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

Kaivalya Walavalkar, Bharath Saravanan, Anurag Kumar Singh, Ranveer Singh Jayani, Ashwin Nair, Umer Farooq, Zubairul Islam, Deepanshu Soota, Rajat Mann, Padubidri V. Shivaprasad, Matthew L. Freedman, Radhakrishnan Sabarinathan, Christopher A. Haiman and Dimple Notani ()
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Kaivalya Walavalkar: Tata Institute of Fundamental Research
Bharath Saravanan: Tata Institute of Fundamental Research
Anurag Kumar Singh: Tata Institute of Fundamental Research
Ranveer Singh Jayani: University of California San Diego
Ashwin Nair: Tata Institute of Fundamental Research
Umer Farooq: Tata Institute of Fundamental Research
Zubairul Islam: Tata Institute of Fundamental Research
Deepanshu Soota: Tata Institute of Fundamental Research
Rajat Mann: Tata Institute of Fundamental Research
Padubidri V. Shivaprasad: Tata Institute of Fundamental Research
Matthew L. Freedman: Dana-Farber Cancer Institute
Radhakrishnan Sabarinathan: Tata Institute of Fundamental Research
Christopher A. Haiman: University of Southern California
Dimple Notani: Tata Institute of Fundamental Research

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17325-y

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