The Study Of BRCA1/2 Genes Among Family Breast Cancer Patients And Their Family Members

Background:The incidence of breast cancer dominate the first place among women with malignant tumor,while the mortality rate rank the second. The occurrence of breast cancer is due to many factors, such as environmental factors, living habits, and hormone level, genetic factors,which is significantly important. Domestic and foreign researches showed that the most significant genetic factors with breast cancer are related to BRCA1 and BRCA2. BRCA1 and BRCA2 are tumor suppressor genes, which can develop different types of mutation, resulting in protein coding function change and then increasing the risk of cancer. The NCCN breast cancer risk reduction points out that the lifetime risk of breast cancer among BRCA1/2 gene mutation carriers is 56-84%, while the ovarian cancer is 16.5-59%. Intervention therapy for BRCA1/2 gene mutation carriers can reduce the risk of breast cancer and ovarian cancer effectively. The American breast cancer BRCA1 / 2 mutation characteristics, cancer risks, prevention and treatment of carriers have studied well. BRCA1 / 2 mutation screening has been incorporated into the NCCN guidelines and NCCN risk reduction guide, which suggested the family breast cancer patients and family members to screen BRCA1/2 genes. However, the study of BRCA1/2 genes about familial breast cancer remain to be researched. Chinese clinical problems: Chinese breast cancer BRCA1/2 mutation type and the site which are different of Europe and the United States race; the small research sample size and the different detection methods, which may cause mutations sieve; BRCA1/2 genes research is almost a blank in Chinese healthy family members; the risk of cancer and treatment among BRCA1/2 mutation carriers is urgent. Therefore, it is necessary to study the BRCA1/2 gene mutations in Chinese familial breast cancer, which will reduce the risk of breast cancer, so as to reduce the incidence and mortality of breast cancer. Objective:China has begun to study BRCA1/2 gene among hereditary breast cancer, however there are still some problems about standard group, measure method, and the sample size. And BRCA1/2 mutation carriers detection and prevention among family members are closely to blank. Therefore, we designed this experiment. The objective is to investigate BRCA1 and BRCA2 mutations among Han familial breast cancer patients and their female relatives. Methods:standard groups: Familial breast cancer patients group: 1. Pathological diagnosis for women with breast cancer; 2. Immediate family(first, second, third degree relatives) has a breast cancer /ovarian cancer patient at least. Family members group: 1. No breast cancer or other malignant tumor history;2. Immediate family(first, second, relatives) has a Familial breast cancer patient at least. The study involved Han familial breast cancer patients and relatives 110 samples totally 62 patients and 48 healthy female relatives). The entire coding exon sequences of BRCA1 and BRCA2 are detected by extracting DNA from peripheral venous blood, using PCR —DNA direct sequencing method. Results:(1)10 BRCA1/BRCA2 deleterious mutations were found in our study. 7 mutations are identified in 62 familial breast cancer patients that included 2 previously reported mutation(BRCA1:4730ins G, 5589del8 reported in BIC database) and 5 novel mutations(BRCA1:1937ins C, 3577 del T,4538 ins AG; BRCA2: 1382 del A, 2820 del A).3 novel mutations are found in 48 family members, the mutation rate is 6.25%(BRCA1: 1370 ins A, 3459 ins A; BRCA2:6502ins T).(2) 11 BRCA1/BRCA2 Potential pathogenic mutation were found in our study. 5 mutations are identified in BRCA1(BRCA1:392T>G,1032T>G,1581A>G,4285G>A,4732A>C),while 6 mutations are identified in BRCA2(BRCA2: 1420C>G,3123G>A,3484A>G,7280C>G, 8415G>T, 9988A>C).(3) 11 BRCA1/BRCA2 polymorphic site were found in our study. 7 Synonymous mutations which not change the encoded amino acid have no clinical significance(BRCA1: 2201C>T, 2430T>C, 4427T>C; BRCA2: 1593A>G. 2457 T>C, 7470A>G, 7683G>A); 4 BRCA gene missense mutation which have confirmed no clinical significance in the breast cancer information database(BRCA1: 2731C>T, 3232A>G, 3667A>G, 4956A>G).(4) The frequency of BRCA1/2 mutations is 11.29% among familial breast cancer patients(BRCA1, 8.06%; BRCA2, 3.23%). And the frequency of BRCA1/2 mutations in early onset breast cancer patients(≤35) is 33.33%(2/6), and in triple negative breast cancer patients is 27.17%(3/11). Conclusion:Chinese familial breast cancer "founder mutation" isn’t discovering in our research. The frequency of BRCA1/2 mutations in Han familial breast cancer patients is significantly lower than abroad. And early onset breast cancer patients or triple negative breast cancer with family history are good candidates for BRCA1/2 testing. Pathogenic BRCA1/2 gene mutations are detected in family members, the mutation frequency and the risk of carriers remain to be researched.