A single-nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy

Authors

  • Raymond H. Mak MD,

    1. Harvard Radiation Oncology Program, Boston, Massachusetts
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    • The first 2 authors contributed equally to this work.

  • Brian M. Alexander MD, MPH,

    1. Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts
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    • The first 2 authors contributed equally to this work.

  • Kofi Asomaning MD,

    1. Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
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  • Rebecca S. Heist MD, MPH,

    1. Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
    2. Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts
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  • Chen-yu Liu PhD,

    1. Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
    2. Institute of Environmental Health, National Taiwan University, Taipei, Taiwan
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  • Li Su PhD,

    1. Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
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  • Rihong Zhai PhD,

    1. Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
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  • Marek Ancukiewicz MD,

    1. Department of Radiation Oncology, Massachusetts General Hospital Boston, Massachusetts
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  • Brian Napolitano MD,

    1. Department of Radiation Oncology, Massachusetts General Hospital Boston, Massachusetts
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  • Andrzej Niemierko MD,

    1. Department of Radiation Oncology, Massachusetts General Hospital Boston, Massachusetts
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  • Henning Willers MD,

    1. Department of Radiation Oncology, Massachusetts General Hospital Boston, Massachusetts
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  • Noah C. Choi MD,

    1. Department of Radiation Oncology, Massachusetts General Hospital Boston, Massachusetts
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  • David C. Christiani MD, MPH

    Corresponding author
    1. Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
    • Harvard School of Public Health, 665 Huntington Avenue, Building 1, Room 1402, Boston, MA 02115

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    • Fax: (617) 432-3441


  • See editorial on pages 3450–4, this issue.

Abstract

BACKGROUND:

This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer.

METHODS:

A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting.

RESULTS:

With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP.

CONCLUSIONS:

This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP. Cancer 2012;3654–3665. © 2011 American Cancer Society.

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