DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations

MARZESE D.M.; SCOLYER R.A.; ROQUÉ M.; VARGAS ROIG L.M.; HUYNH J.L.; WILMOTT J.S.; MURALI R.; BUCKLAND M.E.; BARKHOUDARIAN G.; THOMPSON J.E.; MORTON D.L.; KELLY D.F.; HOON D.S.B.

NEURO-ONCOLOGY

DUKE UNIV PRESS

Año: 2014 vol. 16 p. 1499 - 1509

1522-8517

Background: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods: Genome-wide DNA methylation analyses of MBMs (n=15) and normal brain tissues(n=91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues(99 MBM and 43 extra-cranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. 46.1% and 28.8% of MBMs had BRAF and NRAS missense mutations, respectively. Compared to lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified two clinically-relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.