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

Author

Listed:
  • Kaivalya Walavalkar

    (Tata Institute of Fundamental Research)

  • Bharath Saravanan

    (Tata Institute of Fundamental Research
    Sastra Deemed University, Thanjavur)

  • Anurag Kumar Singh

    (Tata Institute of Fundamental Research)

  • Ranveer Singh Jayani

    (University of California San Diego)

  • Ashwin Nair

    (Tata Institute of Fundamental Research
    Sastra Deemed University, Thanjavur)

  • Umer Farooq

    (Tata Institute of Fundamental Research
    Trans-Disciplinary University)

  • Zubairul Islam

    (Tata Institute of Fundamental Research
    Sastra Deemed University, Thanjavur)

  • 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
    The Eli and Edythe L. Broad Institute
    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)

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.

Suggested Citation

  • 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. , 2020. "A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17325-y
    DOI: 10.1038/s41467-020-17325-y
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    Cited by:

    1. Pingting Ying & Can Chen & Zequn Lu & Shuoni Chen & Ming Zhang & Yimin Cai & Fuwei Zhang & Jinyu Huang & Linyun Fan & Caibo Ning & Yanmin Li & Wenzhuo Wang & Hui Geng & Yizhuo Liu & Wen Tian & Zhiyong, 2023. "Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Pamela X. Y. Soh & Naledi Mmekwa & Desiree C. Petersen & Kazzem Gheybi & Smit van Zyl & Jue Jiang & Sean M. Patrick & Raymond Campbell & Weerachai Jaratlerdseri & Shingai B. A. Mutambirwa & M. S. Rian, 2023. "Prostate cancer genetic risk and associated aggressive disease in men of African ancestry," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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