A DNA Damage Response Gene Panel for Different Histologic Types of Epithelial Ovarian Carcinomas and Their Outcomes.

Ying-Cheng Chiang,Kuan-Ting Kuo,Chia-Ying Wu,Hung Shen,Chia-Yi Lee,Tzu-Pin Lu,Yi-Jou Tai,Po-Han Lin,Wen-Fang Cheng,Heng-Cheng Hsu,Chi-An Chen

doi:10.3390/biomedicines9101384

Ying-Cheng Chiang, Kuan-Ting Kuo + Show 9 more

Open Access

https://doi.org/10.3390/biomedicines9101384

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Abstract

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p < 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma.

Highlights

Epithelial ovarian carcinoma (EOC) is a major cause of death in women worldwide, and patients are usually diagnosed at an advanced stage with a 5-year survival of less than 50% [1,2,3,4]
We investigated the somatic mutations of DNA damage response (DDR) genes in 172 EOC patients using a targeted DDR gene panel using a next-generation sequencing method
Our study showed that nearly half of the epithelial ovarian cancer (EOC) patients had DNA damage response (DDR) gene mutations with varied proportions of histological subtypes

Summary

Introduction

Epithelial ovarian carcinoma (EOC) is a major cause of death in women worldwide, and patients are usually diagnosed at an advanced stage with a 5-year survival of less than 50% [1,2,3,4]. Clinical prognostic factors include cancer stage, histological subtypes, Biomedicines 2021, 9, 1384. Biomedicines 2021, 9, 1384 tumor grade, residual tumor size after debulking surgery and response to chemotherapy. Despite an initial good response to primary treatments of debulking surgery and adjuvant platinum-based chemotherapy, the majority of patients experience a cancer relapse that is resistant to salvage treatments and eventually die of the disease [4,5]. Maintenance therapy with PARPi has revised the management of EOC in newly diagnosed and recurrent diseases. The identification of BRCA mutations or homologous recombination deficiency (HRD) status is critical for selecting potential patients, but both positive and negative patients as defined by current

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