| Background and Objection:According to the “Cancer statistics in China,2015”,breast cancer is the leading cause of cancer in Chinese women,accounting for about 15% of newly diagnosed cancers each year.Breast cancer is the leading cause of cancer death in people younger than 45 years[1].Breast cancer is caused by a combination of factors,among which family history is one of the important factors leading to the incidence of breast cancer.It has been reported that approximately 15-20% of breast cancer patients have clear family history[2].In the United States,people with a high genetic risk of the disease would be recommended to take genetic testing by the Center for Disease Control and Prevention in order to determine its own cancer risk.With the development of gene sequencing and interpretation,more and more genes have been shown to be associated with the pathogenesis of breast cancer.BRCA1/2 gene is the earliest discovered and the most famous gene that considered to be the closely related to hereditary breast cancer[3-5].It is reported that 20-25% of patients with familial breast cancer are carriers of BRCA1/2 gene mutations[6,7].The features of patients with BRCA1/2 gene mutation are different from non-carriers.It has been reported that the risk of contralateral breast cancer significantly increased in patients with BRCA1/2 gene mutations:10-year contralateral breast cancer risk was 1% in people with sporadic breast cancer,while 25% in people with BRCA1/2 gene mutation[8].Fortunately,regular self-examination and physical examination can effectively monitor the tumor,drug prevention or surgical prevention can be taken in people with BRCA1 / 2 deleterious mutation if necessary[9].Moreover,the result of BRCA1 / 2 gene testing can also provide a reference for clinical treatment.Nowadays,more and more drugs that are sensitive to BRCA1 / 2 mutations are gradually being found to provide a good basis for improving the prognosis of patients with hereditary breast cancer.Therefore,effective screening of hereditary breast cancer patients and hereditary breast cancer related gene mutation carriers is essential.At present,the mutation of BRCA1 / 2 gene in Chinese population has not formed consensus due to lack of large-scale sample data and it has not yet formed a uniform standard for how to effectively select the target population for gene detection.In this study,we performed gene testing in 71 hereditarily high-risk breast cancer patients by using NGS,aiming at reporting the specific BRCA1/2 mutations and the SNPs in Chinese population,as well as exploring its relationship with the clinic-pathological features of breast cancer.The purpose of the study is(1)to enrich the BRCA1 / 2 gene mutation database in Chinese population;(2)to establish a better prediction model of breast cancer risk and to set a more suitable BRCA1 / 2 gene detection standard in Chinese population,which may play an important role in breast cancer screening,prevention and treatment.Methods1.Collection of patients In this study,patients with hereditarily high-risk breast cancer which were pathologically diagnosed and treated in Changhai hospital affiliated to Second Military Medical University between May 2015 and May 2016 were enrolled.A total of 71 patients were included in the study.2.Gene testing method 49 exons of BRCA1/2 gene from peripheral blood of each patient was screened by using NGS,in order to identify the deleterious mutations and SNPs.3.Collection of clinic-pathological data The data was collected through the medical records,pathological reports and telephone follow-up confirmation.4.Statistical analysis Differences between groups in categorical data,such as BMI,family history,tumor localization and a serious of pathological features were analyzed with ?2 test.Continuous variables including age at diagnosis,age at menache and age at first pregnancy were analyzed with t test.All statistical analyses were performed with SPSS 22.0 software(IBM,Armonk,New York).A statistical significance was considered to be P<0.05.ResultsPart 1 Characterization of Deleterious Mutations in BRCA1/2 and the Relationship with Clinic-pathological Features of Breast CancerIn this study,13 mutation carriers were detected,accounting for 18.3%.11 deleterious mutations sites were included,among which 6 were located in the BRCA1 and 5 in the BRCA2.Seven of these mutations were never reported in the Asian population.Two of the discovered mutation sites,BRCA1: c.3626T>G and BRCA2: c.3883C>T were nonsense mutations.The Clinic-pathological features of breast cancer was significantly related with BRCA1/2 gene deleterious mutation.Patients with deleterious mutations in the BRCA1 / 2 gene were more likely to be Her2-negative(93.3% vs.57.8%,P=0.014),to have a higher tumor histological grade(P=0.009),and to have a family history of breast or ovarian cancer(66.7% vs.32.8%,P=0.021).BRCA1 gene mutation carriers tend not to express HR and BRCA2 gene mutation carriers are more likely to express HR.Part2 Characterization of SNP in BRCA1 / 2 Coding Region and the Relationship with Clinic-pathological Features of Breast CancerIn this study,34 SNPs were identified,of which 14 were located in the BRCA1 and 20 in the BRCA2.Among 34 SNPs,18 were high frequency mutation sites and 16 were low frequency mutation sites.In the 18 high frequency mutations sites,only the frequency of rs799917 site was lower than it in the normal population.Clinic-pathological features of breast cancer was significantly correlated with the site of rs80356892.The frequency of the mutation in this study was 7.0%,obviously higher than the frequency in normal population.Patients with mutation in rs80356892 tended to have bilateral breast cancer(60.0% vs.7.6%,P=0.004),to have a family history(100.0% vs.43.7%,P=0.008),and to be TNBC(87.5% vs.18.3%,P<0.001).In addition,mutation in rs80356892 was negatively correlated with HR expression.Conclusions1.BRCA1/2 gene mutations which can be currently identified are only one of the causes of hereditary breast cancer,and there are still other harmful mutations in different genes can lead to the occurrence of breast cancer.2.Because of the risk of BRCA1 / 2 gene mutation in patients with hereditary high risk of breast cancer compared to sporadic breast cancer patients and healthy people,it is suggested that they should be tested for genetic testing if necessary,so as to take targeted prevention and control measures.3.The database about BRCA1 / 2 gene mutation in Chinese population and even in Asian population was enriched by the detection of deleterious mutation sites.It may help to establish a better prediction model of breast cancer risk and to set a more suitable BRCA1 / 2 gene detection standard in Chinese population,which may be better to screen,prevent,and treat hereditarily breast cancer. |
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