Humans are increasingly exposed to ionizing radiation as a result of rapidly expanding volume of diagnostic and therapeutic radiation, nuclear power accidents such as Chernobyl and Fukushima, high altitude travel, and other exposures. Exposure to radiation is known to increase the risk of various cancers including thyroid cancer. However, the molecular mechanisms of radiation-induced carcinogenesis remain poorly understood. During the previous cycles of this proposal, we have established the central role of chromosomal rearrangements, such as RET/PTC, in radiation-induced thyroid carcinogenesis, and created in vitro models of dose-dependent induction of RET/PTC in human thyroid cells by ?-radiation. Moreover, we have also obtained and genotyped 70 post-Chernobyl thyroid tumors from patients with carefully reconstructed thyroid dose received from 131I and identified 20 tumors associated with high 131I dose that were negative for all known mutations. Our recent analysis of this cohort revealed a strong link between RET/PTC and leaving in the regions of iodine deficiency, which we will explore in this proposal to study the reasons for the association between iodine deficiency and cancer risk found after Chernobyl. Moreover, our first RNA-Seq run of one of the mutation-negative tumors associated with high 131I dose led to the discovery of a novel chromosomal rearrangement, which we find to be the second most common type of chromosomal rearrangements in post- Chernobyl cancers after RET/PTC. These valuable tools will be used in the current proposal, which will continue to dissect the mechanisms of chromosomal rearrangements and radiation carcinogenesis in the thyroid. Specifically, we will test the hypothesis that the rate of generation of RET/PTC rearrangements by radiation in thyroid cells is influenced by cell cycle stage at the time of exposure and transcriptional status of genes in the regions undergoing recombination. We will also determine whether downregulation of ATM and other homologous recombination repair genes enhances RET/PTC induction by radiation in thyroid cells in vitro, and if these genes are involved in the individual susceptibility to radiation carcinogenesis in humans. Finally, we will continue using new sequencing technologies to identify novel types of chromosomal rearrangements occurring in thyroid cancer associated with high radiation dose to the thyroid, and will test if the newly identified genetic events can be induced in human thyroid cells by in vitro radiation. These studies will expand our understanding of the genetic mechanisms of radiation-induced thyroid cancer and provide novel information that can be used to identify those individuals who are most susceptible to radiation carcinogenesis and to develop measures for better protection of human populations against the carcinogenic effects of ionizing radiation in a variety of settings such as medical therapeutic radiation, occupational radiation exposure, and nuclear power accidents and nuclear terrorism.

Public Health Relevance

Humans are increasingly exposed to ionizing radiation, which is linked to the risk of cancer including thyroid cancer. In this proposal, we will use experimenta cell irradiation and a unique collection of tumors from individuals exposed to radiation to better understand how thyroid cancer is formed after radiation exposure and to find new strategies to protect humans against carcinogenic effects of radiation.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Armstrong, Michaele J; Yang, Huaitao; Yip, Linwah et al. (2014) PAX8/PPAR? rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma. Thyroid 24:1369-74
Dettmer, Matthias S; Perren, Aurel; Moch, Holger et al. (2014) MicroRNA profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights. J Mol Endocrinol 52:181-9
Hsiao, Susan J; Nikiforov, Yuri E (2014) Molecular approaches to thyroid cancer diagnosis. Endocr Relat Cancer 21:T301-13
Kelly, Lindsey M; Barila, Guillermo; Liu, Pengyuan et al. (2014) Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc Natl Acad Sci U S A 111:4233-8
Leeman-Neill, Rebecca J; Kelly, Lindsey M; Liu, Pengyuan et al. (2014) ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer 120:799-807
Nikiforova, Marina N; Wald, Abigail I; Roy, Somak et al. (2013) Targeted next-generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J Clin Endocrinol Metab 98:E1852-60
Gandhi, Manoj; Evdokimova, Viktoria N; Cuenco, Karen T et al. (2013) Homologous chromosomes move and rapidly initiate contact at the sites of double-strand breaks in genes in G?-phase human cells. Cell Cycle 12:547-52
Dettmer, Matthias; Vogetseder, Alexander; Durso, Mary Beth et al. (2013) MicroRNA expression array identifies novel diagnostic markers for conventional and oncocytic follicular thyroid carcinomas. J Clin Endocrinol Metab 98:E1-7
Leeman-Neill, Rebecca J; Brenner, Alina V; Little, Mark P et al. (2013) RET/PTC and PAX8/PPAR? chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics. Cancer 119:1792-9
Niemeier, Leo A; Kuffner Akatsu, Haruko; Song, Chi et al. (2012) A combined molecular-pathologic score improves risk stratification of thyroid papillary microcarcinoma. Cancer 118:2069-77

Showing the most recent 10 out of 40 publications