Research On BRCA1/2 Mutations And Its Clinical Importance In Ovarian Cancer Patients From Families At Risk Of Hereditary Ovarian Cancer And Patients With Sporadic Ovarian Cancer

Background & Objective:Ovarian cancer has the highest mortality rate in gynecological malignancies, and family history is one of the most important risk factors for epithelial ovarian cancer.5% to 10% of ovarian cancer is inherited, and 80% to 90% of hereditary ovarian cancer is due to the mutations of BRCA1 or BRCA2. Currently, genetic testing for BRCA1 and BRCA2 in women with a strong family history of ovarian and/or breast cancer are accepted as the most effective method for the screening of hereditary ovarian cancer. All exons of BRCA1/2 were analyzed in this study, in order to assess the prevalence of BRCA1/2 mutations among clinic-based patients from families at risk of hereditary ovarian cancer and patients with sporadic ovarian cancer in mainland China, and to compare the clinical features of patients with ovarian cancer from different genetic background.Subjects & Methods:The inclusion criteria were:(1) patients from family at risk of hereditary ovarian cancer:①at least two first or second degree relatives with ovarian cancer and/or breast cancer in the family;②at least one relative with double primary ovarian and breast cancer; (2) patients with sporadic ovarian cancer:patient with ovarian cancer, who has no family history of ovarian and breast cancer in her first and second degree relatives, and has no breast cancer history herself. There were 71 patients from 67 independent families enrolled in our study, of which 39 patients were from families at risk of hereditary ovarian cancer, and 32 patients were sporadic.Methods:(1) DNA was abstracted from peripheral blood, and all exons of BRCA1/2 were analyzed using DHPLC followed by direct sequencing; (2) clinical features of patients from families at risk of hereditary ovarian cancer and sporadic patients were compared by statistical analysis; (3) pedigree studies were carried out in four families at risk of hereditary ovarian cancer, and all the female members of these four families accepted DHPLC+DNA direct sequencing after informed consent were signed.Results:Pathogenic mutations were detected in 20 of 71 patients, as the mutation rate was 28.2%, and the frequency of BRCA1 and BRCA2 mutation was 22.5% and 5.6%, respectively. The mutation rates between these two genes were of statistically significant (P=0.004). The differences of BRCA mutation rates between sporadic patients and patients from families at risk of hereditary ovarian cancer were statistically significant, too (12.5% v.s. 41.0%, P=0.008). Sixteen different pathogenic mutations sites were detected in this study and 50% of them were novel. BRCA1 5589del8 was identified in three independent families. It has been reported as a recurrent mutation in Chinese, and may be partial "founder effect" in Chinese people. Both exon 11 of BRCA1/2 have been found to be hotspots of germline mutations.The average onset age of patients with ovarian cancer was similar between each group (patients from families at risk of hereditary ovarian cancer v.s. sporadic patients, patients with and without pathogenic mutations). The differentiation of tumor was worse but the sensitivity of chemotherapy was better in patients with pathogenic mutations and patients from families at risk of hereditary ovarian cancer. There were 10 patients with double primary ovarian and breast cancer in our study. We found that all the first primary tumor of them was breast cancer, and the average onset age was 44.4 years. The average interval between breast and ovarian cancer was 13.1 years. For the families at risk of hereditary ovarian cancer, the more family members with malignancy, the more chance for the family to carry pathogenic mutations, and gastrointestinal malignancies were also common in these families.11 out of 42 female members from the four families in our pedigree analysis were detected to have pathogenic mutations.There were 42 female members from four independent families who accepted BRCA 1/2 gene screening in our pedigree analysis.11 members from two families carried two kinds of BRCA1 pathogenic mutations, and the mutation rate was 26.2%. Several SNPs were found on BRCA2 gene. Several mutations with a high carrier rate in the four families, which clinical importance were still unknown, were all on BRCA1 gene BRCA1 P1099Q, which had a highest carrier rate (28.6%), was detected in three families, and may be unique in Chinese. BRCA mutation with no clinical importance seems to be specificity and accumulation. BRCA1 P1099Q,IVS13+117C＞A and BRCA2 N854K were not reported in BIC database, and we need more research to prove their clinical importance in Chinese people. The patients from families at risk of hereditary ovarian cancer had younger onset age, higher grades and advanced FIGO stage tumors, but better sensitivity to chemotherapy and longer disease-free survival intervals.Conclusions:We performed the comprehensive mutation screening of BRCA1/2 gene in sporadic patients and patients from families at risk of hereditary ovarian cancer. The mutation rate of patients from families at risk of hereditary ovarian cancer is higher than the sporadic ones, and the onset age of patients with ovarian/breast cancer may be younger in the offspring. Therefore, the genetic screening and clinical intervention is necessary and has to be performed as early as possible for the members from families at risk of hereditary ovarian cancer. BRCA1 gene may make greater impact on ovarian cancer in Chinese population. The patients with BRCA pathogenic mutations and patients from families at risk of hereditary ovarian cancer have higher grades and advanced FIGO stage tumor, but better sensitivity to chemotherapy and better prognosis. All the known pathogenic mutations cannot explain the high morbidity of some families. The etiology may be different in patients with different genetic background. The clinical importance of some amount of BRCA gene mutations detected in our research is still unknown. We need further study to confirm their clinical importance.