Abstract LB-377: Promoter methylation of the DAPK1 CLL predisposition gene is associated with chronic lymphocytic leukaemia risk

The pro-apoptotic gene DAPK1 has been identified as a hereditary cancer gene in some cases of chronic lymphocytic leukaemia (CLL). The causative mutation acts to increase the probability of methylation of the DAPK1 gene. Moreover, DAPK1 promoter methylation has been demonstrated to occur in nearly all cases of CLL, leading to down-regulation of the gene. We hypothesized that DAPK1 methylation thus underlies most cases of CLL and that predisposition to CLL might be associated with predisposition to methylate the DAPK1 gene. We thus accessed a large epidemiological cohort in which blood had been collected from participants who were then followed up indefinitely. This enabled us to compare methylation at the DAPK1 promoter in peripheral blood leukocyte DNA taken from individuals who developed CLL and control individuals who did not develop cancer. A quantitative MSP-based approach was used to analyse three regions within the 1.3kb promoter CpG island; (i) 5′ of exon 1 and at the 5′ end of the island. (ii) 3′ of exon 1 and in the centre of the island and (iii) 5′ of exon 2 and at the 3′ end of the island. No significant difference was found at the 5′ or the 3′ends of the island. However, when the central region (immediately after exon 1) was examined, the difference between the cases and controls was highly significant (p = 0.004). These results strongly support an important role for DAPK1 methylation in the early pathogenesis of CLL. Whilst methylation at the central part of the CpG island is not known to regulate any transcript, it may be an important first step in the CLL process as a seeding event. This hypothesis is supported by the fact that methylation at either end of the promoter was more likely if methylation was also present in the centre (p= 0.02 for controls and 0.006 for cases). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-377. doi:1538-7445.AM2012-LB-377