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Heterozygote advantage of methylenetetrahydrofolate reductase polymorphisms on clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy

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Tumor Biology

Abstract

Methylenetetrahydrofolate reductase (MTHFR) enzyme is essential for transmethylation reactions including DNA methylation and DNA synthesis and thereby may contribute to cancer prognosis. In our study, a total of 1,004 advanced non-small cell lung cancer (NSCLC) patients receiving first-line, platinum-based chemotherapy regimens were used for genotyping 10 tag single nucleotide polymorphisms (SNPs) of MTHFR. Association was assessed between the SNPs and treatment outcomes. We found that polymorphism of rs1537514 showed the most significant effect: heterozygote associated with better clinical benefit (P = 0.002) and decreased risk of grade 3 or 4 gastrointestinal toxicity (P = 0.027), while the mutant homozygote associated with increased risk of severe gastrointestinal toxicity (P = 0.031) and thrombocytopenia (P = 0.009). The heterozygotes of exon polymorphisms (rs1801131, rs1801133) also yielded better clinical benefit (P = 0.030 for rs1801131) and decreased risk of severe gastrointestinal toxicity (P = 0.004 for rs1801131) or thrombocytopenia (P = 0.016 for 1801133). However, overall survival (OS) and progression-free survival (PFS) did not differ for the MTHFR polymorphisms, except for heterozygote of rs1537514 showing significant effects with better PFS (P = 0.022). Clinical factors as age, gender, and smoking status had significant effects for the OS (P = 0.003, 0.002, and 0.012, respectively) while performance status and chemotherapy regimens for PFS (P = 0.001 and 3.9 × 10−6, respectively). The results indicate that a heterozygous advantage may exist in certain MTHFR variants, and the polymorphisms (especially rs1537514) may play a predictive role of treatment efficacy and adverse effects in NSCLC patients treated with platinum-based chemotherapy.

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Abbreviations

CI:

Confidence interval

HR:

Hazard ratio

LD:

Linkage disequilibrium

MTHFR:

5,10-Methylenetetrahydrofolate reductase

NSCLC:

Non-small cell lung cancer

OR:

Odds ratio

OS:

Overall survival

PFS:

Progression-free survival

PS:

Performance status

SNP:

Single nucleotide polymorphism

TNM:

Tumor-node-metastasis

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Acknowledgments

We acknowledge greatly the collaboration received from the participating hospitals and the staff. This work was supported by the China National High-Tech Research and Development Program grant (2012AA02A517, 2012AA02A518), National Basic Research Program (973 program) of China (Grant No. 2011CB503802), Shanghai Science and Technology Research Program (09JC1402200, 10410709100), and Scientific and Technological Support Plans from Jiangsu Province (BE2010715).

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Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering, Fudan-VARI Genetic Epidemiology Center and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, 200433, Shanghai, China

    Xiaoying Li, Shiming Wang, Xueying Zhao, Hongyan Chen, Ji Qian, Xiao Song, Jiucun Wang, Li Jin, Junjie Wu & Daru Lu

  2. Department of Pneumology, Chest Hospital, Shanghai Jiaotong University, Shanghai, China

    Minhua Shao, Baohui Han & Zhiqiang Gao

  3. Department of Pneumology, Changhai Hospital, Second Military Medical University, Shanghai, China

    Qiang Li

  4. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China

    Chunxue Bai

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  1. Xiaoying Li
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  2. Minhua Shao
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  3. Shiming Wang
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  4. Xueying Zhao
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Correspondence to Daru Lu.

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Table S1

Overview of previous studies of MTHFR polymorphisms and non-small cell lung cancer with platinum-related treatment (DOCX 14 kb)

Table S2

Demographic and clinical features of NSCLC patients (n = 1,004) by clinical benefit and grade 3 or 4 toxicities (DOCX 21 kb)

Table S3

Ten Genotyped Single-Nucleotide Polymorphisms of the MTHFR gene (DOCX 18 kb)

Table S4

Pairwise linkage disequilibrium relations among the 10 tag SNPs of MTHFR by D′ and r2 (DOCX 15 kb)

Table S5

The association between MTHFR polymorphisms and severe toxicities in patient with platinum-based chemotherapy (DOCX 20 kb)

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Li, X., Shao, M., Wang, S. et al. Heterozygote advantage of methylenetetrahydrofolate reductase polymorphisms on clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Tumor Biol. 35, 11159–11170 (2014). https://doi.org/10.1007/s13277-014-2427-6

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