Noninvasive early differential diagnosis and progression monitoring of ovarian cancer using the copy number alterations of plasma cell-free DNA

Ovarian cancer (OV) is the most lethal gynecological malignancy and requires improved early detection methods and more effective intervention to achieve a better prognosis. The lack of sensitive and noninvasive biomarkers with clinical utility remains a challenge. Here, we conducted a genome-wide copy number variation (CNV) profil -ing analysis using low-coverage whole genome sequencing (LC-WGS) of plasma cfDNA in patients with nonmalig-nant and malignant ovarian tumors and identified 10 malignancy-specific and 12 late-stage-specific CNV markers from plasma cfDNA LC-WGS data. Concordance analysis indicated a significant correlation of identified CNV markers between CNV profiles of plasma cfDNA and tissue DNA (Pearson's r = 0.64, P = 0.006 for the TCGA cohort and r = 0.51, P = 0.04 for the Dariush cohort). By leveraging these specific CNV markers and machine learning algorithms, we developed robust predictive models showing excellent performance in distinguishing between malignant and nonmalignant ovarian tumors with F1-scores of 0.90 and ranging from 0.75 to 0.99, and prediction accuracy of 0.89 and ranging from 0.66 to 0.98, respectively, as well as between early-and late-stage ovarian tumors with F1-scores of 0.84 and ranging from 0.61 to 1.00, and prediction accuracy of 0.82 and ranging from 0.63 to 0.96 in our institute cohort and other external validation cohorts. Furthermore, we also discovered and validated certain CNV features associated with survival outcomes and platinum-based chemotherapy response in multicenter cohorts. In conclusion, our study demonstrated the clinical utility of CNV profiling in plasma cfDNA using LC-WGS as a cost-effective and accessible liquid biopsy for OV.

Automated summary

This study utilized LC-WGS to analyze genome-wide copy number variations (CNVs) in plasma cfDNA, identifying CNV markers associated with ovarian cancer and developing predictive models for tumor classification. Additionally, certain CNV features associated with survival outcomes and chemotherapy response were discovered.