Polymorphisms in DNA repair and environmental interactions

Boer, Johan G. de

doi:10.1016/s0027-5107(02)00217-8

Cited by 68 publications

(33 citation statements)

References 59 publications

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“…27 These polymorphisms are under investigation in pharmacogenetic studies in solid neoplasms and they may influence clinical outcomes of CRC patients treated with irinotecan.…”

Section: Folfiri Pharmacogenetics In Colorectal Cancermentioning

confidence: 99%

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

et al. 2007

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The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3 0 -UTR 6 þ /6 þ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval ¼ 1.56-5.80; P ¼ 0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.

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“…27 These polymorphisms are under investigation in pharmacogenetic studies in solid neoplasms and they may influence clinical outcomes of CRC patients treated with irinotecan.…”

Section: Folfiri Pharmacogenetics In Colorectal Cancermentioning

confidence: 99%

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

et al. 2007

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“…Many recent studies have indicated that sporadic tumours probably arise due to a complex relationship between environmental exposures to carcinogens in individuals with low-penetrance genetic polymorphisms. These polymorphisms may exist in genes involved in carcinogen metabolism, influencing the amount of damaging metabolic intermediates produced from dietary constituents and other environmental agents [191][192][193], or may represent polymorphisms in components of the response pathways to damage, such as repair enzymes [189,194,195]. In isolation, these polymorphisms have little impact on tumour susceptibility, but are important risk factors through their relatively high incidence and the synergistic effects of combinations of variants, exemplified by family studies of sporadic breast cancer not due to BRCA1/2, which showed that the 20% of individuals at highest risk have a 40-fold higher likelihood of cancer than the 20% lowest-risk population [196].…”

Section: Genetic Factors Influencing Genotoxic Responses and Tumourigmentioning

confidence: 99%

Cell and tissue responses to genotoxic stress

Coates

Lorimore

Wright

2005

The Journal of Pathology

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Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell-and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell-and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell-and tissuespecific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell-and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

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“…These pathways play a vital role in maintaining genetic integrity. The ability of an individual to prevent and repair damage is genetically determined and is the result of combinations of multiple genes that may display subtle differences in their activity (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia

Seedhouse

Faulkner

Ashraf

et al. 2004

Clinical Cancer Research

153

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Purpose: Double-strand break repair via homologous recombination is essential in maintaining genetic integrity. RAD51 and XRCC3 are involved in the repair of DNA by this pathway, and polymorphisms have been identified in both the RAD51 (RAD51-G135C) and XRCC3 (XRCC3-Thr241Met) genes. The object of this study was to examine whether these polymorphisms may modulate susceptibility to the development of acute myeloid leukemia (AML), a disease that is characterized by genetic instability.Experimental Design: We studied the distribution of polymorphisms in RAD51 and XRCC3 in 216 cases of de novo AML, 51 cases of therapy-related AML (t-AML), and 186 control subjects using PCR followed by restriction enzyme digestion. The polymorphic deletion of the detoxification gene glutathione S-transferase M1 (GSTM1) was also examined by PCR.Results: The risk of the development of AML was found to be significantly increased when both variant RAD51-135C and XRCC3-241Met alleles are present [odds ratio (OR), 3.77; 95% confidence interval (CI), 1.39 -10.24], whereas the risk of t-AML development is even higher (OR, 8.11; 95% CI, 2.22-29.68), presumably because of the large genotoxic insult these patients receive after their exposure to radiotherapy or chemotherapy. If we further divide the AML group into patients in which the burden of DNA damage is increased, because of the deletion of the GSTM1 gene, the risk of development of AML is further increased (OR, 15.26; 95% CI, 1.83-127.27). Conclusions:These results strongly suggest that DNA double-strand breaks and their repair are important in the pathogenesis of both de novo and t-AML.

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Polymorphisms in DNA repair and environmental interactions

Cited by 68 publications

References 59 publications

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

Cell and tissue responses to genotoxic stress

Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia

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