Research On BRCA Mutations And Clinical Pedigree Analysis In Patients With Sporadic And Familial Ovarian Cancer

Background and purpose:Ovarian cancer?OC?is one of the most common gynecological malignancies,and its early diagnosis is difficult,nearly 80% of patients are diagnosed in advanced stage.The fatality rate of ovarian cancer rank first among gynecological malignancies,seriously endangering the life and health of Chinese women.Genetic factors as one of the important factors in the pathogenesis of ovarian cancer have been widely concerned and studied in recent years.And about 90% of patients with inherited ovarian cancer have mutations in the BRCA gene.In China,studies on BRCA mutations associated with breast cancer are relatively extensive,while studies on the correlation of ovarian cancer are relatively few,most of which are limited to the analysis of BRCA mutations and clinical characteristics of familial ovarian cancer.In order to further enrich the ovarian cancer related BRCA gene mutation in the Chinese people,this study conducted an in-depth study on the BRCA gene mutations and clinical characteristics of ovarian cancer with different family histories and a pedigree analysis of familial ovarian cancer patients with BRCA mutations.Subjects and Methods Subjects:?1?inclusion criteria for patients with sporadic ovarian cancer: 1)patients with primary ovarian cancer confirmed by pathology;2)no history of breast cancer or ovarian cancer in the third generation of lineal blood relatives;3)the patient himself has no history of breast cancer;4)with complete clinical and medical records.?2?inclusion criteria for patients with familial ovarian cancer: 1)pathologically confirmed primary ovarian cancer;2)at least two first or second degree relatives in the family have primary ovarian cancer or both have ovarian cancer and breast cancer;3)there is at least one patient in the family with ovarian and breast cancer,with or without other relatives in the family with ovarian cancer or breast cancer.The following criteria should be met for ovarian and breast cancer: 1)each tumor is malignant;2)two tumors of the same patient are not related;3)each tumor of the same patient has a different pathological morphological characteristics;4)with complete clinical and medical records.A total of 95 patients with sporadic ovarian cancer and 21 patients with familial ovarian cancer were included.Methods :?1?after obtaining the informed consent of each patient involved in the study,peripheral blood DNA of ovarian cancer patients was extracted for BRCA gene mutation detection.For mutations with unclear meanings,Align-GVGD,Mutation Taster and Predict SNP were used to predict them,and their effects on protein structure and function were preliminarily analyzed.?2?the age of onset,menopausal status,family history of cancer,abdominal volume,tumor markers at the time of first treatment,tumor grade,stage,chemotherapy sensitivity and prognosis of the BRCA mutation group and the non-mutation group in patients with sporadic ovarian cancer were analyzed and compared.?3?investigate the membership information of familial ovarian cancer patients with BRCA mutations,draw the pedigree tree and analyze the incidence and characteristics of cancer in the proband and each generation of the family.Results:?1?In 116 cases of ovarian cancer,the total BRCA1/2 mutation rate was 16.4%?19/116?,in which the BRCA1/2 mutation rate was 11.2%?13/116?and 5.2%?6/116?,respectively.The BRCA1/2 mutation rate in sporadic ovarian cancer patients was10.5%?10/95?,and that in familial ovarian cancer patients was 42.9%?9/21?,with a statistically significant difference?P=0.001?.75%?9/12?of the BRCA1 pathogenic mutations and 71.4%?5/7?of the BRCA2 pathogenic mutations were located in exon 11.One case of the pathogenic mutation of BRCA1?c.2138C>G?was a repeat mutation.Three pathogenic mutations of BRCA1?c.3689T>A,c.5332 del G,c.5384 dup T?and two pathogenic mutations of BRCA2?c.3471₃473delins ATG,c.4936₄940del GAAAC?were found.17 cases of BRCA1/2 mutations with unknown significance were found,and the results of computer simulation analysis on 3 controversial mutations reported in Clin Var suggested that NM₀07294.3:c.2286A>T and NM₀00059.3:c.2946A>G were more likely to be benign,while NM₀07294.3:c.5339T>C was more likely to be pathogenic.9 BRCA mutations of unknown significance were found,including 2 BRCA1 mutations?c.3083G> c,c.4293G>T?,and 7 BRCA2 mutations?c.1370A>C,c.3803C>A,c.5901G>T,c.6710 A >G,c.8187G>T,c.8382C>A,c.8657C>A?.The results of NM₀07294.3:c.1367T>C,NM₀07294.3:c.4293G>T,NM₀00059.3:c.1367T>C,NM₀00059.3:c.4293G>T in the three analytical tools are inconsistent respectively.Their properties need to be further determined.?2?Among the 95 patients with sporadic ovarian cancer,11 were in the BRCA mutation group and 84 were in the non-BRCA mutation group.The average age of onset was56.73±12.21 years in the mutant group and 53.29±14.48 years in the non-mutant group,with no significant difference?P=0.453?.There was no significant difference between the mutant group and the non-mutant group in age of menarche?P=0.172?,menopausal status at onset?P=0.517?,family history of tumor?P=0.684?,level of tumor marker CA125?P=0.520?and level of HE4?P=0.726?before treatment.However,the BRCA mutation rate was less than that of the non-mutation rate in patients with large ascites before treatment,which showed significant statistical significance?P=0.014?.There was no significant difference in tumor stage?P=0.318?,grade?P=0.468?,lymph node metastasis rate?P=1.000?,and surgical satisfaction rate?P=1.000?between the mutant group and the non-mutant group.The tumor pathology of the BRCA mutant group was 100% serous carcinoma,while that of the non-mutant group was only 71.4% serous carcinoma?P=0.060?.The BRCA mutation group had a higher proportion of patients with postoperative adjuvant chemotherapy sensitivity?100.0% vs.67.1%?than the non-mutant group,with a statistically significant difference?P=0.030?.The BRCA mutant group was followed up for 10-32 months,with a median follow-up of 22 months;the non-mutant group was followed up for 1-32 months,with a median follow-up of 16 months.Kaplan-Meier analysis showed significant effects of BRCA mutations?P=0.022?,age of onset?P=0.003?,menopause?P=0.001?,initial abdominal volume?P=0.003?,tumor stage?P=0.003?,chemotherapy sensitivity?P<0.001?,and surgical satisfaction?P=0.001?on progression-free survival?PFS?.The results of multivariate analysis showed that chemotherapy sensitivity was an only independent factor influencing progression-free survival?OR=12.61,95%Cl 4.69-33.90,P<0.001?.Kaplan-Meier factor analysis results show that the initial abdominal water?P=0.003?,tumor staging surgery?P=0.042?,surgical satisfaction?P<0.001?,the sensitivity of chemotherapy?P<0.001?has a significant impact on overall survival?OS?,multi-factor analysis showed that the initial abdominal water,chemotherapy sensitivity,surgical satisfaction were independent influent factors for overall survival?OS?.?3?The mean age of onset was 54.50±8.98 years for the 10 BRCA mutant probands,with no significant difference from that?56.73±12.21 years?of the BRCA mutant patients with sporadic ovarian cancer?P=0.657?.However,most of the probands were sensitive to platinum-based chemotherapy,and the only two drug-resistant patients were all carry the same BRCA1 mutation?c.2138c>G?.More studies are needed to explore the correlation between the two.The total incidence of malignant tumors among first-degree relatives of the probands was 26.4%.The incidence rate of malignant tumors among male first-degree relatives was 21.2%?7/33?,with colorectal cancer and lung cancer common.The cancer incidence rate of female first-degree relatives was 30.8%,and the cancer types of female first-degree relatives were mainly ovarian cancer and breast cancer.The mean age of onset of ovarian cancer in the proents' parents was 64.00±8.76 years,and the mean age of onset was53.08±8.81 years in all the second-generation ovarian cancer patients?the probands and the patients that of the same generation with the probands in predigree tree?,with a statistically significant difference?P=0.046?.Conclusions :?1?The frequency and type of BRCA mutant ovarian cancer patients in China are specific to some extent.No BRCA mutations with significant founder effect have been found in this study,but some repeated mutations and mutations of unknown significance need further exploration.?2?It is necessary to conduct comprehensive BRCA gene testing for all ovarian cancer patients.?3?For BRCA mutant sporadic ovarian cancer patients that have no familicial cancer history,low ascites,ype of serous pathology and sensitivity to first-line platinum based chemotherapy are possible predictors of BRCA positivity?4?Attention should be paid to timely detection and effective intervention for offsprings of BRCA mutant ovarian cancer patients to avoid the occurrence of early-onset cancers.At the same time,BRCA gene mutation should be taken into consideration for genetic testing and counseling for families with digestive system tumors or lung cancer.