Liquid biopsies can detect actionable mutations and infer broad tumour states from genome-wide cfDNA measurements, but quantitative transcriptome-like phenotyping at single gene resolution still largely
requires tissue. In this preprint, researchers at the National Cancer Institute asked whether 6-base whole-genome sequencing that jointly quantifies 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) could infer gene expression directly from plasma.
The group found gene-level epigenetic measurements tracked with RNA abundance, particularly when using a composite score combining 5hmC in gene bodies and the inverse of 5mC (1-5mC) in promoters, which was more effective than using 5mC or 5hmC alone, demonstrating the unique value of complete 6-base information.
The group then linked changes in inferred transcriptional programs to shifts in clonal architecture over time, effectively integrating phenotype with evolutionary dynamics in the same samples. This combined analysis was capable of delineating two treatment resistance behaviours.
These findings suggest a practical approach where features detectable in baseline plasma, along with early treatment responses, could be used to stratify patients, anticipate routes to resistance, and guide subsequent treatment decisions.
Integration of genomics with complete epigenetic information was crucial to enabling this approach. The team demonstrate that duet evoC’s 6-base 5mC and 5hmC resolution is uniquely positioned to support a paradigm shift; with 6-base data, a tissue sample is not required to understand fundamental tumour biology and better inform treatment decisions. With 6-base you can get it all from a cfDNA sample.
