DNA repair proficiency: Potential susceptibility factor for breast cancer
DNA repair proficiency: Potential susceptibility factor for breast cancer
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DOI：
10.1093/jnci/88.11.754
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发表时间：
1996-06-05
期刊：
影响因子：
--
通讯作者：
Sanford, KK
中科院分区：
文献类型：
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作者：
Helzlsouer, KJ;Harris, EL;Sanford, KK
DNA修复系统被《科学》杂志选为1994年“年度分子”。DNA不断受到内源性机制（如氧化产物）和外源性暴露（如电离辐射）的破坏。损伤的修复对于防止致癌过程的基因改变至关重要。电离辐射是一种公认的乳腺癌病因（2-7）。在患有共济失调毛细血管扩张症（AT）（一种常染色体隐性遗传综合征，与细胞对电离辐射过敏相关）的女性生物学亲属中，发现乳腺癌易感性增加(8)。在AT基因杂合的个体中，电离辐射后淋巴细胞中染色单体断裂和间隙水平增加(9)。因此，我们假设DNA损伤的次优修复可能是女性易患乳腺癌的易感性因素，因为它对电离辐射等环境暴露的致癌损伤的敏感性增加。我们之前报道了一项关于在青春期和成年早期反复进行胸部透视检查的姐妹中发生乳腺癌群集的调查（10）。在几个家庭成员中测量了辐射后淋巴细胞染色体损伤的持久性，并发现与辐射暴露史有关。虽然结果不是决定性的，但乳腺癌的发生模式和DNA损伤的次优修复与假设的遗传-环境相互作用是一致的。随后，我们进行了这项试点病例对照研究，以调查乳腺癌高风险妇女的DNA损伤修复是否处于次优状态。我们从约翰霍普金斯医疗机构的乳房监测服务部门招募女性以及约翰霍普金斯医疗机构的女性雇员。高危妇女（n= 17）以前没有癌症诊断，并且至少有一个一级亲属或两个二级亲属在同一侧患有乳腺癌。对照妇女（n= 19）以前没有癌症或增生性乳腺良性疾病的诊断，并且很少有乳腺癌家族史（即，每一方家庭中最多有一位二度亲属发生乳腺癌）。四名患有乳腺癌的女性也接受了评估。这项研究得到了约翰霍普金斯医院临床研究联合委员会的批准；所有参与者均给予书面知情同意。我们使用由Sanford， Parshad和同事（9,11）开发的检测方法来测量DNA修复能力。血液样本采用盲法分析；每批样品至少包含一个对照样品。DNA修复能力的衡量标准是断裂和间隙的数量，代表x照射后0.5-1.5小时观察到的未修复的DNA链断裂（12）。先前的一项研究（75）表明，断裂和间隙的分布是双峰的；每100个中期细胞中超过60个断裂和间隙被认为是次优修复（9,12）。在我们的研究中发现的断裂和间隙的数量从110到164次为次优修复，从16到50次为正常修复。参考样本以盲法分析了10次，发现了正常修复的证据。采用Fisher精确检验评估DNA修复熟练程度与乳腺癌风险之间的相关性的统计学意义。
DNA repair systems were voted the 1994" molecule of the year" by Science (7). DNA is continually damaged by endogenous mechanisms such as products of oxidations and by exogenous exposures such as ionizing radiation. Repair of damage is critical to preventing genetic alterations of the carcinogenic process. Ionizing radiation is a well-established etiologic agent for breast cancer (2-7). Increased susceptibility to breast cancer has been observed among female biological relatives of persons with ataxia telangiectasia (AT)(8), an autosomal, recessively inherited syndrome associated with cellular hypersensitivity to ionizing radiation. Increased levels of chromatid breaks and gaps in lymphocytes following ionizing radiation have been demonstrated in individuals heterozygous for the AT gene (9). Thus, we hypothesized that suboptimal repair of DNA damage may be a susceptibility factor predisposing women to breast cancer through increased sensitivity to carcinogenic damage from environmental exposures such as ionizing radiation. We previously reported an investigation of a breast cancer cluster among sisters who had had repeated fluoroscopic examinations of the chest during adolescence and early adulthood (10). Persistence of chromosomal damage to the lymphocytes following irradiation was measured in several family members and was found to be associated with a history of radiation exposure. Although the results were not conclusive, the pattern of breast cancer occurrence and suboptimal repair of DNA damage was consistent with the hypothesized genetic-environmental interaction. Subsequently, we conducted this pilot casecontrol study to investigate whether women at high risk of developing breast cancer have suboptimal repair of DNA damage.We recruited women from the Breast Surveillance Service of The Johns Hopkins Medical Institutions as well as female employees of The Johns Hopkins Medical Institutions. Women at high risk (n= 17) had no previous diagnosis of cancer and at least one first-degree relative or two second-degree relatives on the same side of the family with breast cancer. Control women (n= 19) had no previous diagnosis of cancer or of proliferative benign breast disease and a minimal family history of breast cancer (ie, breast cancer occurring in at most one second-degree relative on each side of the family). Four women with breast cancer were also evaluated. The study was approved by The Johns Hopkins Hospital Joint Committee on Clinical Investigation; all participants gave written informed consent. We used the assay developed by Sanford, Parshad, and co-workers (9, 11) to measure DNA repair proficiency. Blood samples were assayed in a blinded fashion; each batch contained at least one control sample. A measure of DNA repair proficiency is provided by the number of breaks and gaps, representing unrepaired DNA strand breaks observed 0.5-1.5 hours after x irradiation (12). A previous study (75) showed that the distribution of breaks and gaps is bimodal; more than 60 breaks and gaps per 100 metaphase cells is considered to be suboptimal repair (9, 12). The number of breaks and gaps found in our study ranged from 110 to 164 for suboptimal repair and from 16 to 50 for normal repair. A reference sample was assayed in a blinded fashion 10 times, and evidence of normal repair was found. Statistical significance of the association between DNA repair proficiency and breast cancer risk was evaluated by use of Fisher's exact test.