Kote-Jarai Z, Salmon A, Mengitsu T, Copeland M, Ardern-Jones A, Locke I, Shanley S, Summersgill B, Lu Y-J, Shipley J, Eeles R
Translational Cancer Genetics Team, The Institute of Cancer Research, 15 Cotswold Rd, Sutton Surrey SM2 5NG, UK.
Br J Cancer. 2006 Jan 30;94(2):308-10. doi: 10.1038/sj.bjc.6602912.
Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.
BRCA1基因中的有害突变使女性患乳腺癌和卵巢癌的风险增加。许多功能研究表明，BRCA1在DNA损伤修复中起作用，而DNA损伤反应途径的缺陷通常会导致染色体畸变的积累。在此，我们将正常淋巴细胞与携带BRCA1突变的杂合子淋巴细胞进行了比较。使用高剂量率对短期培养物进行照射（8Gy），随后通过24色染色体涂染（M-FISH）分析中期相。我们在照射6天后对5名BRCA1突变携带者和5名非携带者对照样本的中期相中染色体重排进行了评分。与正常对照相比，在携带BRCA1突变的杂合子淋巴细胞中检测到显著更高水平的染色体损伤；每个有丝分裂期的畸变平均数为3.48，而对照组为1.62（P = 0.0001）。这提供了新的证据，表明与非携带者相比，杂合子突变携带者对DNA损伤有不同的反应，并且BRCA1在DNA损伤监测中起作用。我们的发现对于使用涉及照射的方式治疗和筛查BRCA1突变携带者具有重要意义。
