Johns Hopkins University
In almost two decades since the discovery of altered DNA methylation in cancer, epigenetic alterations have been linked to gene activation, gene silencing, chromosomal instability, and most recently genomic imprinting in cancer. We have focused our recent attention on a domain of imprinted genes distributed over approximately 1 megabase of human 1lp15, and their role in pediatric and adult cancers. We have found a diverse group of imprinted genes within this region including IGF2 (an autocrine growth factor), p57Kip2 (a cyclin-dependent kinase inhibitor), KvLQT1 (a voltage-gated potassium channel), TSSC3 (related to an apoptosis-inducing gene), and TSSC5 (a putative transmembrane protein). We have also discovered loss of imprinting (LOI) affecting several of these genes in cancer, and we have found that LOI may be associated with cancer risk in the hereditary disorder Beckwith-Wiedemann syndrome (BWS), as well as in patients with colorectal cancer with microsatellite instability. Furthermore, the 11p15 imprinted domain is itself divided into two subdomains. LIT1, within the more centromeric domain, shows LOI more frequently in BWS; and IGF2, within the more telomeric domain, shows LOI more frequently in cancer. Since there are likely to be multiple regulatory sequences important for imprinting, in the >95% of this region that is noncoding, we and our collaborators recently have taken a comparative genomics approach to identify species-conserved sequences throughout this entire domain. We have also taken a general strategy to identify CpG island that are methylated in normal tissues, as an approach to identifying additional imprinted genes and/or sites of altered methylation in cancer, throughout the genome.