摘要
目的乳腺小叶癌具有独特的遗传学背景,目前针对我国乳腺小叶癌人群的遗传学研究较少,本研究探讨我国家族性乳腺小叶癌患者BRCA1、BRCA2和CDH1基因的胚系突变情况。方法收集2007-09-28-2014-12-06浙江省肿瘤医院183个家系符合家族性乳腺癌诊断标准,选择其中的乳腺小叶癌患者为研究对象,提取外周血DNA,采用PCR-测序方法检测BRCA1、BRCA2和CDH1基因所有编码外显子以及内含子和外显子拼接区的突变情况,对比基因组数据库以及in silico分析,明确突变是否为致病性;通过多重连接探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)筛查BRCA1和BRCA2基因大基因组重排情况。结果共有12个家系符合家族性乳腺小叶癌入选标准,所有家系中无胃癌患者。12个家系的乳腺癌先证者接受BRCA1、BRCA2和CDH1基因胚系突变研究。发现2例患者携带BRCA2基因致病性突变,分别为c.5682C>G(p.Y1894X)和c.6359C>G(p.S2120X),突变率为16.7%(2/12)。未发现BRCA1和CDH1基因明显的致病性突变。共有5个新发突变,分别为BRCA1基因c.1537C>G和c.1966A>T、CDH1基因c.1937-13T>C、c.1008+139insAG和c.48+53del13。In silico分析发现,BRCA1基因非同义突变c.1966A>T和CDH1基因c.48+53del13可能具有致病性。在12例家族性乳腺小叶癌患者中未发现BRCA1和BRCA2基因大基因组重排。结论我国家族性乳腺小叶癌患者中BRCA2是常见的遗传易感基因,BRCA1和CDH1突变少见,但由于病例数少,需要大组病例研究予以验证。新发现的BRCA1基因c.1966A>T和CDH1基因c.48+53del13可能与乳腺小叶癌遗传相关,值得进一步研究。
OBJECTIVE Lobular breast cancer has a unique genetic background.Few studies have been conducted on the genetic screening in lobular breast cancer in china.The purpose of this study was to explore the germline mutations of BRCA1,BRCA2 and CDH1 genes in Chinese familial lobular breast cancer patients.METHODS A total of 183 familial breast cancer patients who were diagnosed in Zhejiang Cancer Hospital were enrolled from September 28 th,2007 to December 6 th,2014.Those patients diagnosed as lobular breast cancer were selected for this study.Genomic DNA was extracted from peripheral blood leukocytes of proband of each family.The entire coding regions and exon-intron boundaries of BRCA1,BRCA2 and CDH1 genes were screened using PCR-sequencing assay.The genomic databases and in silico prediction were used to identify deleterious mutations.Large genomic rearrangements in BRCA1 and BRCA2 genes were screening by multiplex ligation-dependent probe amplification（MLPA）assay.RESULTS A total of 12 unrelated patients with personal of lobular breast cancer and family history of breast cancer were enrolled in this study.There was none of gastric cancer in any of the 12 families.All of the 12 patients were underwent BRCA1,BRCA2 and CDH1 germline mutation screening.Two BRCA2 deleterious mutations c.5682 C〉G（p.Y1894 X）and c.6359 C〉G（p.S2120 X）were found in two patients with a frequency of 16.7%（2/12）.None of apparent deleterious mutation in BRCA1 and CDH1 was found.Five novel mutations were identified including BRCA1 c.1537 C〉G and c.1966 A〉T,CDH1 c.1937-13 T〉C,c.1008＋139 insAG and c.48＋53 del13.The nonsynonymous variant BRCA1 c.1966 A〉T and CDH1 c.48＋53 del13 were predicted to be potential pathogenic by in silico prediction.None of large genomic rearrangement in BRCA1 and BRCA2 was identified.CONCLUSIONS This study implys that BRCA2 is the common genetic factor for Chinese familial lobular breast cancer patients,meanwhile germline mutations of BRCA1 and CDH1 were rare.However,the number of cases in t
作者
曹文明
高赟
丁小文
黄圆
楼彩金
王晓稼
CAO Wen-ruing;GAO Yun;DING Xiao-wen;HUANG Yuan;LOU Cai-jin;WANG Xiao-jia(Zhejiang Cancer Hospital, Hangzhou 310022, P. R. China)
出处
《中华肿瘤防治杂志》
CAS
北大核心
2018年第10期689-695,共7页
Chinese Journal of Cancer Prevention and Treatment
