Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients

Kentaro Sugino,Ituro Inoue,Sosuke Adachi,Masayuki Yamaguchi,Takayuki Enomoto,Ryo Tamura,Yutaro Mori,Kazuaki Suda,Tatsuya Ishiguro,Masanori Isobe,Manako Yamaguchi,Teiichi Motoyama,Kosuke Yoshihara,Katsunori Kashima,Kaoru Yamawaki,Nozomi Yachida,Hirofumi Nakaoka

doi:10.1038/s41598-019-54116-y

Kentaro Sugino, Ituro Inoue + Show 15 more

Open Access

https://doi.org/10.1038/s41598-019-54116-y

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Abstract

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

Highlights

We explored the frequency of germline and somatic mutations in homologous recombination (HR)associated genes in major histological types of ovarian cancer
More than half of high-grade serous ovarian carcinoma (HGSC) and low-grade serous carcinoma (LGSC) patients were at stage III, over 60% of cell carcinoma (CCC), endometrioid carcinoma (EC), and mucinous carcinoma (MC) patients were at stage I
We demonstrated the frequency of germline and somatic HR-associated gene mutations in Japanese patients with ovarian cancer

Summary

Introduction

We explored the frequency of germline and somatic mutations in homologous recombination (HR)associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). HR pathway alterations are most frequently observed in high-grade serous ovarian carcinoma (HGSC) and breast cancer[2]. We aimed to identify the frequency of germline and somatic HR-associated gene mutations per major histological subtypes of ovarian cancer in Japan, suggesting the therapeutic strategy of PARP inhibitors for ovarian cancers with HR-associated gene mutations

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