Novel gene identified for treating retinoblastoma
MedWire News: Genomic and epigenetic analyses have identified a gene that could be targeted for the treatment of retinoblastoma.
"Our key finding is that SYK [spleen tyrosine kinase] is important in retinoblastoma," write Michael Dyer (St Jude Children's Research Hospital, Memphis, Tennessee, USA) and co-investigators in Nature. "This is important not only for expanding our understanding of the biology of retinoblastoma but also for advancing immediate therapeutic options that were not previously considered."
Retinoblastoma is an aggressive childhood cancer of the retina that can develop in a sporadic or a heritable form and is fatal if untreated. Inactivation of the gene encoding the retinoblastoma protein (RB1) results in rapid tumor progression, but the underlying mechanism is currently unknown.
To address this, Dyer et al sequenced the whole genome of four retinoblastomas and their paired germline DNA samples.
They report that the retinoblastoma tumors had a "relatively stable genome." Indeed, the estimated mean mutation rate (6.7 x 10-8 per base) was 15-fold lower than what has previously been reported in nearly all other cancers sequenced. In one patient's tumor, RB1 was the only known cancer gene mutated.
"These results are surprising because previous studies have shown that the functional inactivation of RB1 can cause genomic instability," remark the authors.
To further explore whether epigenetic deregulation of genes or pathways promote tumorigenesis in retinoblastoma, the team performed an integrated analysis of chromatin immunoprecipitation, DNA methylation, and gene expression data.
This revealed that the proto-oncogene SYK is upregulated in human retinoblastoma.
"SYK is expressed throughout the haematopoietic system, regulates immunomodulatory signaling, and has been implicated in several haematologic malignancies," explain Dyer and team. They add: "Small molecule inhibitors of SYK have been developed to treat autoimmune disorders."
The researchers found that SYK was required for tumor cell survival, and when they exposed retinoblastoma cell lines that express high levels of SYK to various concentrations of SYK inhibitors, morphologic features consistent with cell death were observed, both in vitro and in vivo.
Commenting on their findings, the authors say: "No recurrent genetic lesions in SYK were identified by WGS [whole genome sequencing] or SNP [single nucleotide polymorphism] array analysis to suggest that this gene drives retinoblastoma tumorigenesis. Only by integrating epigenetic and gene expression analyses did we identify SYK as an important oncogene in retinoblastoma."
They conclude: "This study highlights the value of integrating WGS analyses of the genetic and epigenetic features of tumour genomes to finding a cure for cancers such as retinoblastoma."
By Nikki Withers