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Cancer: A Genetic Disease
Published in Jeremy R. Jass, Understanding Pathology, 2020
Conceivably mutations could inactivate the very genes that detect and repair mutations in other genes. This would allow mutations in cancer-causing genes to accumulate rapidly, a state of hypermutability. A long-established clinical model for this premise is provided by xeroderma pigmentosum, a rare autosomal dominant condition characterised by defective nucleotide excision repair. Affected individuals are extremely sensitive to ultraviolet light and develop multiple skin tumours at a young age.
Cutaneous Malignant Melanoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The XP (xeroderma pigmentosum) genes (XPA, XPC, and XPD) encode proteins involved in nucleotide excision repair (NER), a specialized type of DNA repair for UV radiation-induced photoproducts and DNA adducts. Mutations in XP genes are implicated in xeroderma pigmentosum syndrome, which presents with malignant melanoma, basal cell carcinoma, and squamous cell cancer of the skin.
Neoplasia
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Ultraviolet irradiation is strongly implicated in the aetiology of skin tumours, especially malignant melanoma, of which >90% of cases can be attributed to exposure. As ultraviolet light is of low energy it does not penetrate deeply and the effects are confined to the skin. Ultraviolet rays induce the formation of pyrimidine dimers, which lead to base-pair substitutions during replication. Abnormalities of DNA-repair systems, e.g. defective nucleotide excision repair in Xeroderma pigmentosum, lead to greatly increased risks of skin cancer.
Modulatory effect of myricitrin against chromosome instability and cytostasis induced by bleomycin and oxaliplatin in CHO-K1 cells
Published in Drug and Chemical Toxicology, 2023
Ana Paula de Souza, Raíne Fogliati Schardosim, Juliana Escouto Al Kateeb, Mauricio Lehmann, Ivana Grivicich, Rafael Rodrigues Dihl
The assessment of MYR against chromosomal instability induced by OXL indicated an increase in the frequencies of MNi and NPBs, in the post-treatment protocol, at all concentrations tested, when compared to the results obtained from the action of OXL alone. This result revealed that MYR was able to potentiate OXL-induced lesions. OXL causes DNA damage through the formation of inter- and intra-chain adducts in the DNA molecule (Ganaie et al. 2019, Rottenberg et al. 2021). The adducts interfere with essential cellular processes, such as cell cycle and DNA repair mechanisms (Howells et al. 2007, Rottenberg et al. 2021). In mammalian cells, nucleotide excision repair (NER) is the main DNA repair mechanism to remove bulky (helix distorting) lesions, nucleotide deletion being part of this process (Lee and Kang 2019). Thus, NER is impaired due to the binding of OXL to DNA, resulting in genomic lesions that give rise to chromosomal aberrations and fragmentation, sister chromatid breaks and translocations, hence increasing the frequency of MNi, NPBs and NBUDs (Povirk 1996, Jagetia et al. 2007, Danesi et al. 2012, Brandt and Gerrietes 2020).
Clinical value of identifying genes that inhibit hepatocellular carcinomas
Published in Expert Review of Molecular Diagnostics, 2022
Ugo Testa, Elvira Pelosi, Germana Castelli
Alterations of DNA repair genes are frequent in HCC. DNA repair processes are constantly active to limit damage in the DNA structure through several reparative mechanisms implying base excision repair, nucleotide excision repair, mismatch excision repair and homologous recombination. Various gene sets, including checkpoint factors, homologous recombination, mismatch repair, base excision repair, nucleotide excision repair, nonhomologous end-joining and Fanconi anemia; somatic alterations in at least one gene pertaining to DDR pathways are observed in about 20% and 3%, respectively of HCC patients; ATM (6%) and ATR (2.5%) are among the DDR genes most frequently mutated; BRCA1/BRCA2 genes are mutated in about 2.5% of HCC patients [28]. Mezina et al. showed that 11.5% of HCC patients possess pathogenic germline variants: 1.8% with BRCA2, 0.9% with MSH6, 0.9% PMS2, 2.2% FANCA, 1.8% BRIP1 [29]. In another cohort of HCC patients, BRCA2 mutations were observed in about 3% of patients [29]. The presence of DDR gene mutations in HCC patients may have some potential implications for precision treatment.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
Alterations in or deficiency of genes involved in the DNA damage response pathways is a known cause of oncogenesis in both adult and pediatric malignancies [16]. The resulting defective response to DNA damage allows cells to progress unchecked through the cell cycle causing the accumulation of mutations leading to oncogenic evolution [17]. There are several germline gene defects which lead to syndromes characterized by defective DNA repair and an increased risk of malignancy. Xeroderma pigmentosum is caused by defects in one of the genes involved in nucleotide excision repair and results in an exquisite sensitivity to UV light and a > 1000-fold increase risk of melanoma [18]. Similarly, heterozygous germline mutations in the MLH1 and MSH2 genes result in the mismatch repair defect, Lynch syndrome with an increased risk of colorectal cancer [18]. Homozygosity for these same mutations results in constitutional mismatch repair deficiency (CMMRD) syndrome, which results in an exceptionally high risk for a number of pediatric malignancies including brain tumors, leukemia, and gastrointestinal and female reproductive tract tumors along with various rare pediatric tumors [19].