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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113507-07
Application #
8735084
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckee, Tawnya C
Project Start
2005-04-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhang, Tao; Shen, Xiaopei; Liu, Rengyun et al. (2017) Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness. Oncotarget 8:900-914
Wang, Fei; Yu, Xiaolong; Shen, Xiaopei et al. (2017) The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer. J Clin Endocrinol Metab 102:3241-3250
Shen, Xiaopei; Liu, Rengyun; Xing, Mingzhao (2017) A six-genotype genetic prognostic model for papillary thyroid cancer. Endocr Relat Cancer 24:41-52
Shi, Xiaoguang; Liu, Rengyun; Basolo, Fulvio et al. (2016) Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants. J Clin Endocrinol Metab 101:264-74
Xing, Mingzhao (2016) Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer. BMC Med 14:12
Zhang, Tao; Xing, Mingzhao (2016) HABP2 G534E Mutation in Familial Nonmedullary Thyroid Cancer. J Natl Cancer Inst 108:djv415
Cheng, Weiwei; Liu, Rengyun; Zhu, Guangwu et al. (2016) Robust Thyroid Gene Expression and Radioiodine Uptake Induced by Simultaneous Suppression of BRAF V600E and Histone Deacetylase in Thyroid Cancer Cells. J Clin Endocrinol Metab 101:962-71
Liu, Rengyun; Xing, Mingzhao (2016) TERT promoter mutations in thyroid cancer. Endocr Relat Cancer 23:R143-55
Mao, Yushan; Xing, Mingzhao (2016) Recent incidences and differential trends of thyroid cancer in the USA. Endocr Relat Cancer 23:313-22
Liu, Dingxie; Shen, Xiaopei; Zhu, Guangwu et al. (2015) REC8 is a novel tumor suppressor gene epigenetically robustly targeted by the PI3K pathway in thyroid cancer. Oncotarget 6:39211-24

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