Deconvolution of cancer methylation patterns determines that altered methylation in cancer is dominated by a non-disease associated proliferation signal

All cancers are associated with massive reorganisation of cellular epigenetic patterns, including extensive changes in the genomic patterns of DNA methylation. However, the huge scale of these changes has made it very challenging to identify key DNA methylation changes responsible for driving cancer development. Here, we present a novel approach to address this problem called methylation mapping. Through comparison of multiple types of B-lymphocyte derived malignancies and normal cell populations, this approach can define the origins of methylation changes as proliferation-driven, differentiation-driven and disease-driven (including both cancer-specific changes and cancer absent changes). Each of these categories of methylation change were found to occur at genomic regions that vary in sequence context, chromatin structure and associated transcription factors, implying underlying mechanistic differences behind the acquisition of methylation at each category. This analysis determined that only a very small fraction (about 3%) of DNA methylation changes in B-cell cancers are disease related, with the overwhelming majority (97%) being driven by normal biological processes, predominantly cell proliferation. Furthermore, the low level of true disease-specific changes can potentially simplify identification of functionally relevant DNA methylation changes, allowing identification of previously unappreciated candidate drivers of cancer development, as illustrated here by the identification and functional confirmation of SLC22A15 as a novel tumour suppressor candidate in acute lymphoblastic leukaemia. Overall, this approach should lead to a clearer understanding of the role of altered DNA methylation in cancer development, facilitate the identification of DNA methylation targeted genes with genuine functional roles in cancer development and thus identify novel therapeutic targets.