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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.

SUBMITTER: Vanderstichele A

PROVIDER: S-EPMC9050708 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Vanderstichele Adriaan A Busschaert Pieter P Landolfo Chiara C Olbrecht Siel S Coosemans An A Froyman Wouter W Loverix Liselore L Concin Nicole N Braicu Elena Ioana EI Wimberger Pauline P Van Nieuwenhuysen Els E Han Sileny N SN Van Gorp Toon T Venken Tom T Heremans Ruben R Neven Patrick P Bourne Tom T Van Calster Ben B Timmerman Dirk D Lambrechts Diether D Vergote Ignace I

NPJ genomic medicine 20220428 1

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 adnex ...[more]

PMID: 35484288

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Project description:BackgroundDifferential gene expression analysis is important to understand pregnancy processes and disease development. However, no non-invasive and comprehensive methods exist to identify differentially expressed genes (DEGs) in the fetus and placenta during pregnancy or pregnancy complications. Nucleosome footprints in maternal peripheral blood plasma cell-free DNA (cfDNA) reflect the gene expression profile of the cell of origin, mainly immune cells in the maternal blood and placenta. This study aimed to validate the feasibility of detecting changes in gene expression profiles as differentially depth gene (DDGs) based on plasma nucleosome footprints as a potential biomarker for pregnancy and pre-eclampsia.MethodsDeep sequencing was performed on separated plasma cfDNA collected from 34 women, including eight non-pregnant women, 14 healthy pregnant women, and 12 pre-eclamptic pregnant women. The number of reads in the promoter region of each gene was extracted and normalized. Normalized depths of genes were compared between healthy pregnant vs. non-pregnant women, all pregnant women vs. non-pregnant women, and healthy pregnant women vs. pre-eclamptic pregnant women using the Wilcoxon rank-sum test to identify statistically significant DDGs. The roles of these genes were identified by functional enrichment analysis using gene ontology.ResultsPlasma cfDNA revealed different nucleosome footprints in preeclampsia pregnant, healthy pregnant, and non-pregnant women. Gene annotation revealed that the functions of 629 DDGs in pregnant and non-pregnant women mainly involved immune regulation, regardless of pre-eclampsia. 1978 DDGs between healthy pregnant and pre-eclamptic pregnant women displayed differences in immune regulation, cell cycle regulation, and sensory perception. These results are consistent with prior microarray and RNA-sequencing data.ConclusionsThe depth of the cfDNA nucleosome footprint in maternal plasma can be used to reflect changes in the gene expression profile during pregnancy and pre-eclampsia. The plasma cfDNA nucleosome footprint is a potential non-invasive biomarker for pregnancy and placental-origin pregnancy complications.

Project description:Chromosomal aneuploidy is the most common birth defect. However, the developmental mechanism and gene expression profile of fetuses with chromosomal aneuploidy are relatively unknown, and the maternal immune changes induced by fetal aneuploidy remain unclear. The inability to obtain the placenta multiple times in real-time is a bottleneck in research on aneuploid pregnancies. Plasma cell-free DNA (cfDNA) carries the gene expression profile information of its source cells and may be used to evaluate the development of fetuses with aneuploidy and the immune changes induced in the mother owing to fetal aneuploidy. Here, we carried out whole-genome sequencing of the plasma cfDNA of 101 pregnant women carrying a fetus with trisomy (trisomy 21, n = 42; trisomy 18, n = 28; trisomy 13, n = 31) based on non-invasive prenatal testing (NIPT) screening and 140 normal pregnant women to identify differential genes according to the cfDNA nucleosome profile in the region around the transcription start sites (TSSs). The plasma cfDNA promoter profiles were found to differ between aneuploid and euploid pregnancies. A total of 158 genes with significant differences were identified, of which 43 genes were upregulated and 98 genes were downregulated. Functional enrichment and signaling pathway analysis were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases found that these signal pathways were mainly related to the coordination of developmental signals during embryonic development, the control of cell growth and development, regulation of neuronal survival, and immune regulation, such as the MAPK, Hippo, TGF-β, and Rap1 signaling pathways, which play important roles in the development of embryonic tissues and organs. Furthermore, based on the results of differential gene analysis, a total of 14 immune-related genes with significant differences from the ImmPort database were collected and analyzed. These significantly different immune genes were mainly associated with the maintenance of embryonic homeostasis and normal development. These results suggest that the distribution characteristics of cfDNA nucleosomes in maternal plasma can be used to reflect the status of fetal development and changes of the immune responses in trisomic pregnancies. Overall, our findings may provide research ideas for non-invasive detection of the physiological and pathological states of other diseases.

Project description:Sepsis is a common life-threatening disease in the intensive care unit (ICU) that is usually treated empirically without pathogen identification. As a non-invasive and high-throughput technology, plasma microbial cell-free DNA (mcfDNA) sequencing can detect unknown pathogens independent of previous clinical or laboratory information. In this study, a total of 199 cases suspected of bloodstream infection (BSI) from January 2020 to June 2020 were collected, and potential pathogens were detected by simultaneous blood culture and plasma mcfDNA sequencing. Other clinical microbiological assays were performed within 7 days of plasma mcfDNA sequencing, including smear, culture of samples taken from relevant infected sites, and β-D-glucan/galactomannan (BDG/GM) tests, among others. The diagnoses were classified as sepsis [94 (47.2%)], non-sepsis [87 (43.7%)], and non-infectious disease [18 (9.0%)]. The sensitivity and specificity of plasma mcfDNA sequencing for diagnosing sepsis were 68.1 and 63.2%, respectively, which were significantly better than those of blood culture, especially for the common bacteria that cause hospital-acquired infection, namely, Acinetobacter baumannii (p < 0.01) and Klebsiella pneumoniae (p < 0.01), and DNA viruses (plasma mcfDNA sequencing only, p < 0.01). However, there was no significant difference in the rate of positivity between plasma mcfDNA sequencing and blood culture for antibiotic-non-exposed cases (43.6 vs. 30.9%, p = 0.17). In the non-sepsis group, 44.8% of cases (13/29) detected only by plasma mcfDNA sequencing showed infections in other parts of the body, such as lower respiratory infection (LRI), intra-abdominal infection (IAI) and central nervous system infection (CNSI). For some common pathogens (not including anaerobes), turnaround time (TAT) 3 (TAT from the initiation of blood sample processing by nucleic acid extraction to the completion of sequencing analysis) was longer than TAT1 (TAT from blood culture bottles in Virtuo to off Virtuo). With disease progression, significant dynamic changes in microbial species were clearly detected by plasma mcfDNA sequencing.

Dataset Information

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

Publications

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

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