140例中国遗传高风险乳腺癌患者BRCA1和BRCA2基因突变研究

BRCA1 and BRCA2 mutations of 140 Chinese breast cancer patients with genetic high risk

目的探索中国遗传高风险乳腺癌患者BRCA1和BRCA2突变情况。方法本研究为探索性研究,按照纳入标准选择2014年9月至2016年6月就诊解放军307医院乳腺外科的遗传高风险乳腺癌患者140例,按免疫组织化学结果分为三阴性乳腺癌组(35例)和非三阴性乳腺癌组(105例),运用二代测序对入组患者BRCA1和BRCA2的49个外显子及其邻近部分内含子序列进行检测,对检测到的致病突变与乳腺癌信息中心(BIC)、ClinVar数据库中进行对照确定是否为新发现致病突变。采用χ~2检验分析致病突变在三阴性乳腺癌与非三阴性乳腺癌组中的分布差异。结果 BRCA1/2致病突变率为21.4%(30/140),其中BRCA1致病突变率为7.9%(11/140),BRCA2致病突变率为13.6%(19/140)。20个突变位点(BRCA1基因上的17_18delAA,1535_1536insATGA,2013_2014insGT,3266delT,3458delT。BRCA2基因上的1527delA,2059_2063delGATTA,2440delC,3919G>T,5461dup A,6304delG,6368dup A,6446_6447insTA,6552delG,8016dup A,8800C>T,8942_8943delAA,8899delA,9070_9073delAACA,9274_9277delTATT)在BIC、ClinVar数据库均未见报道,并发现1例患者携带BRCA1 c.5470_5477delTGCCCAAT。三阴性遗传高风险性乳腺癌患者携带BRCA1/2致病突变率为34.3%(12/35),高于非三阴性者的17.1%(18/105)(χ2=4.582,P=0.032)。三阴性乳腺癌组中BRCA1致病突变率31.4%(11/35),非三阴性组为0(0/105),组间差异有统计学意义(χ~2=31.604,P<0.001);三阴性乳腺癌组中BRCA2致病突变为2.9%(1/35),非三阴性组为17.1%(18/105),组间差异也无统计学意义(χ~2=3.430,P=0.064)。结论新发现的20个突变位点可能为中国人特有,丰富了中国人群BRCA1和BRCA2突变谱。BRCA1 c.5470_5477delTGCCCAAT有可能成为中国人的始祖突变,但仍需后续扩大样本量进一步证实。遗传高风险乳腺癌患者BRCA1和BRCA2突变情况值得关注,尤其是三阴性乳腺癌患者。三阴性遗传高风险乳腺癌患者BRCA1致病突变率较高。

Objective To investigate the BRCA1 and BRCA2 mutations in Chinese breast cancer patients with genetic high risk. Methods This was an exploratory study. According to the inclusion and exclusion standard, 140 breast cancer patients with genetic high risk in 307 Hospital of PLA from September 2014 to June 2016 were selected as objects. According to the immunohistochemical results, the patients were divided into triple negative breast cancer （TNBC） group （35 cases） and non-TNBC group （105 cases）. The next-generation sequencing was used to test the sequences of 49 exons and adjacent parts in BRCA1 and BRCA2 of these patients. The detected pathogenic mutations were compared with the mutations recorded in Breast Cancer Information Core （BIC） and ClinVar databases to screen the newly discovered ones. X2 test was used to analyze the difference of pathogenic mutation rates between TNBC group and non-TNBC group. Results The mutation rate of BRCA1/2 was 21.4% （30/140）, including 7.9% （11/140） in BRCA1 and 13.8% （19/140） in BRCA2. There were 20 new mutations （1718delAA, 15351536insATGA, 2013 2014insGT, 3266delT, 3458delT in BRCA1, and 1527de1A, 20592063delGATrA, 2440delC, 3919G〉T, 5461dupA, 6304delG, 6368dupA, 64466447insTA, 6552delG, 8016dupA, 8800C〉T, 89428943delAA, 8899delA, 90709073delAACA, 92749277delTATF in BRCA2）, which had never been reported in BIC and ClinVar databases. BRCA1 c. 54705477delTGCCCAAT was found in one patient. The frequency of BRCA1/2 mutation in TNBC patients was 34. 3% （ 12/35 ）, significantly higher than 17. 1% （ 18/105 ） in non-TNBC patients （χ^2 = 4. 582, P = 0. 032）. BRCA1 mutation rate was 31.43% （11/35） in TNBC patients, 0 （0/105） in non-TNBC patients, indicating a significant difference between two groups （χ^2= 31. 604,P〈 0. 001 ）. BRCA2 mutation rate was 2. 86% （ 1/35 ） in TNBC patients, 17.14% （ 18/105 ） in non-TNBC patients, indicating no significant difference between two groups （χ^2 = 3.430, P = 0.064 ）. Conclusions Twenty newly discovered mutations may be unique in Chinese population, which enriches the spectrum of BRCA1/2 mutations in Chinese people. BRCA1 e. 5470 5477delTGCCCAAT may be the founder mutation in Chinese, which needs to be further confirmed. The doctors should pay attention to BRCA1/2 mutations in breast cancer patients with genetic high risk, especially in TNBC patients. TNBC patients with genetic high risk have relatively high mutation rate of BRCA1.