Papillary thyroid cancer (PTC), the most common endocrine malignancy, harbors several important oncogenic events, including BRAF mutation, Ras mutation, RET/PTC rearrangements, and methylation- induced silencing of the tumor suppressor gene RASSF1 A. Silencing of the thyroid-specific genes that are involved in iodide metabolism, such as the genes for thyroid-stimulating hormone receptor (TSHR) and sodium/iodide symporter (NIS), is responsible for the failure of some PTC patients to respond to radioiodine treatment. It is hypothesized that the oncogenic events, by activating the MAP kinase pathway, result in epigenetic alterations that are responsible for thyroid-specific gene silencing. To test this hypothesis, mutual exclusivity of the oncogenic events will first be tested in specific subtypes of PTC to support the concept that each oncogenic event is able to cause PTC through activating their shared MAP kinase pathway. Methylation status of thyroid-specific genes will be subsequently examined in the same tumors, with a focus on the TSHR and NIS genes, to define the relationship of oncogenic events with thyroid gene methylation. Human thyroid tumor cell lines with various oncogenic alterations, either naturally existing or experimentally created, will be used to study the functional relationship between the oncogenic events and thyroid gene methylation. Epigenetic histone modification and its relationship to DNA methylation in silencing thyroid genes and to oncogenic alterations will also be studied in cell lines. Specific kinase inhibitors and cell transfection with oncoproteins and siRNAs will be used to alter MAP kinase pathway activities in these studies. The role of BRAF mutation, the most common oncogenic event in PTC, and related MAP kinase pathway aberration in the epigenetic alteration and silencing of thyroid-specific genes will be the primary focus of these studies. We expect to discover important molecular information on the mechanisms of PTC pathogenesis and novel therapeutic targets for this most common endocrine cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113507-02
Application #
7244434
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Tricoli, James
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2007-07-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$278,177
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Shen, Xiaopei; Zhu, Guangwu; Liu, Rengyun et al. (2018) Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer. J Clin Oncol 36:438-445
Liu, Rengyun; Zhang, Tao; Zhu, Guangwu et al. (2018) Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer. Nat Commun 9:579
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
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
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
Zhang, Tao; Shen, Xiaopei; Xing, Mingzhao (2016) Response. J Natl Cancer Inst 108:
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
Xing, Mingzhao (2016) Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer. BMC Med 14:12

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