Exome sequencing of ABCB5 identifies recurrent melanoma mutations that result in increased proliferative and invasive capacities

Abstract ABCB5 is an ATP-binding cassette (ABC) transporter that was shown to confer low-level multidrug resistance in cancer. In this study, we show that ABCB5 was mutated in 13.75% of the 640 melanoma samples analyzed. Besides nonsense mutations, two mutation hotspots were found in the ABCB5 protein, in the drug-binding pocket and the nucleotide-binding domains. Four mutations, which are representative of the mutation pattern, were selected. ATPase assays showed that these mutations resulted in a decrease in basal ATP hydrolysis by ABCB5. To select informative melanoma cell lines, mutational profiles of the clinical samples were further analyzed. This study revealed mutations in the tumor suppressor CDKN2A gene and the NRAS oncogene, in 62.5% and 75% of the samples which had mutations in the ABCB5 gene, respectively. No mutation was found in the tumor suppressor PTEN gene, while the activating V600E mutation in the BRAF oncogene was found in 25% of the samples with a mutated ABCB5 gene. Studies in four melanoma cell lines with various genetic backgrounds showed an increase in the proliferation and migration capacity of mutant ABCB5-expressing cells, suggesting that ABCB5 play a role in the development of melanoma as a tumor suppressor gene.