scholarly journals Cell-Free-DNA-Based Copy Number Index Score in Epithelial Ovarian Cancer—Impact for Diagnosis and Treatment Monitoring

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 168
Author(s):  
Elena Ioana Braicu ◽  
Andreas du Bois ◽  
Jalid Sehouli ◽  
Julia Beck ◽  
Sonia Prader ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Copy Number ◽  
High Grade ◽  
Copy Number State ◽  
Cell Free Dna ◽  
Blood Samples ◽  
Free Dna ◽  
Genome Wide ◽  
A Genome

Background: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment. Methods: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set. Results: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively. Conclusion: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.

scholarly journals A novel decision tree model based on chromosome imbalances in cell-free DNA and CA-125 in the differential diagnosis of ovarian cancer

2021 ◽  
pp. 172460082199235
Author(s):  
Weina Zhang ◽  
Yu-min Zhang ◽  
Yuan Gao ◽  
Shengmiao Zhang ◽  
Weixin Chu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Differential Diagnosis ◽  
Decision Tree ◽  
Copy Number ◽  
Malignant Tumors ◽  
Copy Number Variations ◽  
Ca 125 ◽  
Benign Tumors ◽  
Cell Free Dna ◽  
Free Dna

Objective: CA-125 is widely used as biomarker of ovarian cancer. However, CA-125 suffers low accuracy. We developed a hybrid analytical model, the Ovarian Cancer Decision Tree (OCDT), employing a two-layer decision tree, which considers genetic alteration information from cell-free DNA along with CA-125 value to distinguish malignant tumors from benign tumors. Methods: We consider major copy number alterations at whole chromosome and chromosome-arm level as the main feature of our detection model. Fifty-eight patients diagnosed with malignant tumors, 66 with borderline tumors, and 10 with benign tumors were enrolled. Results: Genetic analysis revealed significant arm-level imbalances in most malignant tumors, especially in high-grade serous cancers in which 12 chromosome arms with significant aneuploidy ( P<0.01) were identified, including 7 arms with significant gains and 5 with significant losses. The area under receiver operating characteristic curve (AUC) was 0.8985 for copy number variations analysis, compared to 0.8751 of CA125. The OCDT was generated with a cancerous score (CScore) threshold of 5.18 for the first level, and a CA-125 value of 103.1 for the second level. Our most optimized OCDT model achieved an AUC of 0.975. Conclusions: The results suggested that genetic variations extracted from cfDNA can be combined with CA-125, and together improved the differential diagnosis of malignant from benign ovarian tumors. The model would aid in the pre-operative assessment of women with adnexal masses. Future clinical trials need to be conducted to further evaluate the value of CScore in clinical settings and search for the optimal threshold for malignancy detection.

scholarly journals A Ten-MicroRNA Signature Identified from a Genome-Wide MicroRNA Expression Profiling in Human Epithelial Ovarian Cancer

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96472 ◽  
Author(s):  
Lin Wang ◽  
Miao-Jun Zhu ◽  
Ai-Min Ren ◽  
Hong-Fei Wu ◽  
Wu-Mei Han ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Expression Profiling ◽  
Microrna Expression ◽  
Genome Wide ◽  
A Genome

scholarly journals Genome‑wide bioinformatics analysis reveals CTCFL is upregulated in high‑grade epithelial ovarian cancer

2019 ◽  
Author(s):  
Mi Gong ◽  
Changsheng Yan ◽  
Yi Jiang ◽  
Huangyang Meng ◽  
Mingming Feng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Bioinformatics Analysis ◽  
High Grade ◽  
Genome Wide

scholarly journals Genome-wide cell-free DNA termini in patients with cancer.

2021 ◽  
Author(s):  
Norbert Moldovan ◽  
Ymke van der Pol ◽  
Tom van den Ende ◽  
Dries Boers ◽  
Sandra Verkuijlen ◽  
...  
Keyword(s):  
Residual Disease ◽  
Fragmentation Pattern ◽  
Healthy Controls ◽  
Cell Free Dna ◽  
Free Dna ◽  
Genome Wide ◽  
A Genome ◽  
Pattern Length ◽  
Cancer Types ◽  
End Sequences

The structure, fragmentation pattern, length and terminal sequence of cell-free DNA (cfDNA) is under the influence of nucleases present in the blood. We hypothesized that differences in the diversity of bases at the end of cfDNA fragments can be leveraged on a genome-wide scale to enhance the sensitivity for detecting the presence of tumor signals in plasma. We surveyed the cfDNA termini in 572 plasma samples from 319 patients with 18 different cancer types using low-coverage whole genome sequencing. The fragment-end sequence and diversity were altered in all cancer types in comparison to 76 healthy controls. We converted the fragment end sequences into a quantitative metric and observed that this correlates with circulating tumor DNA tumor fraction (R = 0.58, p < 0.001, Spearman). Using these metrics, we were able to classify cancer samples from control at a low tumor content (AUROC of 91% at 1% tumor fraction) and shallow sequencing coverage (mean AUROC = 0.99 at >1M fragments). Combining fragment-end sequences and diversity using machine learning, we classified cancer from healthy controls (mean AUROC = 0.99, SD = 0.01). Using unsupervised clustering we showed that early-stage lung cancer (n = 13) can be classified from control or later stages based on fragment-end sequences. We observed that fragment-end sequences can be used for prognostication (hazard ratio: 0.49) and residual disease detection in resectable esophageal adenocarcinoma patients, moving fragmentomics toward a greater clinical implementation.

scholarly journals Nuclease deficiencies alter plasma cell-free DNA methylation profiles

2021 ◽  
pp. gr.275426.121
Author(s):  
Diana Siao Cheng Han ◽  
Meng Ni ◽  
Rebecca Wing Yan Chan ◽  
Danny Ka Lok Wong ◽  
Linda T Hiraki ◽  
...  
Keyword(s):  
Fragment Size ◽  
Cpg Islands ◽  
Periodic Pattern ◽  
Open Chromatin ◽  
Cell Free Dna ◽  
Free Dna ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale ◽  
Deficient Mice

The effects of DNASE1L3 or DNASE1 deficiency on cell-free DNA (cfDNA) methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wild-type cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice, demonstrating the preference of DNASE1 to cleave in hypomethylated OCRs and CGIs. We also observed a substantial decrease of fragment ends and coverage at methylated CpGs in the absence of DNASE1L3, thereby demonstrating that DNASE1L3 prefers to cleave at methylated CpGs. Furthermore, we found that methylation levels of cfDNA varied by fragment size in a periodic pattern, with cfDNA of specific sizes being more hypomethylated and enriched for OCRs and CGIs. These findings were confirmed in DNASE1L3-deficient human cfDNA. Thus, we have found that nuclease-mediated cfDNA fragmentation markedly affected cfDNA methylation level on a genome-wide scale. This work provides a foundational understanding of the relationship between methylation, nuclease biology and cfDNA fragmentation.

scholarly journals A Genome-Wide Association Study Identifies UGT1A1 as a Regulator of Serum Cell-Free DNA in Young Adults: The Cardiovascular Risk in Young Finns Study

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e35426 ◽  
Author(s):  
Juulia Jylhävä ◽  
Leo-Pekka Lyytikäinen ◽  
Mika Kähönen ◽  
Nina Hutri-Kähönen ◽  
Johannes Kettunen ◽  
...  
Keyword(s):  
Young Adults ◽  
Cardiovascular Risk ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Cell Free Dna ◽  
Free Dna ◽  
Genome Wide ◽  
A Genome ◽  
Young Finns Study
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