Rare variant, gene-based association study of hereditary melanoma using whole-exome sequencing

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Background: Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods: Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by largescale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Fourmodels were used to estimate the association among different types of variants. In vitro functional validation was performed using three humanmelanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of humanmelanoma A375melanoma cells in nudemice (eightmice per group). All statistical tests were two-sided. Results: Strong signals were detected for CDKN2A (Pmin = 6.16×10-8) in the CM cohort (n=273) and BAP1 (Pmin = 3.83×10-6) in the OM (n=99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75×10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37×10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions: The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.


  • Mykyta Artomov
  • Alexander J. Stratigos
  • Ivana Kim
  • Raj Kumar
  • Bobby Y. Reddy
  • Benchun Miao
  • Carla Daniela Robles-Espinoza
  • Aravind Sankar
  • Ching Ni Njauw
  • Kristen Shannon
  • Evangelos S. Gragoudas
  • Anne Marie Lane
  • Vivek Iyer
  • Julia A. Newton-Bishop
  • D. Timothy Bishop
  • Elizabeth A. Holland
  • Graham J. Mann
  • Tarjinder Singh
  • Jeffrey C Barrett
  • David J Adams
  • Mark J. Daly
  • Hensin Tsao
Enheter & grupper
Externa organisationer
  • Broad Institute
  • Harvard University
  • National and Kapodistrian University of Athens
  • Massachusetts General Hospital
  • Wellcome Trust Sanger Institute
  • National Autonomous University of Mexico
  • Massachusetts Eye and Ear Infirmary
  • University of Leeds
  • University of Sydney
  • Wellcome Trust

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
TidskriftJournal of the National Cancer Institute
Utgåva nummer12
StatusPublished - 2017
Peer review utfördJa