Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients

Pérez-Ramírez, Cristina; Cañadas-Garre, Marisa; Alnatsha, Ahmed; Villar, Eduardo; Valdivia-Bautista, Javier; Faus-Dáder, María José; Calleja‐Hernández, Miguel Ángel

doi:10.1038/s41397-018-0014-8

“…In the current study, the MDM2 rs1690924 mutation was significantly associated with grade 3-4 GI toxicity, and the carriers of the TT + TC genotype had a markedly increased risk of grade 3-4 GI toxicity than the carriers of the CC genotype did. To date, only one study found an association between this polymorphism and overall survival (41). However, the function of MDM2 rs1690924 polymorphism is unknown.…”

Section: Discussionmentioning

confidence: 99%

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

Liu

¹

,

Wang

²

,

Hu

³

et al. 2020

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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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“…There are two polymorphisms of XRCC1 , rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), that are believed to change the DNA repair activity and affect the sensitivity of tumor cells to platinum drugs 14 . Thus, they have been widely investigated for the association with response to platinum-based chemotherapy in NSCLC patients 15 – 17 , mostly in Asian populations 18 – 22 . However, the results remain inconclusive.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum‐Based Chemotherapy in Asian Patients with NSCLC: A Meta‐Analysis

Zhang

¹

,

Ouyang

²

,

Chang

³

et al. 2020

BioMed Research International

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Background. Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis. Methods. Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models. Results. Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln ( OR = 1.71 , 95% CI: 1.16-2.52, p = .007 , I 2 = 56.8 % ) and GlnArg ( OR = 1.23 , 95% CI: 1.07-1.40, p = .003 , I 2 = 29.0 % ) were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS ( HR = 0.60 , 95% CI: 0.40-0.88) and PFS ( HR = 0.64 , 95% CI: 0.46-0.90). We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles (TrpTrp vs. ArgArg: OR = 1.73 , 95% CI:1.31-2.27; TrpArg vs. ArgArg: OR = 1.28 , 95% CI: 1.06-1.55), suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS. Conclusion. Our results showed that rs25487 and rs1799782 of XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC.

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“…Previous study also revealed that rs25487 GG genotype could decrease the function of XRCC1, and those with rs25487 GG genotype showed significantly better ORR; thus, this genotype could act as predictive factors in NSCLC patients treated with platinum-based chemotherapy. 39 Therefore, in our paper, we observed that patients with rs3213245 minor C allele tended to have good response to chemotherapy, although there are no significant differences.…”

Section: Discussionmentioning

confidence: 48%

The association of XRCC1 polymorphism with osteosarcoma risk, clinicopathologic features, and prognosis in a Chinese Han population

Wu

¹

,

Li

²

,

Ren

³

et al. 2018

CMAR

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IntroductionThe association of single-nucleotide polymorphisms at X-ray repair cross-complementing group-1 (XRCC1) with osteosarcoma (OS) development has not been fully clear to date. The aim of the present study is to evaluate the association of XRCC1 polymorphisms with risk, clinicopathologic features, and prognosis in Chinese OS patients.MethodsA total of 146 patients with primary OS and 248 age- and gender-matched controls were included in the present study. The frequencies of four XRCC1 polymorphisms (rs25487, rs1799782, rs25489, and rs3213245) were determined between OS patients and controls. The association of XRCC1 polymorphism with clinicopathologic characteristics, prognosis, and XRCC1 expression was further evaluated.ResultsCompared with TT genotype, individuals carrying the minor C allele (TC+ CC) of rs3213245 had significantly increased risk of OS development (OR =1.83, 95% CI 1.14–3.00). OS patients carrying TC genotype and C allele at rs3213245 were more likely to be with larger tumor size and metastasis. Survival analysis demonstrated that OS patients carrying C allele (TC + CC) at rs3213245 had shorter survival time than those with TT genotype. The T to C substitution at rs3213245 could decrease XRCC1 gene transcriptional activity in vitro. XRCC1 mRNA and protein expression levels were lower in OS patients carrying TC or CC genotype at rs3213245. Besides, no significant association of rs25487, rs1799782, and rs25489 with OS was observed.ConclusionIn conclusion, these findings revealed that XRCC1 rs3213245 polymorphism was associated with increased risk of OS, which could affect XRCC1 expression in vitro and in vivo.

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Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients

Cited by 27 publications

References 99 publications

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

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

Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum‐Based Chemotherapy in Asian Patients with NSCLC: A Meta‐Analysis

The association of XRCC1 polymorphism with osteosarcoma risk, clinicopathologic features, and prognosis in a Chinese Han population

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