Frequency of homologous recombination associated gene mutations in Japanese patients with ovarian cancer

Abstract

<h3>Objectives:</h3> Homologous recombination deficiency (HRD) is a well-known biomarker of PARP inhibitor sensitivity. The Cancer Genome Atlas (TCGA) has clarified that about 50% of high-grade serous ovarian cancer shows HRD. However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. The aim of JGOG3025 study (NCT03159572) is to identify the frequency of HR-associated gene mutations in ovarian cancer, especially non-serous histologic types. <h3>Methods:</h3> The JGOG3025 study is a collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 711 patients were eligible for JGOG3025 criteria. After central pathological review, we used frozen tumor tissues to extract DNA and performed targeted sequencing for 51 HR-associated genes in 711 ovarian cancers (298 high-grade serous, 189 clear cell, 142 endometrioid, 15 mucinous, 4 low-grade serous, and 63 others). <h3>Results:</h3> To focus on pathogenic mutations of HR-associated genes which led to HRD, we used only loss-of-function (LOF) mutations (nonsense, readthrough, and frameshift) to perform subsequent analysis. At least one HR-associated gene was mutated in 105 high-grade serous (35.2%), 21 clear cell (11.1%), 36 endometrioid (25.4%), 1 low-grade serous (25.0%) carcinomas. Although 81.8% of ovarian cancers with <i>BRCA1</i> LOF mutation were diagnosed as high-grade serous type, one case of mucinous carcinoma harbored <i>BRCA1</i> c.1961delA. On the other hand, 71.4% of ovarian cancers harboring <i>BRCA2</i> LOF mutation were high-grade serous type. Mutant allele frequencies of <i>BRCA1</i> and <i>RAD51D</i> were apparently higher than that of other HR-associated genes, suggesting allelic imbalance. <h3>Conclusions:</h3> Our findings demonstrated that mutations in HR-associated genes were detected in not only high-grade serous but also non-serous histologic type ovarian cancers. To clarify the frequency of HRD in Japanese patients with ovarian cancer, we need to assess the pathogenicity of missense mutations and investigate the correlation between HR associated gene mutations and HRD score based on copy number assay.