Improving cell-free DNA detection in advanced-stage high-grade serous ovarian cancer using combined TP53 mutational status and copy number changes

Abstract

Circulating tumor DNA (ctDNA) is a promising biomarker in patients with high-grade serous ovarian cancer (HGSOC). However, the detection rate of TP53 mutations in ctDNA of HGSOC patients has previously been shown to be inadequate. Given the prevalence of copy number aberrations (CNAs) in HGSOC, this study aimed to improve ctDNA detection by combining TP53 sequencing with shallow whole-genome sequencing (sWGS), and to evaluate the correlation with clinicopathological features and survival outcomes. This exploratory, retrospective cohort study included 53 advanced-stage HGSOC patients, comprising 18 treatment-naive patients and 35 patients treated with two neoadjuvant chemotherapy cycles. TP53 targeted sequencing was integrated with sWGS (<5x coverage) for CNA estimation using ichor copy number aberration tumor fraction (ichorCNA TF). TP53 mutations were detected in 28 patients (52.8 %), and 17 patients (32.1 %) showed positive ichorCNA TF. Combining TP53 mutation detection with ichorCNA TF identified 62.3 % (n = 33) of patients as ctDNA-positive, showing a trend towards improved detection compared to TP53 mutation alone (p = .063). Treatment-naive patients exhibited higher TP53 mutation (72.2 % vs. 42.9 %, p = .043) and ichorCNA TF (66.7 % vs. 14.3 %, p < .001) detection rates compared to chemotherapy-treated patients. No correlations between ctDNA metrics and clinicopathological characteristics or survival outcomes were found. In conclusion, the integration of ichorCNA TF with TP53 mutation analysis showed a trend towards improved ctDNA detection in advanced-stage HGSOC patients. Future studies should further explore ctDNA detection rates by ichorCNA TF and its potential clinical implications in HGSOC.

Keywords: Circulating tumor DNA; Copy number aberrations; Epithelial ovarian cancer; Shallow whole-genome sequencing.