DNA repair pathways, cell cycle arrest checkpoints, and cell death induction are present in cells to process DNA damage and prevent genomic instability caused by various extrinsic and intrinsic ionizing factors. Mutations in the genes involved in these pathways enhances the ionizing radiation sensitivity, reduces the individual’s capacity to repair DNA damages, and subsequently increases susceptibility to tumorigenesis. BRCA1 and BRCA2 are two highly penetrant genes involved in the inherited breast cancer and contribute to different DNA damage pathways and cell cycle and apoptosis cascades. Mutations in these genes have been associated with hypersensitivity and genetic instability as well as manifesting severe radiotherapy complications in breast cancer patients. The genomic instability and DNA repair capacity of breast cancer patients with BRCA1/2 mutations have been analyzed in different studies using a variety of assays, including micronucleus assay, comet assay, chromosomal assay, colony-forming assay, γ -H2AX and 53BP1 biomarkers, and fluorescence in situ hybridization. The majority of studies confirmed the enhanced spontaneous & radiation-induced radiosensitivity of breast cancer patients compared to healthy controls. Using G2 micronucleus assay and G2 chromosomal assay, most studies have reported the lymphocyte of healthy carriers with BRCA1 mutation are hypersensitive to invitro ionizing radiation compared to non-carriers without a history of breast cancer. However, it seems this approach is not likely to be useful to distinguish the BRCA carriers from non-carrier with familial history of breast cancer. In overall, breast cancer patients are more radiosensitive compared to healthy control; however, inconsistent results exist about the ability of current radiosensitive techniques in screening BRCA1/2 carriers or those susceptible to radiotherapy complications. Therefore, developing further radiosensitivity assay is still warranted to evaluate the DNA repair capacity of individuals with BRCA1/2 mutations and serve as a predictive factor for increased risk of cancer mainly in the relatives of breast cancer patients. Moreover, it can provide more evidence about who is susceptible to manifest severe complication after radiotherapy.

中文翻译：

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BRCA1 和 BRCA2 对乳腺癌患者基因组不稳定的分子贡献：放射敏感性测定的回顾


细胞中存在 DNA 修复途径、细胞周期停滞检查点和细胞死亡诱导，以处理 DNA 损伤并防止由各种外在和内在电离因素引起的基因组不稳定。参与这些途径的基因突变会增强电离辐射敏感性，降低个体修复 DNA 损伤的能力，从而增加肿瘤发生的易感性。 BRCA1 和 BRCA2 是参与遗传性乳腺癌的两个高度渗透性基因，有助于不同的 DNA 损伤途径以及细胞周期和细胞凋亡级联。这些基因的突变与乳腺癌患者的过敏和遗传不稳定性以及严重的放疗并发症有关。具有BRCA1/2突变的乳腺癌患者的基因组不稳定性和DNA修复能力已在不同的研究中使用多种测定法进行了分析，包括微核测定法、彗星测定法、染色体测定法、集落形成测定法、γ-H2AX和53BP1生物标志物，和荧光原位杂交。大多数研究证实，与健康对照相比，乳腺癌患者的自发放射敏感性和放射敏感性增强。使用G2微核测定和G2染色体测定，大多数研究报告，与没有乳腺癌病史的非携带者相比，具有BRCA1突变的健康携带者的淋巴细胞对体外电离辐射过敏。然而，这种方法似乎不太可能用于区分 BRCA 携带者和有乳腺癌家族史的非携带者。 总体而言，与健康对照相比，乳腺癌患者对放射线更加敏感；然而，目前放射敏感技术在筛查 BRCA1/2 携带者或易受放射治疗并发症影响的携带者方面的能力存在不一致的结果。因此，仍然有必要开发进一步的放射敏感性测定来评估 BRCA1/2 突变个体的 DNA 修复能力，并作为主要在乳腺癌患者亲属中癌症风险增加的预测因素。此外，它可以提供更多关于谁在放疗后容易出现严重并发症的证据。