Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Abstract

Simple Summary

Melanoma is the third most common cause of brain metastasis with a reported incidence of up to 80% leading to patients’ early mortality. Clinical activity at intracranial sites is often less and unsatisfactory when compared to extracranial metastases by using novel targeted or immune therapies. Thus, the identification of genetic alterations may provide new insights into the pathogenesis of brain metastases and this will facilitate the improvement of precision oncology. Therefore, the aim of our study was to address site-specific oncogenic alterations in intracranial metastases of 29 recurrently mutated driver genes in melanoma by next generation sequencing. In line with the branched evolution model of metastasis, we identified in our cohort of intracranial and corresponding patient-matched extracranial melanoma metastases novel genetic variants and site-specific nucleotide modifications. Therapeutic targeting of the new-identified genetic variants could help to facilitate novel, more effective therapies for prevention and/or treatment of melanoma brain metastases.

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.