Studies On The Expression Of Key Proteins Of Homologous Recombination Repair And The Abnormal Mutation Of The Related Genes In Epithelial Ovarian Cancer

Research objectivesOvarian cancer is the most lethal gynecologic malignancy.More than 90% of ovarian malignancy originates from epithelial tissue.Within cells,PARP is mainly responsible for the repair of DNA single-strand break(SSB).PARP inhibitors can inhibit SSB repair and convert SSB into DNA double-strand break(DSB).The survival of cells with DSB often depends on the complete homologous recombination(HR)repair pathway.Ovarian cancer patients with BRCA mutations are suitable for the treatments using PARP inhibitors due to their defects in HR pathway.In recent years,researchers have found that PARP inhibitors also have certain inhibitory effects on ovarian cancer with HR-defects caused by other reasons.Therefore,this study aims to investigate the proportion and the phenotypes of patients with HR-defects and the possible mechanisms.Basing on this knowledge,we hope we can provide a theoretical basis for the clinical application of PARP inhibitors in epithelial ovarian cancer.Research methodsParaffin sections of 84 cases of primary epithelial ovarian cancer and 6 cases of normal ovarian epithelial tissues were collected and subjected to immunohistochemistry.Expression of the four key proteins of HR repair pathway,namely BRCA1,BRCA2,FANCD2 and RAD51,were accessed in these tissues.The mutations in 30 HR-related genes were detected by whole exome sequencing.Research resultsThe 84 epithelial ovarian cancer cases included 55 serous,16 mucinous,and 13 clear cell ovarian cancers.The results of immunohistochemistry showed that the positive expression rates of BRCA2,FANCD2 and RAD51 in epithelial ovarian cancer tissues were significantly higher than those in normal ovarian epithelial tissues(P=0.008,P=0.036,P=0.000).The results of whole exome sequencing indicated that 62.5% of patients with epithelial ovarian cancer harboring abnormal HR gene mutations,and there were 78 mutation sites in total.In addition,the abnormal mutation frequencies of HR repair genes of BRCA2,BRCA1,FANCM,RAD54 B,ATM,ATR,PALB2,RAD51 B,BRIP1,FANCA,FANCD2,RAD54 L,BLM,DNA2,FANCG,FANCI,RAD51 C,CHEK2,FANCC,FANCE,FANCF and RPA1 in 72 epithelial ovarian cancer were 15.28%,11.11%,8.33%,8.33%,6.94%,6.94%,6.94%,6.94%,5.56%,5.56%,4.17%,4.17%,2.78%,2.78%,2.78%,2.78%,2.78%,1.39%,1.39%,1.39%,1.39% and 1.39%,respectively.No abnormal variants were detected in CHEK1,CtIP,EXO1,FANCB,FANCL,RAD51,RAD52 and RAD51 D.Research conclusions and significanceThe significantly increased levels of BRCA2,FANCD2 and RAD51 proteins are highly correlated with the occurrence of epithelial ovarian cancer.More than half of epithelial ovarian cancer patients have abnormal mutations in HR genes.This study provides a new reference and research direction for the diagnosis and treatment of ovarian cancer.