Ionizing radiation or mitomycin-induced micronuclei in lymphocytes of BRCA1 or BRCA2 mutation carriers
Ionizing radiation or mitomycin-induced micronuclei in lymphocytes of BRCA1 or BRCA2 mutation carriers
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DOI：
10.1007/s10549-010-1017-6
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发表时间：
2011-06-01
影响因子：
3.8
通讯作者：
Diez, Orland
中科院分区：
文献类型：
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作者：
Gutierrez-Enriquez, Sara;Ramon y Cajal, Teresa;Diez, Orland
BRCA 1和BRCA 2基因是维持基因组完整性的关键基因，但杂合性状态是否会影响BRCA 1或BRCA 2的功能尚不明确。这可能对乳腺癌（BC）筛查模式和基于DNA损伤或DNA修复抑制药物的癌症治疗中BRCA 1和BRCA 2突变携带者的临床管理产生影响。我们研究了携带BRCA 1或BRCA 2突变的淋巴细胞是否对体外治疗的辐射或丝裂霉素C（MMC）敏感性增加。对21例BRCA 1突变携带者（12例BC和9例健康）、24例BRCA 2携带者（13例BC和11例健康）、15例未检测到BRCA 1或BRCA 2突变的家族性BC患者和16例无癌症家族史的对照者（5例BC和11例健康）的外周血进行照射或MMC治疗。使用微核阻断试验测量染色体损伤。我们评价了微核（MN）和核质桥（NPB）。BRCA 2突变携带者和家族性BC患者中未检测到BRCA 1或BRCA 2突变者的基础NPB低于BRCA 1携带者和对照组。BRCA 1（+/-）或BRCA 2（+/-）淋巴细胞在照射后MN和NPB频率没有增加。相比之下，BRCA 2（+/-）淋巴细胞在MMC暴露后呈现出比BRCA 1携带者和对照组更高的MN水平。单等位基因BRCA 1或BRCA 2致病性突变似乎与放射敏感性增强无关。一个BRCA 2等位基因的突变赋予了对MMC的敏感性增加，可能是因为该基因在MMC诱导的DNA损伤修复中的作用。这一发现表明MMC诱导的MN分析可能有助于识别BRCA 2或BRCA 2相关基因的功能缺陷。由于MMC可用作抗癌药物，因此这些数据可能与BRCA 2突变携带者的管理和随访相关。
BRCA1 and BRCA2 genes are essential in preserving the integrity of genome, and it is not unambiguously clear whether the heterozygosity status may affect BRCA1 or BRCA2 functions. This may have implications for the clinical management of BRCA1 and BRCA2 mutation carriers both in breast cancer (BC) screening modality and in cancer treatment based on DNA-damaging or DNA-repair-inhibiting drugs. We investigated whether lymphocytes carrying BRCA1 or BRCA2 mutations displayed an increased sensitivity to radiation or mitomycin C (MMC) in vitro treatments. Peripheral blood from 21 BRCA1 mutation carriers (12 with BC and 9 healthy), 24 BRCA2 carriers (13 with BC and 11 healthy), 15 familial BC patients without detected mutation in BRCA1 or BRCA2 and 16 controls without familial history of cancer (5 with BC and 11 healthy) were irradiated or treated with MMC. Chromosomal damage was measured using the cytokinesis-block micronucleus assay. We evaluated micronuclei (MN) and nucleoplasmic bridges (NPBs). The BRCA2 mutation carriers and familial BC patients without detected mutation in BRCA1 or BRCA2 showed less basal NPB than BRCA1 carriers and controls. The BRCA1 (+/-) or BRCA2 (+/-) lymphocytes did not have increased frequencies of MN or NPB after irradiation. In contrast, BRCA2 (+/-) lymphocytes presented higher levels of MN after MMC exposure than BRCA1 carriers and controls. The monoallelic BRCA1 or BRCA2 pathogenic mutations seem not to be associated with an enhanced radiosensitivity. The mutation of one BRCA2 allele conferred an increased sensitivity to MMC, presumably because of the role of this gene in the repair of MMC-induced DNA damage. This finding indicates that the MMC-induced MN analysis could be useful in identifying functional deficiencies of BRCA2 or genes related to BRCA2. Since MMC can be used as an anti-cancer drug, these data may be relevant for the management and follow-up of BRCA2 mutation carriers.