Gamma-ray-induced mutagen sensitivity in breast cancer

描述（由申请人提供）： 研究表明，相对较高比例的散发性乳腺癌女性表现出异常高水平的放射敏感性，这是通过PHA刺激的淋巴细胞G2期中电离辐射暴露（如X射线和γ射线）诱导的染色体畸变频率来测量的。由于电离辐射导致DNA链断裂，未修复的DNA双链断裂可导致染色体断裂，因此G2染色体辐射敏感性增加是内源性或外源性诱变剂诱导的染色体损伤的细胞修复能力的标志。DNA双链断裂修复（DSBR），包括非同源末端连接（NHEJ）和同源重组（HR），负责修复可能导致染色体断裂的DNA双链断裂。参与这些途径的十几个DNA修复基因是多态性的，但它们在G2染色体放射敏感性中的作用尚未得到充分研究，特别是在乳腺癌的病因学中。R 03申请的主要目标是利用由我们的机构种子基金资助的现有乳腺癌试点研究，该研究帮助收集和储存乳腺癌患者和无癌症对照的血液样本。利用现有的资源，我们建议调查的作用，G2染色体放射敏感性的乳腺癌的病因，并确定可能与放射敏感性表型的遗传变异。我们的具体目标是：1）、确定年轻白人（<=55岁）女性G2染色体放射敏感性（表型）与乳腺癌风险之间的关系。这一目标将通过评价200例病例和200例对照和额外招募的短期培养淋巴细胞中的染色体畸变来实现，这些淋巴细胞已接受γ射线照射处理，收获并储存在-20 ℃冰箱中。我们推测，高放射敏感性表型（通过γ射线诱导的诱变剂敏感性测量）与乳腺癌风险增加相关。2）、确定DSBR中涉及的三个选择的DNA修复基因（XRCC 3、XRCC 7和RAD 51）多态性与G2染色体放射敏感性（表型）之间的相关性，以及它们对这些妇女中与放射敏感性增加相关的乳腺癌风险的调节。我们假设这些选择基因的不良基因型与G2染色体放射敏感性相关，并调节与β 2染色体放射敏感性相关的乳腺癌风险。这项研究的最终目标是识别高危人群，并帮助设计旨在预防和控制乳腺癌的新的临床和公共卫生策略。为了实现这一目标，这项研究将有助于确定与放射敏感性表型和年轻（<=55岁）女性个体发生乳腺癌风险增加相关的易感基因的变体。

DESCRIPTION (provided by applicant): Studies suggest that a relatively high proportion of women with sporadic breast cancer exhibit an abnormally high level of radiosensitivity as measured by the frequency of chromosomal aberrations induced by ionizing radiation exposure (such as X- and gamma-ray) in the G2 phase of PHA stimulated lymphocytes. Because ionizing radiation causes DNA strand breaks and unrepaired DNA double-strand breaks can lead to chromosomal breaks, increased G2 chromosomal radiosensitivity is a marker of cellular repair capacity for chromosomal damage induced by endogenous or exogenous mutagens. DNA double-strand break repair (DSBR), including non-homologous end joining (NHEJ) and homologous recombination (HR), is responsible for repair of DNA double-strand breaks that may lead to chromosomal breaks. About a dozen DNA repair genes involved in these pathways are polymorphic, but their role in G2 chromosomal radiosensitivity has not been fully investigated, particularly in the etiology of breast cancer. The major goal of this R03 application is to utilize an existing pilot study of breast cancer funded by our institutional seeds funds that had helped collect and store blood samples from breast cancer patients and cancer-free-controls. Using this existing resource, we propose to investigate the role of G2 chromosomal radiosensitivity in the etiology of breast cancer and to identify genetic variants that may correlate with the radiosensitivity phenotype. Our specific aims are: 1): To determine the associations between the G2 chromosomal radiosensitivity (phenotype) and risk of breast cancer in young Caucasian (<=55 years) women. This aim will be achieved by evaluating chromosomal aberrations in short-term cultured lymphocytes that have already been treated by gamma-irradiation, harvested and stored in -20 degrees C freezer from among 200 cases and 200 controls and additional recruitment. We hypothesize that a high-radiosensitivity phenotype as measured by the gamma-ray-induced mutagen sensitivity is associated with increased risk of breast cancer. 2): To determine the correlation between polymorphisms of three select DNA repair genes (XRCC3, XRCC7 and RAD51) involved in DSBR and the G2 chromosomal radiosensitivity (phenotype) and their modulation of risk breast cancer associated with increased radiosensitivity in these women. We hypothesize that adverse genotypes of these select genes correlate with G2 chromosomal radiosensitivity and modulate risk of breast cancer associated with (72 chromosomal radiosensitivity. The ultimate goal of this study is to identify individuals at high risk and help design new clinical and public health strategies aimed at preventing and controlling breast cancer. Towards this goal, this study will help identify variants of the susceptibility genes that will correlate with radiosensitivity phenotype and subgroups of individuals of young (<=55 years) women at increased risk of developing breast cancer.