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

Abstract

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.

Circulating Histones to Detect and Monitor the Progression of Cancer

“…Recently, Vanderstichele et al showed that the fragmentation of nucleosome-associated circulating plasma DNA predicted the presence of malignant tumors in 271 plasma samples from patients with an adnexal mass [ 101 ]. Of note, nucleosomal DNA fragmentation performed better at distinguishing ovarian cancer malignancies with low chromosomal instability than low-coverage whole genome sequencing [ 131 ]. The study suggests circulating plasma nucleosome-DNA complexes could serve as a complementary cancer detection approach, especially in subtypes with a low mutational burden.…”

Analysis of Cell-Free DNA to Predict Outcome to Bevacizumab Combination Therapy in Metastatic Colorectal Cancer Patients

“…As we had previously demonstrated that the read outs of CIN and NF, derived from the same cfDNA LC-WGS data, acted complementarily to detect invasive ovarian tumors 21 , here, we applied a similar approach to investigate whether NFs could also be used to distinguish mCRC clusters. Having established a nucleosome score that reflected the degree of nucleosome position deviation for each mCRC plasma sample, we observed a significant difference in the nucleosome scores between cluster 1 and 2 samples (within the AC-ANGIOPREDICT cohort), although not with cluster 3 since these samples displayed a heterogeneous nucleosome score profile.…”

“…Moreover, we previously demonstrated the utility of detecting CNAs using cfDNAbased low coverage whole-genome sequencing (LC-WGS) analysis for the early detection of ovarian cancer 20 . In addition to WGS read-outs based on CNA, cfDNA can also be leveraged to study nucleosome footprinting (NF) and methylation changes 21 . When cfDNA is released into blood, specific fragmentation patterns can be detected in LC-WGS data using NF.…”

Potential Impact of Preoperative Circulating Biomarkers on Individual Escalating/de-Escalating Strategies in Early Breast Cancer

“…The analysis of plasma DNA with whole-genome sequencing could be useful in identifying transcription start sites (TSSs) and the different nucleosome occupancy that characterizes tumoral gene signatures associated with different gene expressions or silencing [129]. Nucleosome position may be helpful to identify the tissue of origin and to distinguish cancer from benign tumors, improving early diagnosis [130,131].…”