A novel retinoblastoma therapy from genomic and epigenetic analyses.

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. 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 the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss

Motif discovery in upstream sequences of coordinately expressed genes

The paper presents a genetic mining approach to discover highly conserved motifs amongst upstream sequences of co-regulated genes. These motifs represent putative cis-regulatory elements that could play an important role in the co-ordinated expression of these genes. A structured genetic algorithm (St-GA) was used to evolve candidate motifs of variable length. Fitness values were assigned as a function of high scoring alignments performed with NCBI BLAST. The St-GA performed favorable with respect to existing methods on simple (l,k) insertion problems, but was unable to overcome the (l,4) insertion problem that has proved elusive to other methods. Deterministic crowding was added to the St-GA to help cope with the multimodal nature of real-world genomic data. The genetic search was performed on a set of genes selected based on their expression values as highly predictive of a subtype of pediatric ALL. Four high scoring motifs were obtained that successfully matched subsequences of cis-elements found in the TRANSFAC database. Results demonstrated that the St-GA approach to motif finding has the potential to be a competitive method for this type of problem. © 2003 IEEE

A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481: 329

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. 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 the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss

A novel retinoblastoma therapy from genomic and epigenetic analyses

Retinoblastoma 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