The stability of epigenetic cell identity in cancer

Cell-type-specific DNA methylation patterns encode cell identity and are largely preserved over mitotic divisions across the organism's lifespan. These patterns have shown strong potential as diagnostic markers in cancer. However, DNA methylation is also plastic, dynamically remodeled in development and diseases, including cancer, due to interaction with genetic, cellular, and environmental factors. Despite wide utilities, a unified and quantitative framework for assessing the stability of cell-identity-defining methylation signatures during tumorigenesis is lacking. We systematically quantified the extent to which the DNA methylation-based definitions of cell identity, as established in healthy tissue, are maintained or disrupted in 324 human cancer types. We found that cell-type-specific methylation signatures are remarkably stable across diverse cancer types, including metastatic lesions and tumors harboring mutations in epigenetic regulators. While signature erosions were common, particularly in in vitro cell lines, complete loss in primary tumors was rare and often pointed to mischaracterized or ambiguous cells of origin. Based on these insights, we developed computational strategies to infer tumor cell-of-origin from cancer methylomes, enabling a better understanding of cancers with poorly defined origins. Our findings deepen the understanding of epigenetic maintenance in cancer and guide the development of more robust methylation-based cancer diagnosis.