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Small Cell Lung Cancer Detection, Classification Achieved Using Cell-Free DNA Methylation

NEW YORK – New research from a team at the University of Manchester and other centers in the UK and the US suggests that DNA methylation profiles in circulating, cell-free tumor DNA can offer tumor subtype and potential survival clues in individuals with small-cell lung cancer (SCLC).

"Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring, and molecular subtyping of patients with SCLC," co-senior and co-corresponding author Caroline Dive, a researcher with the nucleic acid biomarker, bioinformatics and statistics, and preclinical and pharmacology teams at University of Manchester's Cancer Research UK Manchester Institute, and her colleagues wrote.

For a technical report published in Nature Cancer on Monday, the researchers initially applied a bisulfite-free, enrichment-based sequencing method to more than a dozen health lung samples and to almost 100 patient derived tumor xenograft models or circulating tumor cell-derived explant models DNA methylation, showing that the approach could successfully pick up differentially methylated regions in SCLCs compared to the cancer-free lung samples.

From there, the team used the same next-generation sequencing strategy — T7 RNA polymerase promoter tagging-based "methyl-CpG binding domain protein-enriched sequencing," or T7-MBD-seq — to assess methylation patterns in cfDNA samples from 157 individuals with or without SCLC.

"Collectively, these data suggest that our T7-MBD-seq approach provides reproducible and characteristic SCLC methylation profiles in tissue, which are also readily detectable in cfDNA, prompting us to extend our research efforts on cfDNA methylation as a potential biomarker for clinical application in patients with SCLC," the authors explained.

Past studies have uncovered extensive heterogeneity in SCLC tumors, including a range of transcriptomic, epigenetic, and morphological features, as well as treatment responses, the researchers explained. As such, they set out to unearth potential markers for specific tumor features, clinical outcomes, and lasting responses in patients receiving a combination of chemotherapy and immunotherapy treatments.

"DNA methylation is considered an important regulator of SCLC biology and [past] analysis of SCLC primary tumor samples revealed epigenetically distinct subgroups," they noted, "though differential methylomes have not been explored in cfDNA."

With the differentially methylated regions detected using the DNA methylation profiling approach, the researchers identified methylation features in circulating cfDNA that coincided with clinical outcomes, for example, while distinguishing between different transcription factor-based SCLC subtypes.

"Overall, these data indicate that cfDNA methylation profiling has potential clinical utility in SCLC by allowing sensitive blood-based tumor detection and providing prognostic information beyond clinical stage," the researchers reported, though they cautioned that "further work is needed with increased sample sizes and independent validation data to determine an optimal and robust cutoff."

The blood-based methylation profiling approach also appeared to outperform copy number-based approaches for distinguishing between healthy samples and samples from individuals with metastatic "extensive stage" forms of SCLC (ES-SCLC) or earlier, "limited stage" SCLC (LS-SCLC), based on a machine learning analysis of cfDNA from 119 SCLC patients or cancer-free control individuals trained with data spanning nearly 4,100 differentially methylated regions.

Together, the authors noted, results from the analyses suggest that "circulating tumor DNA methylation may serve as a liquid biopsy to inform SCLC evolution, acquired resistance, and future clinical trials of personalized treatment of patients with SCLC."