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

Nat Commun. 2020 Jul 17;11(1):3598. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • African Americans / genetics*
  • Alleles
  • Chromosomes, Human, Pair 8 / genetics*
  • Cohort Studies
  • Enhancer Elements, Genetic*
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms / genetics*
  • RNA, Long Noncoding / genetics*

Substances

  • RNA, Long Noncoding