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Biological data: The use of -omics in outcome models
Published in Issam El Naqa, A Guide to Outcome Modeling in Radiotherapy and Oncology, 2018
Issam El Naqa, Sarah L. Kerns, James Coates, Yi Luo, Corey Speers, Randall K. Ten Haken, Catharine M.L. West, Barry S. Rosenstein
Gene dosage, or copy number variations (CNVs), are a second genetic variable that may be relevant to radiotherapy toxicities [205, 206]. CNVs capture a much larger part of the genome, spanning thousands to millions of base pairs, whereas SNPs each describe changes specific to only one nucleotide. Thus, CNVs are indicative of more macro-scale changes in the genome that may play more significant roles when using a datamining approach. The objective of CNV analysis is to identify the chromosomal regions at which the number of copies of a gene deviates from two. These could be gains (CNV > 2) or losses (CNV < 2) [207]. CNVs have been identified in several complex diseases such Crohn’s disease [208], psoriasis [209]), autism [210, 211], and susceptibility to cancer [212, 213]. CNVs are less numerous than SNPs but they affect up to 10% of the genome, disrupting coding sequences or interrupting long range gene regulation, therefore, accounting for more differences among individuals [214]. In addition, there is evidence to suggest that there is limited overlap between SNPs and CNVs indicating potential complementary effect [215]. As an example application, the XRCC1 CNV has been shown as a potential risk factor of radiation-induced toxicities in prostate cancer [216].
Biomarkers of Toxicant Susceptibility
Published in Anthony P. DeCaprio, Toxicologic Biomarkers, 2006
XRCC1 (X-ray repair cross-complementing) plays a role in the BER pathway, interacts with DNA polymerase β, poly-ADP-ribose polymerase (PARP), and DNA ligase III, and has a BCRT domain, characteristic of proteins involved in cycle checkpoint functions and response to DNA damage. Ionizing radiation and alkylating agents cause DNA base damage and strand breaks, which elicit the BER system. Shen et al. (30) identified three coding polymorphisms in the XRCC1 gene at codons 194 (Arg → Trp), 280 (Arg → His), and 399 (Arg→Gln), coding for nonconservative amino acid changes (including the Arg 399Gln change in the PARP binding domain), which suggests potential functional importance, but their impact on phenotype is unknown. Genotype and allele frequencies for XRCC1 polymorphisms 194Trp and 280His alleles are low in blacks (0.05 for 194Trp and 0.02 for 280His) and Caucasians (0.06 for 194Trp and 0.03 for 280His), but are significantly more prevalent in Taiwanese (0.27 for 194Trp and 0.11 for 280His). The 399Gln-allele frequency is significantly different among all three populations, with the frequency being highest in Caucasians (0.37), intermediate in Taiwanese (0.26), and lowest in blacks (0.17).
Respiratory Tract Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Susceptibility to lung cancer may also be modulated by DNA repair but whether defects in DNA repair may be a common predisposing factor for lung cancer has not yet been established. There is, however, some evidence indicating that defects in DNA repair may be involved in the development of lung cancer. Recent findings suggest that individuals with reduced DNA repair capacity (DRC) are at an increased risk of lung cancer: in vitro lymphocyte assays has been utilized to measure individual variation in DRC. Sensitivity to mutagen damage, based on the quantification of bleomycin-induced chromatid breaks in vitro, may be a significant determinant of susceptibility. In case-control studies, lung cancer patients, and head and neck cancer patients expressed increased sensitivity to muta-gens (56,57). The underlying mechanisms that account for the observed differences in chromosomal sensitivity to bleomycin among individuals are multiple, one mechanism may be alteration in the DNA repair process. Further, studies have shown that this assay can be used to assess the sensitivity also to other carcinogens such as B(a)P. Molecular epidemiological studies have also been conducted in which DNA repair capacity is measured in the host-cell reactivation assay (HCR) where a damaged recombinant plasmid, i.e., by UV or B(a)P, harboring a chloramphenicol acetyltransfer-ase reporter gene is introduced into lymphocytes (58). Since B(a)P-adducts and thymine dimer repair can block reporter gene expression, the measured chloramphenicol transferase activity is the net result of DNA repair in the cell. B(a)P-adducts are repaired by the nucleotide excision repair (NER) pathway and XPD is one of the genetic complementation groups encoding for proteins involved in the NER pathway. One study on DRC and XPD genotypes suggested that the XPD variant Gln751Gln (exon 23) and Asp312Asn (exon 11) genotypes were associated with less DRC and significantly increased risk for lung cancer (59). In a case–control study the XPD Asp312Asp genotype was found to have almost twice the risk of lung cancer when the Asp/Asn plus Asn/Asn combined genotype served as reference. In light smokers, the XPD Asp312Asp genotype was more frequent among cases than in controls and was associated with increase risk for NSCLC (60). XPD variant alleles have also been associated with reduced repair of aromatic DNA adducts (61). In a case–control study, a significant interaction between cumultative cigarette smoking and XPD polymorphisms (Asp312Asn and Lys751Gln) were found (62). XRCC1 protein is involved in the base excision repair (BER) through the interaction with poly (ADP-ribose) polymerase, DNA polymerase β, and DNA ligase III. Three polymorphisms have been identified (63). Recently, XRCC1 polymorphisms have been show to modulate lung cancer susceptibility (64,65). The human OGG1 (hOGG1) gene encodes a DNA glycosylase/AP-lyase that catalyzes the removal of 8-OH-dG adducts. Several polymorphisms at the hOGG1 locus have been found and recent studies have suggested that the Ser326Cys hOGG1 polymorphism may be associated with increased lung cancer risk and orolaryngeal cancer risk (66,67).
DNA repair in lung cancer: a large-scale quantitative analysis for polymorphisms in DNA repairing pathway genes and lung cancer susceptibility
Published in Expert Review of Respiratory Medicine, 2022
Zexi Liao, Minhan Yi, Jiaxin Li, Yuan Zhang
The repair of DNA base damage and single strand breaks brought on by X-rays, oxygen radicals, and alkylating chemicals is carried out through the crucial DNA repair mechanism known as BER [42]. A key protein in the BER pathway, XRCC1, whose gene was the first to be cloned in the single strand break repair (SSBR) process, accelerates the whole repairing reaction by interacting with polynucleotide kinase (PNK) and negatively regulating poly (ADP-ribose) polymerase (PARP) [43,44]. In this study, we discovered that in the general population and East Asian populations, respectively, 2 SNPs of XRCC1 (rs1001581 and rs915927) raised LC risk whereas rs3213245 and rs25487 lowered it. However, a prior meta-analysis utilizing recessive and dominant models in a variety of cancer types revealed that XRCC1 rs25487 had no association with cancer risk [45] and was only described to increase LC risk in Asian population in another meta-analysis using allele model [27]. The distinct function of XRCC1 in the carcinogenesis of LC is indicated by the different analytical results between various malignancies and just LC. APEX1 is a crucial BER pathway starter by cleaving damaged DNA known as apyrimidinic sites [46]. We identified APEX1 rs1760944 as a SNP lowing LC risk and this result was correspond to former research [47,48]. Functional research also proved the protective role of APEX1 rs1760944 in LC [49].
Genetic variations as molecular diagnostic factors for idiopathic male infertility: current knowledge and future perspectives
Published in Expert Review of Molecular Diagnostics, 2021
Mohammad Karimian, Leila Parvaresh, Mohaddeseh Behjati
XRCC1 gene is involved in DNA repair. It encodes a 70 kDa multi-domain protein encoded by various enzymes such as DNA polymerase-b (Pol-b), poly-ADP ribose polymerase (PARP), AP Endonuclease-1 (APE1), and human glycosylase DNA (hOGG1). DNA ligase (LIG3) III facilitates HR and SSB DNA modification and plays a critical role in the base excision repair (BER) pathway [62]. XRCC1 is located on chromosome 19q13.2 and contains 17 exons [63]. This gene acts as a scaffold for delivering various proteins to the site of DNA damage and improves the efficiency of BER pathway. XRCC1 gene expression has been demonstrated in rodents and primates. However, its expression in human testis and its importance in male infertility have recently been investigated. Serine-139 phosphorylation in H2A histone type H2 AX, which forms γ-H2 AX, acts as an early cellular response to induction of DNA double-strand breaks (DSBs) [64]. XRCC1 deficient cells, which compresses SSBs during BER, contains high levels of γ-H2 AX hormones compared to wild-type cells [65]. Indeed, spontaneous γ-H2AX levels are higher in XRCC1-deficient cells compared with wild-type cells [64]. In this case, many mononuclear polymorphisms have been identified which probably alter the function of XRCC1 protein. Some studies using human lymphocytes demonstrated the association of this polymorphism with impaired DNA repair and high level of DNA adducts [62].
Association between Single Nucleotide Polymorphisms and Glioma Risk: A Systematic Literature Review
Published in Cancer Investigation, 2020
Cléciton Braga Tavares, Francisca das Chagas Sheyla Almeida Gomes-Braga, Emerson Brandao Sousa, José Nazareno Pearce de Oliveira Brito, Mariella de Almeida Melo, Viriato Campelo, Fidelis Manes Neto, Ricardo Marques Lopes de Araújo, Iruena Moraes Kessler, Leonardo de Moura Sousa Júnior, Luís Carlos Carvalho Filho, Yousef Qathaf Aguiar, Pedro Vitor Lopes Costa, Benedito Borges da Silva
The gene XRCC1 is considered one of the most promising candidates that may influence the pathogenesis of glial cell tumors. It is located on chromosome 19q13.2-13.2, comprises 33 kb and 17 exons, and coordinates several protein interactions, such as those between DNA ligase III, DNA polymerase, and poly ADP-ribose polymerase, which together play an important role in DNA repair (7,11,14,15). Numerous studies have shown a positive correlation between XRCC1 SNPs and the risk of glial neoplasm development; the most commonly identified SNPs are Arg194Trp (rs1799782), in which nucleotide C is changed to T in exon 6; Arg399Gln (rs25487), with G changed to A in exon 9; and Arg280His (rs25489), with G changed to A in exon 10. However, some controversial results remain, such as those reported by Gao et al. that showed no influence by Arg194Trp on glioma risk; those by Li et al., Fanet al., and Rodriguez-Hernandes et al. that found no significant correlation between Arg399Gln and glial tumor susceptibility; and those by Xu Gaofeng et al. that demonstrated no association between Ar280His and glial tumors (7,11,14,15).