Landscape of rare mutations in hereditary cutaneous and ocular melanoma — ASN Events
  1. Schedule
  2. Session 1: Systems Biology - Trans Omics
  3. Landscape of rare mutations in hereditary cutaneous and ocular melanoma

Landscape of rare mutations in hereditary cutaneous and ocular melanoma (#5)

Mykyta Artomov 1 , Alexander Stratigos 2 , Ivana Kim 3 , Ching-Ni Njauw 4 , Kristen Shannon 5 , Evangelos S. Gragoudas 3 , Anne Marie Lane 3 , Martin Lauss 6 , Raj Kumar 4 , Benchun Miao 4 , Goran Jonsson 6 , Mark J. Daly 7 , Hensin Tsao 4
  1. Harvard University, Cambridge, MA, United States
  2. Andreas Sygros Hospital, Athens, Greece
  3. Retina Service, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
  4. Dermatology, Wellman Center for Photomedicine, Boston, MA, USA
  5. Melanoma Genetics Program, Massachusetts General Hospital, Boston, MA, USA
  6. Oncology, Lund University, Lund, Sweden
  7. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

Background. Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Since 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) using 12,033 jointly processed cases and controls.  

Methods. Whole exome sequencing was performed followed by large-scale joint variant calling using GATK. Plink/SEQ was used for statistical analysis of genetic variation. Four analytical models were used to estimate association among different types of variants. Functional validation was performed using somatic, cellular and tumorigenesis assays.

Results. Strong signals were detected for CDKN2A (p=6.16E-08) and BAP1 (p=3.83E-06) in the CM (n=273) and OM (n=99) cohorts, respectively. Eleven genes which exhibited borderline association (p<10-4) were independently validated using the TCGA melanoma cohort (379 CM, 47 OM) and a matched set of 3,563 European controls. CDKN2A (p=9.31E-03), BAP1 (p=0.026) and EBF3 (p=4.75E-04), a novel CM risk locus, all showed evidence of replication. Functionally, loss of EBF3 expression was found to correlate with progression, poorer outcome and lower levels of melanocyte lineage genes, including MITF. Induction of EBF3 in melanoma cells reduced MITF levels, arrested cell growth and retarded tumor formation in xenografts.

Conclusions. This is the largest rare variant germline association study in melanoma and the results refine the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.