Retrospective analysis of non-BRCA gene pathogenicity variation in Chinese patients with ovarian cancer.

person Li yuan Guo Harbin Medical University Cancer Hospital, Harbin, China info_outline Li yuan Guo, Tiantian Han, Didi Guo, Juan Ma, Yaping Zhao, Fanfeng Bu, Siqi Chen, Wanglong Deng, Ran Ding

Authors person Li yuan Guo Harbin Medical University Cancer Hospital, Harbin, China info_outline Li yuan Guo, Tiantian Han, Didi Guo, Juan Ma, Yaping Zhao, Fanfeng Bu, Siqi Chen, Wanglong Deng, Ran Ding Organizations Harbin Medical University Cancer Hospital, Harbin, China, The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China, The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China, Jiangsu Simcere Diagnostics Co., Nanjing, China, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China Abstract Disclosures Research Funding No funding received Background: Ovarian cancer (OC) is the most lethal gynecologic cancer. Pathogenic (harmful) variants（PV) in BRCA1 and BRCA2 are the strongest hereditary risk factors for the development of ovarian cancer. To date, there is little information regarding the frequency of non- BRCA gene PV in Chinese women with OC that undergo genetic cancer risk assessment. In this study we analyzed wild-type BRCA1/2 OC patients (pts) registered in our database. Methods: Peripheral blood of 766 women, diagnosed with ovarian cancer, were taken from the recruited cases with the consent of performing germline genetic testing. Germline mutations including SNV, small INDEL were analyzed by next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 766 OC pts, 460 pts (60%) underwent BRCA1/2 testing only, while 306 pts (40%) consented in multigene panel testing (MGPT). BRCA1/2 detection rate was 16.8% (129/766), while the detection rate for non- BRCA genes was 7.5% (23/306). There was a significant statistical difference in average age that the non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group (62 vs. 57, p=0.018). Wild-type B RCA1/2 OC pathogenic variants (PV), were diagnosed in BLM (n=4, 17.4%), ERCC5 (n=2, 8.7%), MUTYH (n=2, 8.7%), RAD51C (n=2, 8.7%), RAD51D (n=2, 8.7%), ATM (n=1, 4.4%), BRIP1 (n=1, 4.4%), CDH1 (n=1, 4.4%), CHEK2 (n=1, 4.4%), ERCC4 (n=1, 4.4%), LZTR1 (n=1, 4.4%), MSH3 (n=1, 4.4%), PALB2 (n=1, 4.4%), PMS2 (n=1, 4.4%), RAD50 (n=1, 4.4%) and SLX4 (n=1, 4.4%) genes. Of all the 23 non- BRAC gene pathogenicity variations, 57% (13/23) lay in the Homologous Recombination Repair (HRR) pathways. Moreover, a 48-year-old woman with ovarian cancer with two pathogenic variants of the [ BRCA2 - MUTYH ] genes was detected in the retrospective cohort study. Conclusions: BLM , ERCC5 , MUTYH, RAD51C and RAD51D genes are the main contributors to hereditary wild-type BRCA1/2 OC in our cohort. The average age of non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group. Therefore, multi-gene PANEL detection is recommended for ovarian cancer patients, especially for older patients.