中国家族性乳腺癌人群中发现重复出现的BRCA1 1100delAT突变

BRCA1 1100delAT is a recurrent mutation in Chinese women with familial breast cancer

目的观察以前在上海地区家族性乳腺癌人群中发现的 BRCA1基因突变是否在扩大的样本中有重复出现。方法对来自国内4个乳腺癌临床研究中心的60个独立的汉族家族性乳腺癌家系进行检测,家系中至少有2个一级亲属或3个二级亲属患原发性乳腺癌。从外周血白细胞中提取基因组 DNA,对以前报道过的 BRCA1基因致病性突变(1100delAT、IVS17-1G>T、IVS21+1G>C和5640delA)应用聚合酶链式反应(PCR)-变性高效液相色谱(DHPLC)分析-DNA 直接测序的方法进行特异性分析。选取4个与 BRCA1基因连锁的标记(D17S855、D17S1322、D17S1326和 D17S1327)进行等位基因型分析。结果在来自中国北方的2个家系中发现有重复出现的 BRCA1 1100delAT 突变,并在其中一例的患病亲属中发现携带相同的突变。在检测的片段中还发现了1个新的致病性突变-BRCA1 5589del8。用与 BRCA1基因连锁的标记进行等位基因型分析显示,两个来自中国北方的BRCA1 1100delAT 突变携带病例有相同的等位基因型,而与前期研究中发现的上海地区此突变携带者的等位基因型有所差异。BRCA1 1100delAT 突变在所有检测家系中出现的频率为3.16%(3/95)。结论首次在中国大陆家族性乳腺癌人群中发现 BRCA1基因有重复出现的突变。BRCA11100delAT 突变可能是中国家族性乳腺癌人群中 BRCA1基因的突变热点;在中国北方人群中,此突变可能有"始祖效应",需要在大规模人群中进一步研究证实。

Objective Previous investigation on BRCA1 gene mutations in thirty-five breast cancer patients with affected relatives in Shanghai identified four germ-line mutations （1100delAT, IVS17-1G 〉 T, IVS21 ＋ 1G 〉 C and 5640delA）. To our knowledge, up to now, no founder mutation in BRCA1 gene has been identified in Chinese mainland population. The aim of this study was to investigate whether there are recurrent mutations or ＇founder mutations＇ in Chinese mainland population. Methods Peripheral blood samples were collected from 60 breast cancer patients with at least one first-degree relative affected with breast cancer from Shanghai, Jinan, Qingdao, and Shenyang. DNA extracted from lymphocytes was amplified by polymerase chain reaction （PCR） to analyze the 4 germ-line mutations （ 1100delAT, IVS17-1G 〉T, IVS21 ＋ 1G 〉 C and 5640delA） discovered previously： the amplicons were analyzed by denaturing high-performance liquid chromatography （DHPLC） , and those with abnormal chromatographic profiles were confirmed by direct sequencing. Four BRCAl-linked markers were used to do allelotype analysis. Results Only the ll00delAT mutation in BRCA1 gene recurred in two unrelated individuals. Allelotype analysis showed that the two individuals who carried the 1100delAT mutation shared the same allelotype at 4 sites： D17S855, D17S1322, D17S1326, and D17S1327, which was different from the allelotype of the patients who earried the mutation at the site D17S1322 previously reported in Shanghai population. This recurrent mutation gave an overall prevalence of 3. 16% （3/95） in all of our investigated population. A novel mutation, 5589de18, was found in one case. Conclusion Recurrent mutation is found in Chinese mainland familial breast cancer patients for the first time. 1100delAT mutation may be a hotspot in BRCA1 gene in Chinese population. Whether this mutation is a founder mutation in the Northern Chinese community need further investigation.