Impact of glutathione S transferases P1 (Ile105Val) variants on the risk of GSTp, phosphorylated c-Jun kinase, and P53 phenotypic expression and their implications on overall survival outcomes in non-small cell lung cancer patients treated with chemotherapy

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2022-01-01 DOI:10.1016/j.mrfmmm.2022.111775

Anumesh K. Pathak , Nuzhat Husain , Saumya Shukla , Rahul Kumar Pandey , Surya Kant , Lakshmi Bala

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引用次数: 1

Abstract

Aim

This study focused on GST-M1, T1 null, and P1 Ile105Val variant genotypes associated with the risk of altered expression of GSTp, pJNK, and P53 in NSCLC patients. These markers and overall survival (OS) were correlated with a key set of clinicopathological characteristics.

Methods

Genotyping of GST- M1, T1 (+/−), and P1 (Ile105Val) was performed using PCR-RFLP.The expression of GSTp, pJNK, and P53 phenotypes was assessed by immunohistochemistry. The Spearman test was used to examine the correlation between GSTp, pJNK, and P53. Kaplan-Meier test was used for OS analysis.

Results

GSTP1 Val/Val and Ile/Val genotypes notably increased GSTp expression by 1.8 and 1.7 fold, respectively (p = 0.04,p = 0.06). GSTP1 Val/Val and Ile/Val genotypes considerably reduced P53 expression by 0.61 and 0.57 fold, respectively (p = 0.03& p = 0.05), respectively. GSTp, pJNK, and P53 were significantly co-expressed (p < 0.001). GSTp and pJNK expression showed a moderate negative correlation (ρ = −0.32, p = 0.046). In contrast, GSTp and P53 expression exhibited a strong negative correlation (ρ = −0.53, p < 0.0001). There was no correlation between P53 and pJNK expression(ρ = 0.07, p = 0.54). The patient’s median OS was 8.9 months, and it was significantly related to pack-years, stage, metastasis, and GSTM1(-/-) genotypes (p > 0.05). SQCLC showed poor OS than ADC (5.7 months vs.9.1 months, p = 0.2). Stage IV and metastasis significantly reduced the OS (p = 0.001). The tumour size and lymph nodes reflected poor OS (p = 0.07&p = 0.06). Gemcitabine+Cisplatin and Gefitinib showed a slightly higher rate of survival (9.3 months and 8.1 months) than Pemtrexe+Cisplatin treatment (7.0 months,p = 0.8). Multivariate analysis revealed that pack-years and GSTp were independent predictors for OS (p = 0.03).

Conclusion

GSTp, pJNK, and P53 showed interconnected cascading. Age, pack-year, stage, and GSTp were found to be significant predictive factors for OS.Pack-years, GSTp independent OS predictor.

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谷胱甘肽S转移酶P1 (Ile105Val)变异对非小细胞肺癌化疗患者GSTp、磷酸化c-Jun激酶和P53表型表达风险的影响及其对总生存结局的影响

目的本研究聚焦于GST-M1、T1 null和P1 Ile105Val变异基因型与NSCLC患者GSTp、pJNK和P53表达改变风险的相关性。这些标志物和总生存期(OS)与一系列关键的临床病理特征相关。方法采用PCR-RFLP方法对GST- M1、T1(+/−)和P1 (Ile105Val)进行基因分型。免疫组织化学检测GSTp、pJNK和P53表型的表达。采用Spearman检验检验GSTp、pJNK和P53之间的相关性。OS分析采用Kaplan-Meier检验。结果gstp1 Val/Val和Ile/Val基因型分别显著提高GSTp的1.8倍和1.7倍(p = 0.04,p = 0.06)。GSTP1 Val/Val和Ile/Val基因型分别显著降低P53表达0.61倍和0.57倍(p = 0.03&P = 0.05)。GSTp、pJNK和P53显著共表达(p <0.001)。GSTp与pJNK表达呈中度负相关(ρ = - 0.32, p = 0.046)。相反，GSTp与P53表达呈强负相关(ρ = - 0.53, p <0.0001)。P53与pJNK表达无相关性(ρ = 0.07, p = 0.54)。患者的中位OS为8.9个月，与包年、分期、转移和GSTM1(-/-)基因型显著相关(p >0.05)。SQCLC的OS较ADC差(5.7个月vs.9.1个月，p = 0.2)。IV期和转移显著降低了OS (p = 0.001)。肿瘤大小和淋巴结反映OS较差(p = 0.07& p = 0.06)。吉西他滨+顺铂和吉非替尼组的生存率(9.3个月和8.1个月)略高于培曲xe+顺铂组(7.0个月，p = 0.8)。多因素分析显示，包龄和GSTp是OS的独立预测因子(p = 0.03)。结论stp、pJNK、P53呈连锁反应。年龄、包年、分期和GSTp是OS的显著预测因素。包年，GSTp独立OS预测器。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.