RET/PTC and PAX8/PPARγ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics

Authors

  • Rebecca J. Leeman-Neill MD, PhD,

    1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Alina V. Brenner MD, PhD, MPH,

    1. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Mark P. Little MA, DPhil,

    1. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Tetiana I. Bogdanova PhD,

    1. State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
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  • Maureen Hatch PhD,

    1. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Liudmyla Y. Zurnadzy MD, PhD,

    1. State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
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  • Kiyohiko Mabuchi MD, DrPH,

    1. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Mykola D. Tronko MD, PhD,

    1. State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
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  • Yuri E. Nikiforov MD, PhD

    Corresponding author
    1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    • Department of Pathology, University of Pittsburgh, 200 Lothrop Street, Presbyterian University Hospital, Room C-606, Pittsburgh, PA 15213

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  • It is with great sadness that we report the death of our colleague Dr. Elaine Ron, who was one of the original investigators involved in design of the study. We greatly appreciate her contribution and support. We thank Dr. Gerry Thomas and staff of the Chernobyl Tissue Bank for providing samples. We are grateful to the dosimetry team, including Drs. Ilya Likhtarev, Lina Kovgan (Radiation Protection Institute, Ukrainian Academy of Technological Sciences), Andre Bouville (formerly with the National Cancer Institute [NCI], National Institutes of Health [NIH]), and Vladimir Drozdovich (NCI, NIH) for dose reconstruction efforts. We thank Dr. Alice Sigurdson (NCI, NIH) for critical review of the manuscript.

Abstract

BACKGROUND:

Childhood exposure to iodine-131 from the 1986 nuclear accident in Chernobyl, Ukraine, led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited.

METHODS:

Mutational analysis was performed on 62 PTCs diagnosed in a Ukrainian cohort of patients who were < 18 years old in 1986 and received 0.008 to 8.6 Gy of 131I to the thyroid. Associations between mutation types and 131I dose and other characteristics were explored.

RESULTS:

RET/PTC (ret proto-oncogene/papillary thyroid carcinoma) rearrangements were most common (35%), followed by BRAF (15%) and RAS (8%) point mutations. Two tumors carrying PAX8/PPARγ (paired box 8/peroxisome proliferator-activated receptor gamma) rearrangement were identified. A significant negative association with 131I dose for BRAF and RAS point mutations and a significant concave association with 131I dose, with an inflection point at 1.6 Gy and odds ratio of 2.1, based on a linear-quadratic model for RET/PTC and PAX8/PPARγ rearrangements were found. The trends with dose were significantly different between tumors with point mutations and rearrangements. Compared with point mutations, rearrangements were associated with residence in the relatively iodine-deficient Zhytomyr region, younger age at exposure or surgery, and male sex.

CONCLUSIONS:

These results provide the first demonstration of PAX8/PPARγ rearrangements in post-Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with 131I dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and 131I exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients. Cancer 2013. © 2013 American Cancer Society.

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