Mutation Landscape of Homologous Recombination Repair Genes in Epithelial Ovarian Cancer in China and Its Relationship With Clinicopathlological Characteristics

Qianlan Yao; Yanhui Liu; Lihua Zhang; Lin Dong; Longlong Bao; Qianming Bai; Qian Cui; Jie Xu; Min Li; Jing Liu; Shannon Chuai; Jianming Ying; Zhihong Zhang; Xiaoyan Zhou

doi:10.3389/fonc.2022.709645

Mutation Landscape of Homologous Recombination Repair Genes in Epithelial Ovarian Cancer in China and Its Relationship With Clinicopathlological Characteristics

Front Oncol. 2022 Feb 3:12:709645. doi: 10.3389/fonc.2022.709645. eCollection 2022.

Authors

Qianlan Yao^{1

2

3}, Yanhui Liu⁴, Lihua Zhang⁵, Lin Dong⁶, Longlong Bao^{1

2

3}, Qianming Bai^{1

2

3}, Qian Cui⁴, Jie Xu⁴, Min Li⁷, Jing Liu⁷, Shannon Chuai⁷, Jianming Ying⁶, Zhihong Zhang⁸, Xiaoyan Zhou^{1

2

3}

Affiliations

¹ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Institute of Pathology, Fudan University, Shanghai, China.
⁴ Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
⁵ Department of Pathology, Southeast University, Zhongda Hospital, Nanjing, China.
⁶ Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁷ Burning Rock Biotech, Guangzhou, China.
⁸ Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Abstract

Objective: The status of homologous recombination repair (HRR) gene mutations and their impact on the survival of patients with Chinese epithelial ovarian cancer (EOC) are still unclear. In this study, we retrospectively analyzed the mutations of HRR genes in tumor tissues and evaluated their values for predicting the survival of Chinese EOC patients.

Methods: A total of 273 primary EOC patients from five different hospitals between 2015 and 2016 were recruited. All patients received staging surgeries or debulking surgeries combined with systemic platinum-based chemotherapy. DNA was extracted from formalin-fixed, paraffin-embedded sections and analyzed for mutations using a 21-gene panel (including 13 well-known HRR genes) by next-generation sequencing.

Results: High-grade serous carcinoma (HGSOC) accounted for 76.2% of the cohort. A total of 34.1% (93/273) cases had 99 deleterious mutations in 9 HRR genes, namely, BRCA1 (56/273, 20.5%), BRCA2 (20/273, 7.3%), ATM (5/273, 1.8%), RAD51C (5/273, 1.8%), RAD51D (5/273, 1.8%), BRIP1 (2/273, 1.8%), CHEK2 (2/273, 0.7%), FANCI (2/273, 0.7%), and RAD54L (1/273, 0.4%). There is a strong mutual exclusion between HRR genes. The mutation landscape revealed several unappreciated deleterious variants in BRCA1/2 and other HRR genes reported previously. Estimated according to the mutation allele frequency, about 4.8% of the patients had potential somatic HRR gene mutations, which might be underestimated. Moreover, HRR mutations mainly exist in HGSOC (83/208, 39.9%), clear cell (2/30, 6.7%), and endometroid subtypes (8/20, 40%), but not seen in other rare subtypes. BRCA1 mutations tend to be present in younger patients with family history or multiple primary foci. Patients with BRCA1/2 mutations tend to have a longer progression-free survival and overall survival, while other HRR mutation carriers tend to have a shorter progression-free survival, but no significant difference in overall survival.

Conclusion: This study revealed the distribution of HRR gene mutations in Chinese EOC tissues. BRCA1/2 account for the majority of HRR gene mutations and predict long prognosis in HGSOC. Non-BRCA HRR mutations also account for a very important proportion and might be associated with poor prognosis in HGSOC. It is suggested that HRR gene mutations need to be detected in EOC tissues and germline status be further clarified in clinical algorithm for potential targeted therapy, genetic screening, and prognosis prediction.

Keywords: homologous recombination repair gene; mutation; next-generation sequencing; ovarian cancer; survival.