TitleA rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer.
Publication TypeJournal Article
Year of Publication2020
AuthorsWalavalkar K, Saravanan B, Singh AKumar, Jayani RSingh, Nair A, Farooq U, Islam Z, Soota D, Mann R, Shivaprasad PV, Freedman ML, Sabarinathan R, Haiman CA, Notani D
JournalNat Commun
Date Published2020 Jul 17

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.

Alternate JournalNat Commun
PubMed ID32680982
PubMed Central IDPMC7368061
Grant ListDOD PC180367 / / U.S. Department of Defense (United States Department of Defense) /
SB/S2/RJN-071/2018 / / DST | Science and Engineering Research Board (SERB) /
IA/1/14/2/501539 / / DBT India Alliance (Wellcome Trust/DBT India Alliance) /
12-R&D-TFR-5.04-0800 / / Department of Atomic Energy, Government of India (DAE) /
12-R&D-TFR-5.04-0900 / / TIFR | National Centre for Biological Sciences (NCBS) /