Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2
Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2
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DOI：
10.1002/ijc.10109
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发表时间：
2002-02-10
影响因子：
6.4
通讯作者：
Brock, WA
中科院分区：
文献类型：
--
作者：
Buchholz, TA;Wu, XF;Brock, WA
BRCA1和BRCA2基因产物被认为在DNA损伤的处理过程中发挥重要作用。为了评估这些基因中的杂合突变是否与细胞辐射敏感性相关，我们对从8名经测序证实的BRCA杂合子（6名BRCA1杂合子，2名BRCA2杂合子）获取的皮肤成纤维细胞进行了体外辐射克隆形成存活试验。将这些数据与先前一组17名前瞻性研究的癌症患者（其BRCA突变风险可忽略不计）所获得的结果进行了比较。此外，将对从9名BRCA杂合子（8名BRCA1杂合子，1名BRCA2杂合子）获取的淋巴细胞进行的辐射诱导染色单体断裂试验的结果与18名无癌症病史的女性对照组的结果进行了比较。两项试验的结果均表明，含有BRCA1或BRCA2杂合突变的细胞比对照组对辐射更敏感。在成纤维细胞研究中，携带者在2戈瑞（SF2）时的平均存活分数为0.279，而对照组为0.348（p = 0.007）。在淋巴细胞研究中，在125厘戈瑞辐射后，携带者每个细胞的平均染色单体断裂数为0.79个，而对照组为0.45个（p = 0.0005）。BRCA1突变细胞与BRCA2突变细胞之间的辐射敏感性没有明显差异（p = 0.769），尽管样本量小降低了这一观察结果的确定性。这些初步结果与BRCA1或BRCA2的种系突变和对辐射的超敏感性之间的关系相符。这种表型可能会使辐射诱导的突变和致癌风险增加。（C）2002威利 - 利斯公司
The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, I BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. 0.348 for the control set (p = 0.007). For the lymphocyte studies, the mean number of chromatid breaks after 125 cGy of radiation was 0.79 breaks per cell for the carriers vs. 0.45 for the controls (p = 0.0005). There was no apparent difference in the radiosensitivity between cells with BRCA1 vs. BRCA2 mutations (p = 0.769), although the small sample size minimizes the certainty of this observation. These preliminary results are consistent with a relationship between a germline mutation in BRCA I or BRCA2 and a hypersensitivity to radiation. This phenotype could possibly predispose to an increased risk of radiation-induced mutagenesis and carcinogenesis. (C) 2002 Wiley-Liss, Inc.