Mutation Of DNA Damage Repair Pathway-related Genes In High-grade Serous Ovarian Cancer By Whole-exome Sequencing

Objective: To study the mutations of DNA damage repair pathway(DDR)-related genes in high-grade serous ovarian cancer patients in China by whole-exome sequencing(WES).Methods: The serous ovarian cancer tissue specimens used in this study were from the Fourth Hospital of Hebei Medical University.A total of 12 high-grade serous ovarian carcinomas were screened for this study.DNA was first extracted from the fresh surgical tissues of these 12 patients and then captured using Aglient SureSelect Human All Exon V6,followed by sequencing on the Illumina-NovaSeq 6000.After quality control of the sequencing data,the panel of normals(PON)and the dbSNP database were used to remove the germline mutations,and the 276 genes listed by Knijnenburg et al.were used to screen out the DDR-related genes that were mutated in each ovarian cancer sample.Results:1.The sequencing data by WES of the 12 high-grade serous ovarian cancers were obtained,and the average sequencing depteh is > 200 x.2.The main mutation form of the 12 high-grade serous ovarian cancer is missense mutation,mainly C>T and T>C.3.The mutated genes in the 12 high-grade serous ovarian cancer are related to various physiological activities of cells,such as WNT,NOTCH,Hippo and other signaling pathways.These pathways can be classified into two types: activation of proto-oncogenes,such as RTK-RAS and PI3 K signaling pathways,and inactivation of tumor suppressor genes,such as TP53,NOTCH,cell cycle and other signaling pathways.4.The mutation characteristics of the genes associated with the DDR pathways are the same as that of all the genes,and the main mutation form is missense mutation.The main mutation genes include TP53,GEN1,HERC2,MSH3,BRCA1.The mutation frequency of TP53 is as high as 75%,and there is no hot spot mutation.5.There is correlation between the genes mutated in high-grade serous ovarian cancer.The mutations of TP53,POLN and TOP3 A are mutually exclusive,while MSH3,POLN and WRN are co-mutated.Conclusion:1.Mutations in DDR pathway-related genes are closely related to the occurrence of high-grade serous ovarian cancer.The homologous recombination repair pathway gene was mutated and may benefit from PRAP inhibitors.2.Mutations in the DDR pathway may be associated with a tumor mutation burden.3.The higher frequency of DDR pathway mutations in high-grade serous ovarian cancer are TP53,GEN1,HERC2,MSH3,and BRCA1.4.Correlations are found between the genes mutated in high-grade serous ovarian cancer.The mutations of TP53,POLN and TOP3 A are mutually exclusive,while MSH3,POLN and WRN are co-mutated.Since the sample size is small,further verification is needed.