Publication date: Jul 08, 2019
The strong association between BAP1 mutations and metastasizing Class 2 uveal melanoma (UM) suggests that epigenetic alterations may play a significant role in tumor progression. Thus, we characterized the impact of BAP1 loss on the DNA methylome in UM.
Global DNA methylation was analyzed in 47 Class 1 and 45 Class 2 primary UMs and in UM cells engineered to inducibly deplete BAP1. RNA-Seq was analyzed in 80 UM samples and engineered UM cells.
Hypermethylation on chromosome 3 correlated with downregulated gene expression at several loci, including 3p21 where BAP1 is located. Gene set analysis of hypermethylated and downregulated genes identified axon guidance and melanogenesis as deregulated pathways, with several of these genes located on chromosome 3. A novel hypermethylated site within the BAP1 locus was found in all Class 2 tumors, suggesting that BAP1 itself is epigenetically regulated. Highly differentially methylated probes were orthogonally validated using bisulfite sequencing, and they successfully distinguished Class 1 and Class 2 tumors in 100% of cases. In functional validation experiments, BAP1 knockdown in UM cells induced methylomic repatterning similar to UM tumors, enriched for genes involved in axon guidance, melanogenesis, and development.
This study, coupled with previous work, suggests that the initial event in the divergence of Class 2 UM from Class 1 UM is loss of one copy of chromosome 3, followed by mutation of BAP1 on the remaining copy of chromosome 3, leading to the methylomic repatterning profile characteristic of Class 2 UMs.
Field, M.G., Kuznetsov, J.N., Bussies, P.L., Cai, L., Alawa, K.A., Decatur, C., Kurtenbach, S., and Harbour, J.W. BAP1 loss is associated with DNA methylomic repatterning in highly aggressive Class 2 uveal melanomas. 23323. 2019 Clin Cancer Res.
- Role of Klotho protein in tumorigenesis, cancer progression, and prognosis in patients with high-grade glioma.
- Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/BAF45a.
- Genomic evolution of uveal melanoma arising in ocular melanocytosis.
- The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism.