摘要
目的研究中国上海地区早发性乳腺癌中BRCA1/BRCA2基因的突变位点及携带情况。方法对象为来自上海地区的50例早发性乳腺癌(发病年龄≤40岁),其中13例(26%)有一级亲属患病家族史。由静脉血提取基因组DNA,对BRCA1/2基因的全部编码序列进行扩增。突变分析由变性高效液相色谱分析(DHPLC)进行预筛,之后进行DNA测序证实。结果在BRCA1基因中发现有6个致病突变位点,其中4个为新发现的位点,包括两个移码突变(3449insA,5587-1del8)和两个拼接点突变(IVS17-1G>T,IVS21+1G>C)。BRCA2基因的两个致病突变位点都很接近位于11号外显子上;其中的1个致病突变位点为移码突变(5950delCT),另一个错义突变(5911G>C)可能为新的致病突变位点。另外,共发现有12个新的SNP位点,都未引起氨基酸编码改变;其中,8个在BRCA1基因上,4个在BRCA2基因上。在早发性乳腺癌中,BRCA1基因突变频率(12%)比BRCA2基因(4%)高;BRCA1基因突变频率在有无家族史的患者中分别为30.8%和5.4%。结论新发现的4个BRCA1基因的致病突变位点和一个BRCA2基因的错义突变位点可能是中国人群早发性乳腺癌的特有突变位点;在中国人群中,BRCA1基因突变起着比BRCA2基因更大的作用;本研究为未来的临床基因检测提供了可能的筛查模式。
Objective To investigate the prevalence of BRCA1 and BRCA2 mutations among earlyonset breast cancer patients in Shanghai. Methods Fifty patients unselected for family history, who were diagnosed with breast cancer before the age of 40 years were analyzed. Among them, 13 patients have at least one first-degree relative affected with breast cancer. Mutation screening of BRCAI and BRCA2 was performed in the whole coding sequence through Denaturing High Performance Liquid Chromatography （DHPLC） and subsequent DNA direct sequencing. Results Six deleterious mutations, including 2 novel frameshift mutations （3449insA, 5587-1de18） and 2 novel splice-site mutations （IVS17-1G 〉T, IVS21 ＋ IG 〉 C） in BRCAI were identified. Two deleterious mutations detected in BRCA2, including one frameshift mutation （5950delCT） and one novel missense mutation （5911G 〉 C）, all occurring on exon 11 adjacently. Additional 12 novel sequence variants were also detected including one unclassified variant and 7 intronic variants in BRCAI, and 4 novel intronic variants in BRCA2, all causing no alteration of amino acid coding. The prevalence of BRCAI and BRCA2 mutations in the patients with early-onset breast cancer was 12% and 4%, respectively. Conclusion Four novel mutations in BRCAI and one novel mutation in BRCA2 may be mutations characterized of early-onset breast cancer in Chinese population. Germline mutations in BRCA2 may contribute less than mutations in BRCAI to early-onset breast cancer in Shanghai. These data contribute to information on spectrum of BRCA gene in Chinese population and also offer a recommended screening mode for clinical genetic testing programme in China.
出处
《中华医学杂志》
CAS
CSCD
北大核心
2005年第43期3030-3034,共5页
National Medical Journal of China
基金
国家自然科学基金资助项目(30371580)
国家杰出青年科学基金资助项目(30025015)
国家"十五"攻关项目基金资助(2002AA711A08)
上海市科委重点项目基金资助(03JC14019)
