Pharmacogenetics of the DNA repair and oxidative stress pathways in outcomes of cancer patients
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Introduction . Radiation and chemotherapy, widely used for treatment of neoplasms, cause a variety of DNA damage lesions to the genome. Generation of free radicals and reactive oxygen species (ROS), as well as induction of single- and double-strand DNA breaks, are common mechanisms of action of radiotherapy and chemotherapeutic agents. Overexpression of enzymes participating in detoxification of xenobiotics and enhanced activity of DNA repair pathways are some of the established causes of resistance to treatment. Inherited genetic variation, common throughout the genome, largely contributes to modified effects of anti-cancer treatment through altered activity, encoded by polymorphic genes. In this dissertation, we investigated relationships between treatment outcomes and polymorphisms in (1) glutathione-S-transferases (GST) and other oxidative stress-related enzymes, and (2) base-, nucleotide-excision, and double-strand break repair pathways. Patients and Methods . Early stage breast cancer patients from a German cohort were genotyped for polymorphisms in genes related to oxidative stress, GSTA1, GSTM1, GSTT1, GSTP1, CAT, MnSOD, eNOS , and MPO , in relation to late dermatologic side effects of radiation treatment. Acute myeloid leukemia (AML) adult patients from two study populations (Southwest Oncology Group (SWOG) and Roswell Park Cancer Institute (RPCI)) were genotyped for A PE1, ERCC1, ERCC2/(XPD), XRCC1, XRCC3 and XRCC1, ERCC2/(XPD) polymorphisms respectively. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was used in genotyping of all patients. Logistic and proportional hazards regression models were applied to evaluate relationships between genotypes/haplotypes and toxicities, response to treatment and overall survival. Results . Among women treated with breast-conserving surgery and radiation, patients with variant GSTA1 genotypes were at significantly increased risk of telangiectasia (OR 1.86, 95% CI 1.11-3.11). Conversely, reduced odds of telangiectasia was noted for lower-activity eNOS genotypes (OR 0.58, 95% CI 0.36-0.93). Furthermore, genotype effects were modified by follow-up time. In the AML SWOG cohort, patients with XPD Gln751C/Asp312G ('D') haplotype were more likely to have complete response (CR) [OR=3.06 (95% CI: 1.44-6.70)] and less likely to have resistant disease (RD) [OR=0.32 (95%CI: 0.14-0.72)] than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung ( P =.037) and metabolic ( P =.041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR=0.32, 95%CI: 0.11- 0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. Among RPCI AML patients, differential chemotherapy responses were observed in patients with variant XPD 312, XPD 751 and XPD haplotypes. Effects were modified by AML onset. Among secondary AML patients, XPD 751Gln/Gln variant was associated with 7.07-higher odds of achieving complete remission (CR), (95% CI, 1.42-35.18); XPD 312Asn/Asn genotype was associated with 11.23-fold increase in CR, (95% CI, 2.23-56.63). Patients in 'BB/DA' (751Gln/312Asn-751Gln/312Asn/751Gln/Asp312-Lys751-Asp312) variant diplotype category were more likely to achieve CR (OR=31.10 (95% CI: 3.98-242.88)). Significant associations between better overall survival (OS) and XPD variant genotypes/haplotypes were also observed. Furthermore, variant XPD genotypes/haplotypes were associated with significantly reduced risk of nausea/vomiting; in 'BB/DA' diplotype group this risk was (OR 0.35, 95% CI, 0.13-0.90). Significant relationships between infectious complications after induction chemotherapy and heterozygote XPD genotypes/haplotypes were seen. Conclusions . The findings from this research indicate significant associations between inter-individual genetic variations in oxidative stress and DNA repair enzymes and response to treatment, overall survival, as well as development of radiation- and chemotherapy-induced toxicities. With validation of results in larger samples, these findings could lead to optimizing individual radio- and chemotherapy options for patients with cancer.