Nucleosome footprinting in plasma cell-free DNA for the pre-surgical diagnosis of ovarian cancer

Fragmentation patterns of plasma cell-free DNA (cfDNA) are known to reflect nucleosome positions of cell types contributing to cfDNA. Based on cfDNA fragmentation patterns, the deviation in nucleosome footprints was quantified between diagnosed ovarian cancer patients and healthy individuals. Multinomial modeling was subsequently applied to capture these deviations in a per sample nucleosome footprint score. Validation was performed in 271 cfDNAs pre-surgically collected from women with an adnexal mass. We confirmed that nucleosome scores were elevated in invasive carcinoma patients, but not in patients with benign or borderline disease. Combining nucleosome scores with chromosomal instability scores assessed in the same cfDNA improved prediction of malignancy. Nucleosome scores were, however, more reliable to predict non-high-grade serous ovarian tumors, which are characterized by low chromosomal instability. These data highlight that compared to chromosomal instability, nucleosome footprinting provides a complementary and more generic read-out for pre-surgical diagnosis of invasive disease in women with adnexal masses.

Automated summary

The fragmentation patterns of cfDNA can reflect nucleosome positions and deviations in nucleosome footprints can help diagnose ovarian cancer. Nucleosome scores were elevated in invasive carcinoma patients and combined with chromosomal instability scores can improve malignancy prediction. Nucleosome footprinting provides a more reliable read-out for pre-surgical diagnosis in women with adnexal masses compared to chromosomal instability.