Document Type : Original Article


1 Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran

2 Department of Hematology and Oncology, Hazrat Rasool-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran. Cancer Pharmacogenetics Research Group (CPGRG), Iran University of Medical Sciences, Tehran, Iran

3 Department of Health Information Management, School of Health Management and Information Sciences, Iran University of Medical Sciences, Tehran, Iran

4 Department of Hematology and Oncology, Hazrat Rasool-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran


Background: Lung cancer is the first cause of cancer deaths in the world. Pemetrexed is an antifolate drug used as a first or second-line in the treatment of advanced non-small cell lung cancer (NSCLC) patients. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in a folic acid metabolic pathway and a central role in clinical response to pemetrexed. The aim of this study was to investigate the association between rs1801133 polymorphism and the overall survival of metastatic NSCLC patients.  
Methods: Thirty-four patients with metastatic lung cancer were treated with pemetrexed-based regimen at Rasoul Akram Hospital, Tehran, Iran. Genomic DNA was extracted from the peripheral blood of patients before initiation of treatment. Genotyping of rs1801133 polymorphism was performed at the National Institute of Genetic Engineering by PCR-RFLP methods. Statistical analysis performed with SPSS software, version 21.0.
 Results: Thirty-four patients were enrolled in this study. 21 patients (62%) were male and 13 (38%) were female. The mean age of the patients was 58.90 years. rs1801133 polymorphism were not significantly associated with survival in patients treated with pemetrexed-based chemotherapy.
 Conclusion: Previous studies have demonstrated that MTHFR polymorphism may predict survival among pemetrexed-based regimen treated advanced non-squamous NSCLC patients. However, in this study, the examined polymorphisms were not associated with patients' survival.


1.Abbasian, M. H., Abbasi, B., Ansarinejad, N., Motevalizadeh
Ardekani, A., Samizadeh, E., Gohari Moghaddam, K., & Hashemi,
M. R. (2018). Association of interleukin-1 gene polymorphism
with risk of gastric and colorectal cancers in an Iranian population.
Iranian Journal of Immunology, 15(4), 321-328.
2.Abbasian, M. H., Ansarinejad, N., Abbasi, B., Iravani, M.,
Ramim, T., Hamedi, F., & Ardekani, A. M. (2020). The Role
of Dihydropyrimidine Dehydrogenase and Thymidylate
Synthase Polymorphisms in Fluoropyrimidine-Based Cancer
Chemotherapy in an Iranian Population. Avicenna journal of
medical biotechnology, 12(3), 157.
3.Adjei, A. A. (2004). Pemetrexed (ALIMTA), a novel multitargeted
antineoplastic agent. Clinical Cancer Research, 10(12),
4.Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A.,
& Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394-
5.Chen, C.-Y., Chang, Y.-L., Shih, J.-Y., Lin, J.-W., Chen, K.-
Y., Yang, C.-H., . . . Yang, P.-C. (2011). Thymidylate synthase
and dihydrofolate reductase expression in non-small cell lung
carcinoma: the association with treatment efficacy of pemetrexed.
Lung Cancer, 74(1), 132-138.
6.Chen, F., Wen, T., Lv, Q., & Liu, F. (2020). Associations between
Folate Metabolism Enzyme Polymorphisms and Lung Cancer: A
Meta-Analysis. Nutrition and Cancer, 72(7), 1211-1218.
7.Corrigan, A., Walker, J., Wickramasinghe, S., Hernandez,
M., Newhouse, S., Folarin, A., Marinaki, A. (2014).
Pharmacogenetics of pemetrexed combination therapy in lung
cancer: pathway analysis reveals novel toxicity associations. The
pharmacogenomics journal, 14(5), 411-417.
8.De Mattia, E., & Toffoli, G. (2009). C677T and A1298C MTHFR
polymorphisms, a challenge for antifolate and fluoropyrimidine-
based therapy personalisation. European Journal of Cancer, 45(8),
9.Haerian, M. S., Haerian, B. S., Molanaei, S., Kosari, F., Sabeti, S.,
Bidari-Zerehpoosh, F., . . . Zali, M. R. (2016). MTHFR rs1801133
polymorphism and susceptibility to colorectal cancer in Iranian
population: evidence of a case–control study and meta-analysis.
Pharmacogenomics, 17(17), 1957-1965.
10.Hong, W., Wang, K., Zhang, Y.-p., Kou, J.-y., Hong, D., Su, D.,
. . . Wang, X.-j. (2013). Methylenetetrahydrofolate reductase
C677T polymorphism predicts response and time to progression
to gemcitabine-based chemotherapy for advanced non-small cell
lung cancer in a Chinese Han population. Journal of Zhejiang
University Science B, 14(3), 207-215.
11.Houshmand, M., Seresht-Ahmadi, M., & Alikarami, M. (2020).
Evaluation of the relationship between intronic polymorphism
TPO gene and risk of type 2 diabetes in Tehran population.
Personalized Medicine Journal, 4(16), 9-11.
12.Jiang, H., & Shen, Y. (2019). Methylene tetrahydrofolate
reductase (MTHFR) gene rs1801133 C> T polymorphisms and
response to 5-FU based chemotherapy in patients with colorectal
cancer: a meta-analysis. Pteridines, 30(1), 126-132.
13.Jung, M., Lee, C. H., Park, H. S., Lee, J. H., Kang, Y. A., Kim,
S. K., . . . Kim, J. H. (2013). Pharmacogenomic assessment of
outcomes of pemetrexed-treated patients with adenocarcinoma of
the lung. Yonsei Medical Journal, 54(4), 854-864.
14.Kim, Y.-I. (2009). Role of the MTHFR polymorphisms in cancer
risk modification and treatment.
15.Krawczyk, P., Kucharczyk, T., Kowalski, D. M., Powrózek, T.,
Ramlau, R., Kalinka-Warzocha, E., . . . Kałakucka, K. (2014).
Polymorphisms in TS, MTHFR and ERCC1 genes as predictive
markers in first-line platinum and pemetrexed therapy in NSCLC
patients. Journal of Cancer Research and Clinical Oncology,
140(12), 2047-2057.
16.Kucharczyk, T., Krawczyk, P., Powrózek, T., Kowalski, D. M.,
Ramlau, R., Kalinka-Warzocha, E., . . . Milanowski, J. (2016).
The effectiveness of pemetrexed monotherapy depending on
polymorphisms in TS and MTHFR genes as well as clinical
factors in advanced NSCLC patients. Pathology & Oncology
Research, 22(1), 49-56.
17.Lan, G., Lin, L., Chen, X., Chen, L., & Chen, X. (2017).
Correlation between methylenetetrahydrofolate reductase
(MTHFR) C677T polymorphisms and pemetrexed chemotherapy
efficacy/toxicity in non-squamous non-small cell lung cancer.
Medical science monitor: international medical journal of
experimental and clinical research, 23, 5683.
18.Liew, S.-C., & Gupta, E. D. (2015). Methylenetetrahydrofolate
reductase (MTHFR) C677T polymorphism: epidemiology,
metabolism and the associated diseases. European Journal of
Medical Genetics, 58(1), 1-10.
19.Luo, Y.-H., Luo, L., Wampfler, J. A., Wang, Y., Liu, D., Chen,
Y.-M., . . . Yang, P. (2019). 5-year overall survival in patients
with lung cancer eligible or ineligible for screening according
to US Preventive Services Task Force criteria: a prospective,
observational cohort study. The lancet oncology, 20(8), 1098-
20.Malsagova, K. A., Butkova, T. V., Kopylov, A. T., Izotov, A. A.,
Potoldykova, N. V., Enikeev, D. V., . . . Kaysheva, A. L. (2020).
Pharmacogenetic Testing: A Tool for Personalized Drug Therapy
Optimization. Pharmaceutics, 12(12), 1240.
21.Nishiyama, A., Katakami, N., Yoshioka, H., Iwasaku, M., Korogi,
Y., Hata, A., . . . Uchida, J. (2015). Retrospective efficacy and
safety analyses of erlotinib, pemetrexed, and docetaxel in EGFR-
mutation-negative patients with previously treated advanced non-
squamous non-small-cell lung cancer. Lung Cancer, 89(3), 301-
22.Niyikiza, C., Baker, S. D., Seitz, D. E., Walling, J. M., Nelson,
K., Rusthoven, J. J., . . . Allen, R. H. (2002). Homocysteine and
Methylmalonic Acid: Markers to Predict and Avoid Toxicity from
Pemetrexed Therapy 1 Supported by Eli Lilly and Company. 1.
Molecular Cancer Therapeutics, 1(7), 545-552.
23.Shen, H., Zhu, M., & Wang, C. (2019). Precision oncology of lung
cancer: genetic and genomic differences in Chinese population.
NPJ precision oncology, 3(1), 1-8.
24.Tan, L.-M., Qiu, C.-F., Zhu, T., Jin, Y.-X., Li, X., Yin, J.-Y., . .
. Liu, Z.-Q. (2017). Genetic polymorphisms and platinum-based
chemotherapy treatment outcomes in patients with non-small cell
lung cancer: a genetic epidemiology study based meta-analysis.
Scientific Reports, 7(1), 1-19.
25.Tiseo, M., Giovannetti, E., Tibaldi, C., Camerini, A., Di Costanzo,
F., Barbieri, F., . . . Smit, E. F. (2012). Pharmacogenetic study
of patients with advanced non-small cell lung cancer (NSCLC)
treated with second-line pemetrexed or pemetrexed–carboplatin.
Lung Cancer, 78(1), 92-99.
26.Vázquez, C., Orlova, M., Verzura, M. A., Minatta, J. N., Scibona,
P., Jáuregui, E. G., . . . Belloso, W. H. (2019). Severe toxicity in
adult patients with lung cancer under treatment with pemetrexed:
a prospective cohort study. Journal of Chemotherapy, 31(2), 95-
27.Zhang, X., Zhang, D., Huang, L., Li, G., Chen, L., Ma, J., . . .
Zhou, C. (2019). Discovery of novel biomarkers of therapeutic
responses in Han Chinese pemetrexed-based treated advanced
NSCLC patients. Frontiers in Pharmacology, 10, 944.
28.Zhong, L., Fu, Q., Zhou, S., Chen, L., & Peng, Q. (2018).
Relevance of MTHFR polymorphisms with response to
fluoropyrimidine-based chemotherapy in oesophagogastric
cancer: a meta-analysis. BMJ open, 8(5), e020767