The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients

Powrózek, Tomasz; Mlak, Radosław; Krawczyk, Paweł; Homa, Iwona; Ciesielka, Marzanna; Koziol, P.; Prendecka, Monika; Milanowski, Janusz; Małecka‐Massalska, Teresa

doi:10.1007/s12094-015-1343-6

Cited by 18 publications

(28 citation statements)

References 22 publications

(28 reference statements)

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“…(2) The occurrence of the toxicities in previous studies was quite variable. (3) The majority of articles had a dichotomy in the toxicity grades, where most articles compared the occurrence of grade 3–4 toxicity with that of grade 0–2 toxicity, while other articles compared toxicities in classifications including grade 0–3 versus grade 4 toxicity, grade 0–1 versus grade 2–4 toxicity, and grade 0 versus grade 1–4 toxicity . (4) A part of study only used a chi‐squared test to assess the distribution of genotypes in different groups rather than using multivariate logistic regression to calculate the adjusted OR .…”

Section: Discussionmentioning

confidence: 99%

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Zheng

Deng

Yin

et al. 2017

Intl Journal of Cancer

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Genetic variations in genes involved in repairing platinum-induced DNA lesions may contribute to the toxicity of platinum-based chemotherapy. The role of single-nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross-links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum-based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at p < 0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779 and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with severe gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR = 0.677, 95% CI: 0.510-0.899, p = 0.007; OR = 0.565, 95% CI: 0.368-0.869, p = 0.009; OR = 0.628, 95% CI: 0.439-0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum-induced toxicities.

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Section: Discussionmentioning

confidence: 99%

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Zheng

Deng

Yin

et al. 2017

Intl Journal of Cancer

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“…For example, Cristina et al found that ERCC1 C118T was significantly associated with platinum-induced toxicity while other studies presented contradictory results (14)(15)(16). Similar associations were found for XRCC1 codon 399, XPD Lys751Gln, and other mutations (17,18). Hence, quantitative evaluation is needed for determining the association between gene polymorphisms and platinum-induced toxicities.…”

Section: Introductionmentioning

confidence: 97%

Genetic Polymorphisms and Platinum-Based Chemotherapy-Induced Toxicities in Patients With Lung Cancer: A Systematic Review and Meta-Analysis

Liu

Wang

et al. 2020

Front. Oncol.

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Background: Platinum-based agents, including cisplatin, carboplatin, and oxaliplatin, are indispensable for the treatment of lung cancer. The development of toxicity frequently necessitates dose reduction or discontinuation of therapy, despite the clinical response. Pharmacogenomics studies were reviewed to identify the possible genetic variants that underlie individual susceptibility to platinum-related toxicities. Method:We conducted a systematic search in PubMed and Embase for pharmacogenomics reports that focused on commonly reported platinum-induced toxicities, such as gastrointestinal (GI), hematological, neurological, and other toxicities, in patients diagnosed with lung cancer. Meta-analyses were conducted to determine the association between genetic polymorphisms and platinum-induced toxicity by checking the odds ratio (OR) and 95% confidence interval (CI) using random or fixed-effects models as appropriate.Results: Twenty eligible studies that met the inclusion criteria with sufficient data were extracted and presented comprehensively. A total of 16 polymorphisms from 11 genes were included in the meta-analysis. MTHFR rs1801131 and MDM2 rs1690924 were significantly correlated with platinum-induced GI toxicity (P = 0.04 and P = 0.02, respectively). Patients with the MTHFR rs1801131AA and MDM2 rs1690924TC/CC genotype tended to have a higher risk of GI toxicity than patients with other genotypes did (OR = 1.73, 95% CI = 0.86-2.18; and OR = 0.51, 95% CI = 0.29-0.88, respectively). Compared to carriers of the MTHFR rs1801133CC genotype, carriers of the CT/TT genotype had a significantly increased risk of hematological toxicity (P = 0.01, OR = 1.68, 95% CI = 1.12-2.52). Conclusion:In the future, physicians should pay careful attention to MTHFR and MDM2 for personalized chemotherapy treatment among patients with lung cancer.

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“…The variation in these toxicities is likely due to variation in the NER pathway that is responsible for the removal of PBC‐induced DNA damage, leading to variation in response to toxic platinum agents. DNA repair capacity, particularly of the NER pathway, has been associated with the PBC efficacy and toxicity, and numerous studies have indicated that genetic variations, such as SNPs in the NER pathway genes, may modulate repair functions and cellular apoptosis, prompting individual variation in toxicity outcomes of PBC …”

Section: Discussionmentioning

confidence: 99%

“…DNA repair capacity, particularly of the NER pathway, has been associated with the PBC efficacy and toxicity, and numerous studies have indicated that genetic variations, such as SNPs in the NER pathway genes, may modulate repair functions and cellular apoptosis, prompting individual variation in toxicity outcomes of PBC. 26,27 Published studies on NER pathway variants and PBC toxicity in NSCLC patients have mainly focused on missense variants, with very few investigating a group of core genes in the pathway or considering LD between the variants or noncoding variants. 24,28,29 In the present study, we employed a hypothesis-based approach with a main focus on independent regulatory variants with predicted biological functions.…”

Section: Discussionmentioning

confidence: 99%

An ERCC4 regulatory variant predicts grade‐3 or ‐4 toxicities in patients with advanced non‐small cell lung cancer treated by platinum‐based therapy

Zhang

Jia

et al. 2017

Intl Journal of Cancer

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Platinum-based chemotherapy (PBC) in combination with the 3 generation drugs is the first-line treatment for patients with advanced non-small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3-4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum-induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two-phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR) =1.61 and 2.35, 95% confidence interval (CI)=1.11-2.33 and 1.25-4.41, and P =0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57-0.65 vs. 0.55-0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment.

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The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients

Abstract: Selected SNPs of genes encoding DNA repair enzymes and cell division regulation proteins could be useful biomarkers for prediction of platinum and vinorelbine-based chemotherapy toxicity in patients with advanced NSCLC.

Cited by 18 publications

References 22 publications

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Genetic Polymorphisms and Platinum-Based Chemotherapy-Induced Toxicities in Patients With Lung Cancer: A Systematic Review and Meta-Analysis

An ERCC4 regulatory variant predicts grade‐3 or ‐4 toxicities in patients with advanced non‐small cell lung cancer treated by platinum‐based therapy

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