Niazi Yasmeen, Thomsen Hauke, Smolkova Bozena, Vodickova Ludmila, Vodenkova Sona, Kroupa Michal, Vymetalkova Veronika, Kazimirova Alena, Barancokova Magdalena, Volkovova Katarina, Staruchova Marta, Hoffmann Per, Nöthen Markus M, Dusinska Maria, Musak Ludovit, Vodicka Pavel, Hemminki Kari, Försti Asta
Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Front Genet. 2021 Jun 16;12:691947. doi: 10.3389/fgene.2021.691947. eCollection 2021.
DNA damage and unrepaired or insufficiently repaired DNA double-strand breaks as well as telomere shortening contribute to the formation of structural chromosomal aberrations (CAs). Non-specific CAs have been used in the monitoring of individuals exposed to potential carcinogenic chemicals and radiation. The frequency of CAs in peripheral blood lymphocytes (PBLs) has been associated with cancer risk and the association has also been found in incident cancer patients. CAs include chromosome-type aberrations (CSAs) and chromatid-type aberrations (CTAs) and their sum CAtot. In the present study, we used data from our published genome-wide association studies (GWASs) and extracted the results for 153 DNA repair genes for 607 persons who had occupational exposure to diverse harmful substances/radiation and/or personal exposure to tobacco smoking. The analyses were conducted using linear and logistic regression models to study the association of DNA repair gene polymorphisms with CAs. Considering an arbitrary cutoff level of 5 × 10, 14 loci passed the threshold, and included 7 repair pathways for CTA, 4 for CSA, and 3 for CAtot; 10 SNPs were eQTLs influencing the expression of the target repair gene. For the base excision repair pathway, the implicated genes and encode poly(ADP-ribosyl) transferases with multiple regulatory functions. and have an important role in maintaining genome stability through diverse mechanisms. Other candidate genes with known roles for CSAs included (general transcription factor IIH subunits 4 and 5), Fanconi anemia pathway genes, and , a mismatch repair gene. The present results suggest pathways with mechanistic rationale for the formation of CAs and emphasize the need to further develop techniques for measuring individual sensitivity to genotoxic exposure.
DNA损伤以及未修复或修复不充分的DNA双链断裂，连同端粒缩短，都有助于结构性染色体畸变（CAs）的形成。非特异性CAs已被用于监测暴露于潜在致癌化学物质和辐射的个体。外周血淋巴细胞（PBLs）中CAs的频率与癌症风险相关，并且在新发癌症患者中也发现了这种关联。CAs包括染色体型畸变（CSAs）和染色单体型畸变（CTAs）及其总和CAtot。在本研究中，我们使用了我们已发表的全基因组关联研究（GWASs）的数据，并提取了607名职业性接触各种有害物质/辐射和/或个人接触吸烟的个体中153个DNA修复基因的结果。使用线性和逻辑回归模型进行分析，以研究DNA修复基因多态性与CAs的关联。考虑到5×10的任意截止水平，14个位点通过了阈值，其中包括7个用于CTA的修复途径、4个用于CSA的修复途径和3个用于CAtot的修复途径；10个单核苷酸多态性（SNPs）是影响目标修复基因表达的表达数量性状位点（eQTLs）。对于碱基切除修复途径，涉及的基因和编码具有多种调节功能的聚（ADP - 核糖基）转移酶。和通过多种机制在维持基因组稳定性方面发挥重要作用。其他对CSAs具有已知作用的候选基因包括（通用转录因子IIH亚基4和5）、范可尼贫血途径基因以及一个错配修复基因。目前的结果表明了CAs形成的具有机制原理的途径，并强调了进一步开发测量个体对遗传毒性暴露敏感性的技术的必要性。
