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Bladder Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Fifty-eight significantly mutated genes have been identified; the main features are summarized in Figure 13.1. TP53 and cell cycle genes were mutated in 89% of tumors including TP53 in 48%, MDM2 over-expression in 25%, and RB mutations 17%, CDKN2a mutation/deletion 22%, CDKN1A in 11%. RAS/PI3K pathway was also frequently mutated (in ~70%). An unexpected major feature has been the frequency of chromatin remodeling genes with ten genes mutated at >5% frequency and occurring in over 50% of tumors, the significance of which is unclear. DNA repair genes are also found to be mutated in around 16% cases including ATM (14%), ERCC2 (9%), and RAD51 (2%). FGFR2/3 mutations have reported to occur in 15–20% of cases with the frequency being higher in lower-stage lower-grade tumors.
Xeroderma Pigmentosum
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Homozygous or compound heterozygous mutations in the XPA, ERCC3, XPC, ERCC2, DDB2, ERCC4, and ERCC5 as well as POLH genes produce loss-of-function proteins and compromise the efficiency of the NER pathway to remove and repair DNA lesions caused by UV radiation, leading to the development of hereditary disorders XP, Cockayne syndrome (CS), and trichothiodystrophy (TTD). While XP patients show an increased risk for skin cancer, CS (due to CSA and CSB mutations) and trichothiodystrophy (due to TTDA mutation) patients do not develop skin cancer. However, XP-CS complex patients (due to loss of function ERCC3/XPB, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG) may still have skin cancer similar to XP patients (Table 50.1) [8].
Biomarkers of Toxicant Susceptibility
Published in Anthony P. DeCaprio, Toxicologic Biomarkers, 2006
XPD/ERCC2 (excision repair cross-complementing) is involved in the NER pathway (29), which recognizes and repairs a wide range of structurally unrelated lesions such as bulky adducts and thymidine dimers. The XPD protein is an evolutionarily conserved helicase, a subunit of transcription factor IIH (TFIIH), that is essential for transcription and NER. Recently, the entire coding region of the DNA repair gene XPD/ERCC2 was resequenced in 12 normal individuals, and six polymorphic variants were described (30). Rare XPD mutations, which prevent interaction with p44, another subunit of TFIIH, and reduce its helicase activity result in three distinct clinical genetic diseases: XP, trichothiodystrophy, and XP combined with Cockayne sydrome. The functional significance of these newly identified XPD variants is not known. Many XPD polymorphisms are identified, e.g., C22541A at codon 156 of exon 6, at codon 199 (Ile→Met), at codon 312 (Asp→Asn), and A35931C at codon 751 of exon 23 (Lys→Gln). Allele frequencies are higher than 25% in sample populations from North America, England, and Italy, but homozygous alleles are very rare. XPD-Lys751Gln polymorphism, a conservative substitution, is associated with reduced in vitro repair of X-ray-induced DNA damage.
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
ERCC2 is part of the nucleotide excision repair (NER) pathway, which is an integral part of the basal transcription factor BTF2/TFIIH [71]. Reports of cDNA microarrays have shown that ERCC2 gene expression in azoospermic testes is significantly upregulated compared to normal ones [71]. ERCC1 is another essential component of the NER pathway, where it acts in a complex with XPF to repair DNA damage [72]. Ercc1-deficient testes show increased levels of DSBs, oxidative DNA damage, and apoptosis in their male germ cells [72]. In a case–control study following by a meta-analysis, Singh et al., 2019 reported that ERCC2 751A>C SNP is associated with male infertility. However, they did not find any significant association between ERCC2 751A>C, and ERCC1 C>A 3′UTR polymorphisms and male infertility in their meta-analysis [73].
Posterior subcapsular cataracts are a late effect after acute exposure to 0.5 Gy ionizing radiation in mice
Published in International Journal of Radiation Biology, 2021
Sarah Kunze, Alexander Cecil, Cornelia Prehn, Gabriele Möller, Andreas Ohlmann, Gerhild Wildner, Stephan Thurau, Kristian Unger, Ute Rößler, Sabine M. Hölter, Soile Tapio, Florian Wagner, Andreas Beyerlein, Fabian Theis, Horst Zitzelsberger, Ulrike Kulka, Jerzy Adamski, Jochen Graw, Claudia Dalke
As for PSCs, we observed significant age-dependent effects on the number of anterior and posterior aberrations. In the anterior lens, in comparison to the 4-h time point, an increased incidence was found at 12, 18, and 24 months after irradiation for enlarged and/or swollen fiber cells and mislocated nuclei, at 12 and 18 months for detachments and at 18 and 24 months for fissures. The only significantly increased incidence in the lens bow region was found for fissures at 24 months. Whereas in the posterior part of the lens the number of enlarged and/or swollen fiber cells was significantly increased at 12, 18, and 24 months as well as the number of mislocated micronuclei. The number of subcapsular cataracts was elevated at 18 and 24 months, in comparison to the 4-hour time point. Female mice were significantly more affected by anterior enlarged and/or swollen fiber cells and mislocated nuclei in the lens cortex. A protective association of the heterozygous Ercc2 mutation was observed for anterior detachments. The retinae did not show significant changes 4 h after irradiation or at later time points, independent of sex and genotype. All odds ratios with the corresponding 95% confidence intervals are shown in Tables 1–4.
Dose-dependent long-term effects of a single radiation event on behaviour and glial cells
Published in International Journal of Radiation Biology, 2021
Marie-Claire Ung, Lillian Garrett, Claudia Dalke, Valentin Leitner, Daniel Dragosa, Daniela Hladik, Frauke Neff, Florian Wagner, Horst Zitzelsberger, Gregor Miller, Martin Hrabĕ de Angelis, Ute Rößler, Daniela Vogt Weisenhorn, Wolfgang Wurst, Jochen Graw, Sabine M. Hölter
Hence, in 2013, a lifetime study was initiated that provided a unique opportunity to assess long-term effects of low (0.063 Gy) compared to medium and high (0.125 and 0.5 Gy, respectively) radiation dose exposure in early adulthood on a broad spectrum of different functional readouts and tissues in mice (Dalke et al. 2018). This included selected behaviours that might be early indicators of radiation effects on the brain for up to 18 or 24 months, respectively, after a single radiation event. In addition to wild type (wt) mice, phenotypically healthy heterozygous Ercc2S737P mice (het) were included in this study to test for increased susceptibility to ionizing radiation in vivo, because lymphocytes of heterozygous Ercc2S737P mice demonstrated an increased sensitivity to radiation-induced DNA damage in vitro (Kunze et al. 2015). Ercc2 is a DNA helicase involved in nucleotide excision repair, and mutations of the ERCC2 gene in humans, responsible for the transcription of the XPD protein, are associated with a spectrum of diseases characterized by photosensitivity, developmental and cognitive deficiencies (Manuguerra et al. 2006).