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A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR

  1. Author:
    Xu, Mai
    Mehl, Lindsey
    Zhang, Tongwu
    Thakur, Rohit
    Sowards, Hayley
    Myers, Timothy
    Jessop, Lea
    Chesi, Alessandra
    Johnson, Matthew E
    Wells, Andrew D
    Michael, Helen T
    Bunda, Patricia
    Jones, Kristine
    Higson, Herbert
    Hennessey, Rebecca C
    Jermusyk, Ashley
    Kovacs, Michael A
    Landi, Maria Teresa
    Iles, Mark M
    Goldstein, Alisa M
    Choi, Jiyeon
    Chanock, Stephen J
    Grant, Struan F A
    Chari,Raj
    Merlino, Glenn
    Law, Matthew H
    Brown, Kevin M

  2. Author Address

    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA., Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA., Laboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA., Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Center for Spatial and Functional Genomics, Children 39;s Hospital of Philadelphia, Philadelphia, PA 19104, USA., Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA., Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA., Leeds Institute of Medical Research at St. James 39;s, University of Leeds, Leeds LS2 9NL, UK; Leeds Institute for Data Analytics, University of Leeds, Leeds LS2 9NL, UK., Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA., Center for Spatial and Functional Genomics, Children 39;s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Human Genetics, Children 39;s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Genome Modification Core, Frederick National Lab for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA., Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia., Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: kevin.brown3@nih.gov.,
    1. Year: 2021
    2. Date: Sep 2
    3. Epub Date: 2021 07 27
  2. Journal: American journal of human genetics
    1. 108
    2. 9
    3. Pages: 1611-1630
  4. Type of Article: Article
  5. Article Number: S0002-9297(21)00270-6
  6. ISSN: 0002-9297
  1. Abstract:

    Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure. Published by Elsevier Inc.

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  2. DOI: 10.1016/j.ajhg.2021.07.002
  3. PMID: 34343493
  4. View record in Web of Science®
  5. WOS: 000692378200006
  6. PII : S0002-9297(21)00270-6

Library Notes

  1. Fiscal Year: FY2020-2021
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