Toward the DNA methylation haplotype map of 11 common solid cancers

In heterogeneous tumors, adjacent CpG sites form methylation haplotype blocks (MHBs), genomic regions where methylation status reflects local epigenetic concordance. While MHBs have been implicated in gene dysregulation, their pan-cancer dynamics and clinical relevance remain unclear. We profiled 110 primary tumors across 11 common solid cancer types, identifying 81,567 MHBs. These MHBs exhibit high cancer-type specificity, with enrichment in regulatory elements. Integrative bulk and single-cell analyses reveal that MHBs associate with gene expression independently of mean methylation changes. Moreover, pan-cancer prioritization of MHB-associated differentially expressed genes highlights their roles in oncogenic pathways such as the G2/M checkpoint, MYC targets, and E2F signaling. Inter-tumor heterogeneity links MHB discordance to driver mutations and inflammatory pathways. Finally, we demonstrate that MHBs serve as effective biomarkers for cancer detection, performing competitively to existing methods. This resource positions MHBs as multimodal epigenetic regulators, bridging tumor heterogeneity, transcriptional control, and liquid biopsy diagnostics.