When set the monumental task of studying how the epigenetic mechanisms underlying tumorigenesis, isolating a cell sample usually represents your first analytical port of call; however, research now suggests that liquid biopsies of a patient’s blood may provide a wealth of information from cell-free DNA. Furthermore, widening this approach to DNA methylation analysis may also support the detection, prognosis, molecular subtyping, and monitoring of cancer patients without the need for cells. In other words, “No cells? No problem!”
Researchers led by Caroline Dive (University of Manchester/CRUK Manchester Institute, UK) recently reported the detection of mutational signals in cell-free DNA isolated from blood samples of certain lung cancer patients. Given that DNA methylation regulates lung cancer biology and that epigenetically-distinct lung cancer subtypes exist, the team sought to assess circulating cell-free DNA methylation profiles in lung cancer patients to take a massive step toward developing a liquid biopsy approach to better understand and manage this often incurable and metastatic disease.
Let’s hear from Chemi, Pearce, and colleagues on how a lack of cells didn’t represent a problem when profiling circulating cell-free DNA methylation in lung cancer patients:
- The authors employ a bisulfite-free, enrichment-based next-generation sequencing approach incorporating a library preparation method for sample multiplexing before enrichment (T7-MBD-seq)
- This strategy provides reproducible methylation profiles for DNA inputs as low as 1 ng and permits the segregation of cell-free DNA samples from lung cancer patients from non-cancer controls
- Cell-free DNA methylation profiling combined with machine learning improves lung cancer detection sensitivity in patients with early-stage disease, localized disease, or low tumor burdens
- Tumor-specific methylation patterns in cell-free DNA from lung cancer patients correlate with survival outcomes
- Overall, cell-free DNA methylation profiling provides sensitive blood-based prognostic information, thereby demonstrating potential clinical utility in lung cancer management
- Cell-free DNA methylation profiles also discriminate between transcription factor lung cancer subtypes; however, evaluations using a larger cohort will be required for this approach can provide a broadly applicable and accurate approach for lung cancer patient subtyping
- Of note, this approach allows the consistent detection of the predominating lung cancer subtype before and after chemotherapy, suggesting the utility of this approach to longitudinal disease monitoring
No cells? No problem! The authors report circulating cell-free DNA methylation profiling as a non-invasive and sensitive approach to understanding the epigenetics of tumorigenesis and managing lung cancer patients. This strategy could also accelerate future drug development by evaluating therapeutic responses across subtypes, exploring mechanisms of acquired resistance to therapeutics, and stratifying patients into optimized biomarker-guided clinical trials.
For more on how circulating cell-free DNA methylation profiling may guide lung cancer management, see Nature Cancer, August 2022.