Exome Sequencing of ABCB5 Identifies Recurrent Melanoma Mutations that Result in Increased Proliferative and Invasive Capacities

Géraldine Sana, James P. Madigan, Jared J. Gartner, Marie Fourrez, Jimmy Lin, Nouar Qutob, Jitendra Narayan, Suneet Shukla, Suresh V. Ambudkar, Di Xia, Steven A. Rosenberg, Michael M. Gottesman, Yardena Samuels, Jean Pierre Gillet

Research output: Contribution to journalArticle

Abstract

ABCB5 is an 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 showed mutations in the tumor suppressor CDKN2A gene and the NRAS oncogene in 62.5% and 75%, respectively of the samples that had mutations in the ABCB5 gene. No mutation was found in the tumor suppressor PTEN gene, whereas 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 plays a role in the development of melanoma as a tumor suppressor gene.

Original languageEnglish
Pages (from-to)1985-1992.e10
JournalJournal of Investigative Dermatology
Volume139
Issue number9
DOIs
Publication statusPublished - 1 Sep 2019

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Exome
Melanoma
Genes
Mutation
Tumors
Tumor Suppressor Genes
Cells
Oncogenes
ATP-Binding Cassette Transporters
Adenosine Triphosphatases
p16 Genes
Hydrolysis
Assays
Cell Line
Nucleotides
Adenosine Triphosphate
Nonsense Codon
Multiple Drug Resistance
Pharmaceutical Preparations
Proteins

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Sana, Géraldine ; Madigan, James P. ; Gartner, Jared J. ; Fourrez, Marie ; Lin, Jimmy ; Qutob, Nouar ; Narayan, Jitendra ; Shukla, Suneet ; Ambudkar, Suresh V. ; Xia, Di ; Rosenberg, Steven A. ; Gottesman, Michael M. ; Samuels, Yardena ; Gillet, Jean Pierre. / Exome Sequencing of ABCB5 Identifies Recurrent Melanoma Mutations that Result in Increased Proliferative and Invasive Capacities. In: Journal of Investigative Dermatology. 2019 ; Vol. 139, No. 9. pp. 1985-1992.e10.
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title = "Exome Sequencing of ABCB5 Identifies Recurrent Melanoma Mutations that Result in Increased Proliferative and Invasive Capacities",
abstract = "ABCB5 is an 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 showed mutations in the tumor suppressor CDKN2A gene and the NRAS oncogene in 62.5{\%} and 75{\%}, respectively of the samples that had mutations in the ABCB5 gene. No mutation was found in the tumor suppressor PTEN gene, whereas 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 plays a role in the development of melanoma as a tumor suppressor gene.",
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Sana, G, Madigan, JP, Gartner, JJ, Fourrez, M, Lin, J, Qutob, N, Narayan, J, Shukla, S, Ambudkar, SV, Xia, D, Rosenberg, SA, Gottesman, MM, Samuels, Y & Gillet, JP 2019, 'Exome Sequencing of ABCB5 Identifies Recurrent Melanoma Mutations that Result in Increased Proliferative and Invasive Capacities', Journal of Investigative Dermatology, vol. 139, no. 9, pp. 1985-1992.e10. https://doi.org/10.1016/j.jid.2019.01.036

Exome Sequencing of ABCB5 Identifies Recurrent Melanoma Mutations that Result in Increased Proliferative and Invasive Capacities. / Sana, Géraldine; Madigan, James P.; Gartner, Jared J.; Fourrez, Marie; Lin, Jimmy; Qutob, Nouar; Narayan, Jitendra; Shukla, Suneet; Ambudkar, Suresh V.; Xia, Di; Rosenberg, Steven A.; Gottesman, Michael M.; Samuels, Yardena; Gillet, Jean Pierre.

In: Journal of Investigative Dermatology, Vol. 139, No. 9, 01.09.2019, p. 1985-1992.e10.

Research output: Contribution to journalArticle

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AU - Sana, Géraldine

AU - Madigan, James P.

AU - Gartner, Jared J.

AU - Fourrez, Marie

AU - Lin, Jimmy

AU - Qutob, Nouar

AU - Narayan, Jitendra

AU - Shukla, Suneet

AU - Ambudkar, Suresh V.

AU - Xia, Di

AU - Rosenberg, Steven A.

AU - Gottesman, Michael M.

AU - Samuels, Yardena

AU - Gillet, Jean Pierre

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