Περίληψη:
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 large-scale joint
variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used
for statistical analysis of genetic variation. Four models were used to
estimate the association among different types of variants. In vitro
functional validation was performed using three human melanoma cell
lines in 2D and 3D proliferation assays. In vivo tumor growth was
assessed using xenografts of human melanoma A375 melanoma cells in nude
mice (eight mice per group). All statistical tests were two-sided.
Results: Strong signals were detected for CDKN2A (P-min = 6.16 x 10(-8))
in the CM cohort (n = 273) and BAP1 (P-min = 3.83 x 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 x
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 x 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.
Συγγραφείς:
Artomov, Mykyta
Stratigos, Alexander J.
Kim, Ivana
Kumar,
Raj
Lauss, Martin
Reddy, Bobby Y.
Miao, Benchun and
Robles-Espinoza, Carla Daniela
Sankar, Aravind
Njauw, Ching-Ni
and Shannon, Kristen
Gragoudas, Evangelos S.
Lane, Anne Marie
and Iyer, Vivek
Newton-Bishop, Julia A.
Bishop, D. Timothy and
Holland, Elizabeth A.
Mann, Graham J.
Singh, Tarjinder
Daly,
Mark J.
Tsao, Hensin
