Comprehensive Gene Mutation Profiling of Circulating Tumor DNA in Ovarian Cancer: Its Pathological and Prognostic Impact

Abstract

Liquid biopsies from circulating tumor DNA (ctDNA) have been employed recently as a non-invasive diagnostic tool for detecting cancer-specific gene mutations. Here, we show the comprehensive gene mutation profiles of ctDNA in 51 patients with different histological subtypes of stage I–IV ovarian cancer, and their association with clinical outcomes. The ctDNA extracted from pre-treatment patients’ plasma were analyzed using Cancer Personalized Profiling by Deep Sequencing targeting 197 genes. Of 51 patients, 48 (94%) showed one or more non-synonymous somatic mutations, including TP53 (37.3%), APC (17.6%), KRAS (15.7%), EGFR (13.7%), MET (11.8%), PIK3CA (11.8%), NPAP1 (11.8%), and ALK (9.8%). The most frequently mutated genes were as follows: TP53 in high-grade serous carcinoma (66.7%), APC in clear cell carcinoma (30.8%), PIK3CA in endometrioid carcinoma (40%), and KRAS in mucinous carcinoma (66.7%). Higher cell-free (cf)DNA concentration significantly correlated with worse progression-free survival (PFS) in all patients as well as stage III–IV patients (p = 0.01 and 0.005, respectively). Further, patients with any pathogenic mutations showed significantly worse PFS (p = 0.048). Blood tumor mutational burden detected from ctDNA did not significantly correlate with the histological subtypes or survival. Collectively, clinico-genomic profiles of individual ovarian cancer patients could be identified using ctDNA and may serve as a useful prognostic indicator. These findings suggest that ctDNA-based gene profiling might help in establishing personalized therapeutic strategies.

Diagnostic and Prognostic Value of Circulating Cell-Free DNA for Cholangiocarcinoma

“…Although analysis of cfDNA and ctDNA has been shown to be an attractive diagnostic and prognostic tool in malignancies, including biliary tract cancers [15,20,21,39,40], very few studies have evaluated and compared the diagnostic efficiency of cfDNA analysis with current tumor markers used in clinical practice. In the present study, we assessed the diagnostic and prognostic value of cfDNA level in CCA, particularly to compare with benign biliary diseases using a simple, rapid, and sensitive fluorescence dye-based spectrophotometry as well as investigating the diagnostic value of somatic mutations in ctDNA of CCA patients.…”

Circulating tumor DNA: a noninvasive biomarker for tracking ovarian cancer

“…In a recent prospective study, gene mutations in ovarian cancer were detected using ctDNA analysis; 94% (48/51) patients carrying mutation were identified using the blood sample which highly consistent with surgical verification and related to progression-free survival (PFS) [ 27 ]. Such high detection efficiency is attributed to the advancement of technologies in genomic analysis.…”

“…Very few research currently have investigated the application of ctDNA analysis in addressing TH. Noguchi et al [ 27 ] recently elucidated the possibility of using ctDNA analysis for supervising treatment responses, including “tumor evolution”, which reflects the evolutionary changes in TH in the N-acetylcysteine-treated patients with advanced ovarian cancer [ 86 ]. In addition, Paracchini et al .…”

“…This characteristic, along with its circulating half-life, makes the detection of ctDNA a promising diagnostic tool. A series of comprehensive studies encompassing multiple primary tumor types (such as ovarian, bladder, and colorectal cancers) and/or stages revealed a 6-log variation in ctDNA content [ 26 , 27 ]. In addition, ctDNA has been detected in over half the cases of most cancer types [ 18 ], and has shown remarkable correlations with the molecular pathology of solid tumors [ 24 , 28 , 29 ].…”

How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development

“…Liquid biopsies of circulating tumor DNA (ctDNA) have recently been attracting attention as a non-invasive diagnostic and monitoring tool for solid cancers [ 48 , 49 ]. In s previous study, liquid biopsies from ctDNA and target sequencing were performed in 51 ovarian cancer patients with different histological subtypes [ 50 ]. In CCC, APC and DCAF12L1 were mutated preferentially (30.8%), followed by mutations in TP53 , PIK3CA , and PDGFRA mutations (23.1%).…”