Thyroid cancer, particularly papillary thyroid cancer (PTC), is a common endocrine malignancy that has been rising rapidly in incidence in recent years. There are currently several major dilemmas encountered in its clinical diagnosis, prognostication, and treatment. To tackle them and improve the current practice of thyroid cancer medicine requires a better understanding of molecular mechanisms in the tumorigenesis of thyroid cancer. To this end, the main goal of this R01-supported project has been to discover and characterize genetic and epigenetic alterations in thyroid cancer and to move them toward clinical translation. This project has been a tremendous success for this initial five-year funding cycle, particularly in the areas related to the BRAF mutation (BRAFV600E), a prominent oncogene in the MAP kinase signaling pathway in PTC. To continue the main theme and the strong momentum of this project, in this renewal application we propose to test our novel hypothesis, based on strong recent new data, that extensive genome-wide aberration in the methylation and hence expression of functionally important genes promoted by the BRAFV600E signaling is a previously unrecognized fundamental molecular mechanism in the pathogenesis of thyroid cancer. We propose to test this hypothesis and move it to clinic by achieving three Specific Aims: 1) To examine genome-wide DNA methylation alterations driven by the BRAFV600E/MAP kinase signaling and identify genes whose promoter methylation and expression are altered;2) To directly test the function and role of genes epigenetically altered by the BRAFV600E signaling in thyroid tumorigenesis;3) To examine the diagnostic and prognostic value of novel DNA methylation markers identified in Specific Aims 1 and 2. We will apply the recently established novel and currently most extensive 450K CpG methylation microarray system to this project. With this extensive gene methylation study of thyroid cancer, particularly on the epigenetic mechanisms involved in the BRAFV600E-driven thyroid tumorigenesis, we expect to identify many genes that will be for the first time shown to play a key role in thyroid tumorigenesis and are therefore potential novel therapeutic targets for thyroid cancer. We also expect to uncover many novel DNA methylation markers in the genome from which we will identify the most sensitive and specific ones for the diagnosis and prognostication of thyroid cancer by testing them on thyroid tumor tissues, blood samples, and thyroid fine needle aspiration biopsy specimens. Renewal of this project will allow us to achieve these novel study aims using our well-established expertise, techniques, and research resources, which we believe will have a significant impact on the field of thyroid cancer.

Public Health Relevance

The main theme of this project has been discovery of genetic and epigenetic mechanisms and their clinical translation for papillary thyroid cancer, with significant success having been achieved for this initial five years. To continue this theme and the strong momentum of this project, in this renewal application we propose to test a novel hypothesis, based on our recent new results, that genome-wide alteration in the methylation and hence expression of genes by the BRAFV600E signaling is a fundamental mechanism in tumorigenesis of thyroid cancer. Characterization of this mechanism is expected to lead to discovery of novel therapeutic targets as well as novel diagnostic and prognostic molecular markers for thyroid cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-T (02))
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Mckee, Tawnya C
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Liu, Rengyun; Xing, Mingzhao (2014) Diagnostic and prognostic TERT promoter mutations in thyroid fine-needle aspiration biopsy. Endocr Relat Cancer 21:825-30
Xing, Mingzhao; Liu, Rengyun; Liu, Xiaoli et al. (2014) BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol 32:2718-26
Zhang, Zongjing; Liu, Dingxie; Murugan, Avaniyapuram Kannan et al. (2014) Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer. Endocr Relat Cancer 21:161-73
Xing, Mingzhao (2014) RASAL1 in thyroid cancer: promise from a new friend. J Clin Endocrinol Metab 99:3619-21
Liu, Xiaoli; Qu, Shen; Liu, Rengyun et al. (2014) TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab 99:E1130-6
Xing, Mingzhao; Alzahrani, Ali S; Carson, Kathryn A et al. (2013) Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:1493-501
Xing, Mingzhao; Haugen, Bryan R; Schlumberger, Martin (2013) Progress in molecular-based management of differentiated thyroid cancer. Lancet 381:1058-69
Xing, Mingzhao (2013) Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 13:184-99
Hou, Peng; Liu, Dingxie; Dong, Jianli et al. (2012) The BRAF(V600E) causes widespread alterations in gene methylation in the genome of melanoma cells. Cell Cycle 11:286-95
Murugan, Avaniyapuram Kannan; Xing, Mingzhao (2011) Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res 71:4403-11

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