Multimodal analysis of cell-free DNA for sensitive cancer detection in low-coverage and low-sample settings
Seminar by Antoine Passemiers
Start: 12/09/2024, 11:00 - 12:00
Location: B00.35
Abstract:
Recent advances in cell-free DNA (cfDNA) analysis have focused on the multimodal integration of genetic (e.g., copy number aberrations, variants) and epigenetic (e.g., fragmentomics, methylation) profiles for cancer detection. We hypothesized that combining cfDNA modalities would enhance detection sensitivity and developed a novel analytical framework for their joint analysis.We conducted enzymatic conversion and whole-genome methylation sequencing on blood samples from breast and colorectal cancer patients (predominantly stage I), multiple myeloma patients, and healthy controls, with sequencing depths ranging from 1x to 10x. Enzymatic conversion was chosen for its expected lower GC and fragmentation biases, facilitating the combined analysis of methylome and fragmentome data. A new analytical pipeline was designed for simultaneous methylation calling, copy number aberration analysis, and fragmentomic analysis. These derived modalities were then utilized for downstream analysis using a problem-specific machine learning approach.We report an area under the receiver operating characteristic curve (AUROC) of 0.834 on our colorectal cancer test cohort, and AUROCs of 0.970 and 0.999 cross-validation performance for breast cancer and multiple myeloma detection, respectively. Our results demonstrated significant performance improvements when combining cfDNA properties, underscoring their synergy and complementarity. Furthermore, correlations between modalities suggested that changes in fragmentomic and methylation profiles were influenced not only by the presence of circulating tumor DNA but also by alterations in nuclease activity. These findings emphasize the critical role of orthogonal biomarkers, as their joint analysis can elucidate the underlying causes of changes in genetic and epigenetic profiles.
Organized by: Antoine Passemiers