Abstract
High grade serous ovarian cancer (HGSOC) retains high molecular heterogeneity and genomic instability, which currently limit the treatment opportunities. HGSOC patients receiving complete cytoreduction (R0) at primary surgery and platinum-based therapy may unevenly experience early disease relapse, in spite of their clinically favorable prognosis. To identify distinctive traits of the genomic landscape guiding tumor progression, we focused on the R0 patients of The Cancer Genome Atlas (TCGA) ovarian serous cystadenocarcinoma (TCGA-OV) dataset and classified them according to their time to relapse (TTR) from surgery. We included in the study two groups of R0-TCGA patients experiencing substantially different outcome: Resistant (R; TTR ≤ 12 months; n = 11) and frankly Sensitive (fS; TTR ≥ 24 months; n = 16). We performed an integrated clinical, RNA-Sequencing, exome and somatic copy number alteration (sCNA) data analysis. No significant differences in mutational landscape were detected, although the lack of BRCA-related mutational signature characterized the R group. Focal sCNA analysis showed a higher frequency of amplification in R group and deletions in fS group respectively, involving cytobands not commonly detected by recurrent sCNA analysis. Functional analysis of focal sCNA with a concordantly altered gene expression identified in R group a gain in Notch, and interferon signaling and fatty acid metabolism. We are aware of the constraints related to the low number of OC cases analyzed. It is worth noting, however, that the sCNA identified in this exploratory analysis and characterizing Pt-resistance are novel, deserving validation in a wider cohort of patients achieving complete surgical debulking.
Highlights
High grade serous ovarian cancer (HGSOC) is the most common and lethal epithelial ovarian cancer (EOC) subtype, causing 70–80% of ovarian cancer deaths worldwide [1]
The concept of optimal cytoreduction is evolving along time and, the metric for optimal debulking is still defined as tumor nodules not greater than 1 cm, the literature and meta-data analysis clearly show that R0 patients, those with no residual tumor after primary surgery, have the best overall outcome
To possibly identify molecular traits associated with Pt-resistant disease in R0 patients we analyzed their genomic portrait in comparison to those of R0 patients with good prognosis
Summary
High grade serous ovarian cancer (HGSOC) is the most common and lethal epithelial ovarian cancer (EOC) subtype, causing 70–80% of ovarian cancer deaths worldwide [1]. Standard treatment includes aggressive primary debulking surgery (PDS). Genes 2019, 10, 678 followed by platinum (Pt)-based therapy; but, despite the improvement of surgical approaches and drug development, survival rate has changed little in the last decades [2]. Pt-based therapy remains the cornerstone treatment type and, currently, BRCA1/2 mutation status is the only biomarker that allows up-front identification of patients with Pt-sensitive or resistant disease [3]. Around 30% of patients undergoing Pt-based chemotherapy do not respond to treatment. Around 80% of those patients achieving complete response will relapse with a median progression-free survival of 18 months, developing a disease that progressively becomes
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