The Research Of BRCA1 And BRCA2 Pathogenic Mutations Of The 140 Chinese Breast Cancer Patients With Genetic High-risk

Backgrounds:The incidence of breast cancer is in the first place in malignant tumor in women,which mortality is after lung cancer.Breast cancer is associated with a variety of factors,including genetic factors,hormone level,age,environmental factors,living habits,and so on.The genetic factor is the most significant role.In the genetic factors,breast cancer susceptibility genes,BRCA1 and BRCA2 mutations have the closest relations with breast cancer.BRCA1 and BRCA2 belong to the tumor suppressor genes,the pathogenic mutations are up to more than 3000.Pathogenic mutations cause BRCA1 / 2 protein function changing,losingthe gene repair function,increasing the risk of cancer.NCCN reduce risk guide pointed out that lifetime risk of breast cancer of people with BRCA1/2 gene mutation was 56%-84%,and risk of ovarian cancer was 16.5%-59%.The BRCA1/2 mutations testing in high-risk population has been incorporated into the NCCN guidelines and NCCN reduce breast cancer risk guidelines.Related researches showed that the Chinese people BRCA1/2 mutations have significant differences with Europe.But at present BRCA1/2 standardized testing for Chinese genetic high-risk patients and healthy people was still not published.At present domestic BRCA1 / 2 mutation researches were still in its infancy with some problems,such as widespread small sample size,detection method unified,hot spot testing leading to leakage screen.In China,BRCA1/2 development lag restricted the development of treatment strategy selection in the breast cancer patients with high-risk,and restricted the healthy people at high risk with accepting genetic counseling and accepting breast cancer preventive intervention.Therefore,carrying out BRCA1/2 pathogenic mutation detection with high-risk breast cancer in our country is of great significance.Objective:The BRCA1/2 gene mutations have ethnic and regional differences,BRCA1 / 2 mutation research in Chinese people is still in its infancy,BRCA1/2 mutation testing of high-risk population has not yet reached a consensus.This study aimed to explore the genetic BRCA1 and BRCA2 mutations in patients with high risk of breast cancer,further enrich the Chinese BRCA1 and BRCA2 mutations spectrum,discover high frequency pathogenic mutations,and analyze the the relationships between BRCA1/2 mutations and clinical characteristics.To provide certain reference for breast cancer patients and healthy people that withgenetic high risk to accept genetic counseling and accept breast cancer preventive intervention.Methods:This study is an exploratory work.140 cases genetic high-risk breast cancer patients were enrolled as the research object,that treated in People's Liberation Army?PLA?307Hospital from September,2014 to June,2016.Enter criterion: the breast cancer patients who meet at least one of the following conditions: 1.with a family history of breast or ovarian cancer;2.early-onset breast cancer;3.bilateral breast cancer;4.with epithelial ovarian cancer,fallopian tube cancer or primary peritoneal carcinoma;5.male breast cancer.The second generation sequencing was used to test the 49 exon sequences and adjacent parts sequences of BRCA1 and BRCA2 of these patients.Comparing withinthe BIC and Clin Var database was used to determine whether the pathogenic mutations were new pathogenic mutations.And make genetic interpretation for the pathogenic mutation.?2test was used to analyze the difference of the mutation rates between the groups that divided by pathological feature.Respectively analyzed BRCA1/2 pathogenic mutations in patients with familial breast cancer,early-onset breast cancer,bilateral breast cancer.Results:1.The BRCA1 and BRCA2 general pathogenic mutation rate of 140 cases breast cancer patients with genetic high-risk was 21.43%?30/140?,including BRCA1 pathogenic mutation rate was 7.86%?11/140?,and BRCA2 mutation rate was 13.57%?19/140?.20 mutations found for the first time,and found a case of a patient with the relatively high frequency mutation in Chinese: BRCA1 c.5470₅477del TGCCAAT.2.The BRCA1 and BRCA2 general pathogenic mutation rate of the group with triple negative breast cancer patients was 34.29%?12/35?,higher than the non triple negative group 17.14%?18/105?,??2 = 4.582,p = 0.032?.The BRCA1 pathogenic mutation rate of the group with triple negative breast cancer patients was 31.43%?11/35?,higher than the nontriplenegative group 0.00%?0/105?,??2=31.604,p<0.005?.The BRCA2 pathogenic mutation rate of the group with triple negative breast cancer patients was 2.86%?1/35?,the nontriplenegative group was?18/105?,??2=3.430,p =0.064?.3.The BRCA1 and BRCA2 general pathogenic mutation rate of the breast cancer patients with family history was 28.77%?21/73?,including BRCA1 mutation rate was 10.96%?8/73?,BRCA2 mutation rate was 17.81%?13/73?.In these breast cancer patients with family history,the BRCA1/2 pathogenic mutation rate of the group with triple negative was 62.50%?10/16?,higher than the non triple negative group 19.30%?11/57?,the difference was statistically significant??2=9.368,p =0.002?.4.The BRCA1 and BRCA2 general pathogenic mutation rate of patients with earlyonset breast cancer was 20.27%?15/74?,including BRCA1 pathogenic mutation rate was 6.76%?5/74?,BRCA2 pathogenic mutation rate was 13.51%?10/74?.In the earlyonset breast cancer patients,BRCA1/2 pathogenic mutation rate of the group with family history of breast or ovarian cancer was significantly higher than that without family history group?40.91% to 11.54%?,the difference was statistically significant??2=6.534,p =0.011?.5.The BRCA1 and BRCA2 general pathogenic mutation rate of the bilateral breast cancer patients was 30.43%?7/23?,including BRCA1 pathogenic mutation rate was 8.70%?2/23?,BRCA2 mutation rate was 21.74%?5/23?of the disease.The BRCA1/2 pathogenic mutation rate of male breast cancer patients was 14.29%?1/7?.Conclusions:1.20 newly discovered mutations may be unique to Chinese people.BRCA1:c.5470₅477del TGCCCAAT may be the ancestor mutation of the Chinese people,which needs to be further confirmed.2.Thetriplenegative breast cancer patients with genetic high-risk have a much higher BRCA1 and BRCA2pathogenic mutation rate.3.The patients with genetic high-risk breast cancer have higher BRCA1 and BRCA2 pathogenic mutation rate.When patients have the risks of family history and early-onset at the same time,there will be a much higher rate of BRCA1 and BRCA2 pathogenic mutation.4.The research about BRCA1 and BRCA2 pathogenic mutations in patients with genetic high-risk breast cancer in Chinese people deserves further attention.