Genetic and Epigenomic Analyses of Human Retinoblastoma

Retinoblastoma is a rare childhood cancer that initiates in the retina. Biallelic loss of retinoblastoma susceptibility 1 gene (RB1) is a driving lesion for the initiation and progression of retinoblastoma.  To identify lesions in other cancer genes that cooperate with RB1 loss, we sequenced the whole genome in four human retinoblastoma tumors and matched germline samples and one orthotropic xenograft.  Here we show the overall mutation rate is very low and that RB1 is the only cancer gene mutated in all samples. These analyses led us to investigate nongenetic mechanisms that may deregulate genes in cancer pathways. Surprisingly, we found that the genome is very stable but that the epigenome is not.  Using DNA methylation, ChIP assays and gene expression microarrays we identified several important cancer genes that are epigenetically deregulated.  Our study of the genetic and epigenetic landscape in human retinoblastoma show that RB1 inactivation deregulates multiple cancer pathways through epigenetic mechanisms.