Cancer Res Treat.  2020 Apr;52(2):634-644. 10.4143/crt.2019.207.

Clinical Impact of Somatic Variants in Homologous RecombinationRepair-Related Genes in Ovarian High-Grade Serous Carcinoma

• Choi MC
• Hwang S
• Kim S
• Jung SG
• Park H
• Joo WD
• Song SH
• Lee C
• Kim TH
• Kang H
• An HJ

• KMID: 2500347
• DOI: http://doi.org/10.4143/crt.2019.207

Abstract

Purpose
In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian highgrade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADPribose) polymerase inhibitors.
Materials and Methods
Tissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.
Results
BRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone.
Conclusion
DNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCAmutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

Keyword

Epithelial ovarian carcinomas; Homologous recombination repair; Massively parallel sequencing

Figure

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  Fig. 1. Histologic features of high-grade ovarian serous carcinoma. (A) High-grade serous carcinoma (HGSC) composed of papillary, glandular patterns with large, hyperchromatic, pleomorphic nuclei and numerous mitoses is shown (H&E staining, ×200). (B) Diffuse strong positive reaction to immunohistochemical stain for p53 in HGSC is shown (p53 immunohistochemical stain, ×200).

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  Fig. 2. Pathogenic variants (n=98) in 77 ovarian cancer patients. TP53 was mutated in 80.5% of cases, the highest frequency among the 39 genes analyzed. BRCA1 and BRCA2 were mutated in 28.6% and 5.2% of cases, respectively. The color of each cell represents the type of variant: blue, indel; red, stop-gain; green, missense; orange, splicing; gray, NA (data not available); and white, wild type.

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  Fig. 3. The prognosis of two groups of patients, classified according to pathogenic variants. (A) Two groups were defined by their status for the pathogenic variants described in Fig. 1. Group 1 consisted of patients with any pathogenic mutations in the 38 DNA damage repair genes regardless of TP53 mutation status. Group 2 consists of patients with only TP53 mutations. Overall survival (OS) and disease-free survival (DFS) of the two groups are shown in B and C, respectively. NA, not available.

Reference

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