Abstract #LB-172: Hypomethylation of a LINE-1 Promoter Activates a Truncated MET Transcript in Bladder Cancer

摘要: AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO In addition to hypermethylation, global hypomethylation of repetitive elements such as long interspersed nuclear (LINE-1s or L1s) is also involved in tumorigenesis. Although there are nearly 500,000 L1s the human genome only about 60 100 have potentially functional promoters, which located within CpG islands and silenced by methylation normal somatic cells. A full length L1 sequence has a sense promoter driving transcription its two open reading frames an antisense opposite direction that can act alternate for surrounding genes. We show, first time, specific MET proto-oncogene DNA methylation, H3K9me3, nucleosomal occupancy at transcriptional start sites, resulting tetranucleosomal structure. Upon becomes active allowing form MET, L1-MET. In loss nucleosomes evicted from dinucleosomal structure, those remaining contain histone variant H2A.Z, acetylated H3 H3K4me3. The consequences cancer been subject speculation regarding generation genomic instability potential activation oncogenes. Ever since studies on viable yellow agouti (Avy) mice revealed retrotransposon could induce ectopic expression gene influence disease susceptibility it postulated similar events may occur humans. direct relationship between retrotranspositional element altered humans occurance diseased state. Specifically, LINE-1 induces transcript oncogene bladder tumors across entire urothelium tumor-bearing bladders. robust truncated does not lead clonal expansion cells harboring defect, remains polyclonal. widespread epigenetic alteration more likely be permissive growth newly mutated rather than being directly responsible evolution tumor. Finally, ROC curves based extraordinarily sensitive, providing useful marker diagnosis treatment cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 18-22; CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-172.