR1, PVT1, and protooncogene MYC in the region
To test whether rs72725854 and its linked SNP rs114798100 (r2 = 0.8)[13] has any functional roles, we investigated the presence of androgen receptor (AR) binding using publicly available Chromatin immunoprecipitation (ChIP)-seq data in the prostate cancer cell line LNCaP since, AR modulates gene expression in prostate tumors by binding with distal regulatory elements marked by H3K27ac, H3K4me[1], and RNA polymerase II21

Summary

Introduction

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. 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. We discovered that risk variant of rs72725854 augments the transcriptional activity of the enhancer and sensitizes it to androgen stimulation thereby activating these lncRNAs and c-myc in the region These findings implicate biological mechanisms through which the rare variant rs72725854 influences prostate cancer risk in men of African ancestry

Methods

Results

Conclusion