The Prognostic Analysis Of Serum CA125 Expression Combined With BRCA In Ovarian Cancer Patients

BackgroundOvarian cancer is the leading cause of cancer-associated death in the female reproductive system,and breast cancer susceptibility gene(BRCA)is believed to be the most significant risk factors.BRCA genes have important functions in homologous recombination(HR)during DNA double-stranded damage.If BRCA genes have mutations or abnormalities,it will lead to chromosome instability,promote cell proliferation,prevent normal cell differentiation,and ultimately accelerate the formation of tumors.Studies have found that the prevalence of germline BRCA mutation was 5.8–24.8% in patients with OC,while women with a BRCA mutation have a highly increased lifetime risk and a tendency to develop OC at a younger age.The average cumulative risks of developing OC by age 70 years old for BRCA1 and BRCA2 carriers were estimated to be 39%(ranging 18~54%)and11%(ranging 2.4~19%),respectively.The risks of developing BC by age 70 years old for BRCA1 and BRCA2 mutations were 44~78% and 31~56%,respectively.The OC with BRCA gene mutations had a tendency to develop higher-grade tumor,endometrium or serous ovarian cancer with a favorable progression-free survival(PFS)and overall survival(OS).The National Comprehensive Cancer Network(NCCN)recommended that BRCA gene testing be performed on high-risk groups,and the women who had the BRCA genes mutation needed to take the CA125 levels and vaginal ultrasonography to prevent the risk of ovarian cancer,and take the bilateral mastectomy and bilateral salpingo-oophorectomy to reduce the risk of breast cancer and ovarian cancer.The synthetic lethality of BRCA genes mutation and PARP inhibitors has made the new treatment of OC patients with BRCA mutated type.The development of next generation sequencing and the Standards and guidelines of American College of Medical Genetics and Genomics(ACMG)made it more convenient and standard.In addition,it is not clear whether BRCA mutations were associated with the levels of serum tumor markers(STMs)including CEA,CA125,CA199,and HE4.No studies were found about the diagnostic value of BRCA combined STM detection in ovarian cancer.ObjectiveIn this study,the BRCA gene mutations were screened using next-generation sequencing(NGS),and then analyzed the relation between BRCA mutations and the clinicopathologic features.The serum levels of STM CEA,CA125,CA199,and HE4 were measured by the chemiluminescence methods in these patients to determine the prognostic role of these markers and their association with genetic mutations.We also studied the relationship of family history,BRCA genes mutation,STM expression level and PFS and combined the above indicators to assess the diagnosis and treatment value of ovarian cancer patients.MethodsThis prospective study was approved by the Henan Cancer Hospital ethics committee and all participants signed a written informed consent.The 97 patients,recruited between 2013 and 2014,were categorized as 31 FOC and 66 SOC cases,allof whom were pathologically diagnosed with ovarian cancer.Venous blood was drawn from all ovarian cancer patients on the day of hospitalization to detect serum tumor markers including CEA,CA125,CA199 and HE4 using the chemiluminescence immunoassay analyzers.The patients in both groups received the same treatment(primary cytoreductive surgery followed by chemotherapy with paclitaxel combined platinum).Surgical stage and cell type were categorized according to the FIGO(International Federation of Gynaecology and Obstetrics)and WHO(World Health Organisation)standards.Clinical data including surgery type,menopausal status,tubal ligation and lymphatic metastasis were collected.All patients received standard follow-up examination,including routine clinical examination and measurement of serum CA125,after diagnosis to track the progress of the disease.Abdomino–pelvic computerized tomography(CT)scans were prescribed in cases with symptoms,clinical findings,or CA 125 elevation.Total genomic DNA was isolated from peripheral blood using the TIANamp genomic DNA kit,and the BRCA1/2 gene mutations were screened using next-generation sequencing(NGS)methods.All mutations were valued according to the Standards and guidelines of the American College of Medical Genetics and Genomics(ACMG).Mutations detected by the Miseq platform were confirmed by target directed Sanger sequencing.Statistical analysis was performed using SPSS 21.0 software.Results1 There was a significant difference in the occurring rate of BRCA gene mutations between FOC(54.8%,17/31)and SOC cases(19.7%,13/66)(P < 0.001).However,the proportion of BRCA1 and BRCA2 was not statistically significant between FOC and SOC(P > 0.05).2 Among the familial group,ten OC patients with breast cancer(BC)were selected whose BCs were all the first tumor,of which the mean age of BCs and the relapse of OCs at diagnosis was 46.5(95%CI 42.7-50.3)and 54.2(95%CI 50.1-58.3)years old,respectively.Moreover,the average interval was 7.5(95%CI 3.9-11.1)years.While no significant differences of BRCA mutations were observed betweenthese FOC patients and other SOC patients.3 The mean age at diagnosis for BRCA genes was 51.0 years old,while BRCA1 and BRCA2 was 51.7 and 52.1 years old,respectively(P > 0.05).Besides,no significant differences were observed in menopausal status,stage,distant metastasis between BRCA mutated and wild patients(P > 0.05).4 There was a significant linear correlation(P < 0.001,r = 0.442)between CA125 and HE4 in the linear regression model.We also observed the same correlation(P < 0.001,r = 0.895)between the levels of CEA and CA199.While a significant difference was only found in the level of CA125,but not other STMs,between SOC and FOC or between BRCA-and BRCA+ patients.5 By Fisher's exact tests,we found that the proportion of patients with higher CA125 serum levels was significantly higher in BRCA+ patients than in BRCA-ones in SOC,but not in FOC.There was a trend(P = 0.189)that the percent of patients with a higher level of HE4 was higher in BRCA+ patients than in BRCA-patients.6 Multiple logistic regression analysis of clinical pathological features about FH and CA125 expression with BRCA gene mutation was performed and found that FH and CA125 were significant predictors for BRCA mutations(P < 0.05).The odds ratio of FOC and CA125(>2000u/ml)were 12.135(95%CI,2.786-52.860)and11.450(95%CI,2.437-53.789),respectively.7 Median PFS was significantly longer in the FOC group,CA125(> 2000U/ml)and BRCA mutated OC patients,and CA125 higher expression(> 2000U/ml)combined BRCA mutation and FH showed the longer PFS.Conclusions1 BRCA mutations were more frequently detected in FOC than in SOC,and the he elevated serum level of CA125,but not HE4,CEA,and CA199,was associated with BRCA mutations,which demonstrated that the family history and CA125 expression could be used a good factor to screen BRCA mutations.2 The high level of CA125 expression was associated with BRCA mutations in SOC patients,and could be used to guide the BRCA testing in SOC patients.3 A high level of CA125 was associated with superior prognosis in BRCA+ or FOC patients,and should be further investigated as a prognostic biomarker to assess assess the diagnosis and treatment value of ovarian cancer patients.