BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage
BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage
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DOI：
10.1080/09553000110097974
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发表时间：
2002-04-01
影响因子：
2.6
通讯作者：
Kampinga, HH
中科院分区：
文献类型：
--
作者：
Nieuwenhuis, B;Van Assen-Bolt, AJ;Kampinga, HH
高达90%的遗传性乳腺癌病例与BRCA1或BRCA2基因的两个拷贝之一的生殖系突变有关。Brca1和Brca2蛋白都参与细胞防御DNA损伤，尽管蛋白质的确切功能仍然不清楚。对少量样本的一些研究以及本初步研究也表明，BRCA1杂合性可能导致电离辐射诱导的DNA双链断裂的修复受损。这项研究的目的是测试在一个更大的家庭匹配的研究是否BRCA1或BRCA2突变的载体有一个电离radiation.Materials和方法的敏感性增加：在一个盲研究中，不同的生殖系突变的BRCA1或BRCA2基因的一个等位基因的修复X射线诱导的DNA断裂的能力的影响进行了研究。成纤维细胞和淋巴细胞取自具有不同突变的杂合子个体（BRCA 1 +/-和BRCA 2 +/-）和被证明为BRCA突变非携带者的亲属。DNA断裂的重新连接分析脉冲场凝胶电泳（成纤维细胞）或彗星试验（淋巴细胞）。结果：显着的个体间差异被发现在成纤维细胞和淋巴细胞的能力，重新连接X射线诱导的DNA断裂。结论：BRCA1和BRCA2基因突变的细胞对辐射诱导的DNA断裂的修复能力无明显缺陷。因此，这些携带者在放疗后可能没有发生过度正常组织反应的风险，这与最近的临床研究数据一致。
Purpose: Up to 90% of hereditary breast cancer cases are linked to germ-line mutations in one of the two copies of the BRCA1 or BRCA2 genes. Brca1 and Brca2 proteins are both involved in the cellular defence against DNA damage, although the precise function of the proteins is still not known. Some studies on a small number of samples as well as the present pilot study also suggested that BRCA1 heterozygosity may lead to impaired repair of ionizing-radiation-induced DNA double-strand breaks. The purpose of the study was to test in a larger family-matched study whether carriers of BRCA1 or BRCA2 mutations have an increased sensitivity to ionizing radiation.Materials and methods: In a blind study, the effect of different germ-line mutations in one allele of the BRCA1 or BRCA2 gene on the ability to repair X-ray-induced DNA breaks was investigated. Fibroblasts and lymphocytes were taken from heterozygotic individuals (BRCA1 +/- and BRCA2 +/-) with different mutations and from relatives proven to be non-carriers of the BRCA mutations. Rejoining of DNA breaks was analysed by pulsed-field gel electrophoresis (for fibroblasts) or the comet assay (for lymphocytes).Results: Significant interindividual differences were found in the capacities of the fibroblasts and lymphocytes to rejoin DNA breaks induced by X-radiation. However, these differences were not related to heterozygosity in BRCA1 or BRCA2.Conclusions: Cells from carrier of mutations in one allele of the BRCA1 and BRCA2 genes have no gross defects in their ability to rejoin radiation-induced DNA breaks. Hence, these carriers may not be at risk of developing excess normal tissue reactions after radiotherapy consistent with data from recent clinical studies.