Renáta Váraljai1,2, Susanne Horn1,2,3, Antje Sucker1,2, Daniela Piercianek2,4, Verena Schmitt5, Alexander Carpinteiro6, Katrin Anne Becker6, Julia Reifenberger7, Alexander Roesch1,2, Joerg Felsberg8, Guido Reifenberger2,8, Ulrich Sure2,4, Dirk Schadendorf1,2, Iris Helfrich1,2. 1. Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, 45147 Essen, Germany. 2. German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, 45147 Essen, Germany. 3. Faculty Rudolf-Schönheimer-Institute for Biochemistry, University of Leipzig, 04103 Leipzig, Germany. 4. Department of Neurosurgery, Medical Faculty, West German Cancer Center, University Duisburg-Essen, 45147 Essen, Germany. 5. Institute of Anatomy, Medical Faculty, University Duisburg-Essen, 45147 Essen, Germany. 6. Department of Molecular Biology, Medical Faculty, University Duisburg-Essen, 45147 Essen, Germany. 7. Department of Dermatology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany. 8. Institute of Neuropathology, Heinrich Heine University, 40225 Düsseldorf, Germany.
Abstract
BACKGROUND: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients' quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. EXPERIMENTAL DESIGN AND RESULTS: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.
BACKGROUND: Development of brain metastases in advanced melanomapatients is a frequent event that limits patients' quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. EXPERIMENTAL DESIGN AND RESULTS: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.
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