A novel retinoblastoma therapy from genomic and epigenetic analyses

Abstract

SUMMARYRetinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of the RB1 gene. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated RB1’s role in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. Here we show that the retinoblastoma genome is stable, but multiple cancer pathways can be epigenetically deregulated. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, RB1 inactivation may allow preneoplastic cells to acquire multiple hallmarks of cancer through epigenetic mechanisms, resulting directly or indirectly from RB1 loss. These data provide novel targets for chemotherapeutic interventions of retinoblastoma.

The landscape of genomic alterations across childhood cancers

“…External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).…”

“…Ninety-five per cent of the patients were under 18 years of age (or age unspecified but confirmed age group paediatric), but available data were included for patients up to 25 years, as these were considered relevant for cancer types that typically peak at a young age. All centres have approved data access and informed consent had been obtained from all patients.External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).The final cohort included 914 individual patients of no more than 25 years of age including primary tumours for 879 patients with 47 matched relapsed tumours, and an additional 35 independent relapsed tumours ( Supplementary Tables 1, 2). Deep-sequencing (~ 30× ) whole-genome data (WGS) were available for 547 samples with matched control, whole-exome sequencing (WES) for 414, and low-coverage whole-genome sequencing (lcWGS) for an additional 54 germline and 186 tumour samples.…”

Syk Interacts with and Phosphorylates Nucleolin To Stabilize Bcl-xL mRNA and Promote Cell Survival

“…In certain malignancies of B-cell origin, it is tonic signaling from the BCR that is proposed to activate Syk to promote cell survival (4,7,8). Interestingly, the repertoire of cells in which Syk functions as a prosurvival factor extends to tumors of B-cell origin that have not yet rearranged immunoglobulin genes, hematological malignancies not of B-cell origin, and nonhematological cancers, such as retinoblastoma and certain carcinomas of the lung and pancreas (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Whether ITAM-bearing receptors other than the BCR are involved in sending tonic signals via Syk in these cell types is as yet unclear.…”

“…These K-Ras-dependent cells undergo apoptosis in response to the inhibition of Syk activity or knockdown of Syk expression. Retinoblastoma cells in which the expression of Syk is induced by changes in gene methylation also undergo apoptosis in response to reductions in the activity or level of the kinase (18). The survival of breast and ovarian cancer cells is promoted by the alternative splicing of SYK transcripts in response to epidermal growth factor, which enhances expression of the long form of the kinase (19).…”

An epigenomic mechanism in retinoblastoma: the end of the story?

“…Zhang and colleagues [2] documented some hundreds of sequence variants in the non-coding portion of the genome, the impact of which cannot be deduced from exome sequencing or RNA-Seq of poly-A selected mRNAs. This 'dark matter' of the genome is largely intergenic, where these additional mutations were found.…”