Papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are the most common thyroid malignancies and a subgroup of them can become aggressive and incurable, creating significant prognostic and therapeutic challenges. Our group has made an award-winning landmark discovery of TERT promoter mutations in thyroid cancer (Liu X et al. Endocr Relat Cancer 2013;20:603-610) and has recently published two more articles partially documenting the pathologic role and clinical relevance of these mutations in thyroid cancer (Liu et al. J Clin Endocrinol Metab 2014; Xing et al. J Clin Oncol 2014). In this early phase of this exciting new research area, however, much is unknown about the TERT promoter mutations; their pathologic roles and clinical significance in thyroid cancer remain to be fully defined and the molecular mechanisms remain to be elucidated. Based on our strong preliminary data, we hypothesize that TERT promoter mutations play an important role in the tumorigenesis and aggressiveness of thyroid cancer, particularly when in cooperation with classical driver genetic alterations activating the MAP kinase pathway in PTC and the PI3K pathway in FTC, which is further modified by a common polymorphism rs2853669 T>C in the TERT promoter; this has two important clinical implications, 1) co-existence of TERT promoter mutations with classical genetic alterations, depending on the rs2853669 status, may be associated with particularly poor outcomes of PTC and FTC and therefore has a unique prognostic value; and 2) therapeutically targeting both TERT and the signaling pathway harboring the co-existing genetic alterations in such thyroid cancer may be particularly effective. We propose to pursue the following three Specific Aims to test this hypothesis: 1) To extensively explore TERT promoter mutations 1,295,228 C>T and 1,295,250 C>T and SNP rs2853669 in PTC, their relationship with classical genetic alterations in the MAPK pathway and clinicopathological outcomes, and their prognostic value for PTC; 2) To similarly explore these TERT promoter variants in FTC, their relationship with genetic alterations in the PI3K pathway and clinico-pathological outcomes, and their prognostic value for FTC; and 3) To use in vitro and in vivo approaches to functionally test the role of TERT promoter variants in cooperation with classical oncogenes as well as the mechanistic role of the EST system in thyroid tumorigenesis and the therapeutic potential of targeting them. These studies are among our strongest research areas and will likely have a major impact on the field of thyroid cancer by unveiling new genetic patterns and mechanisms, based on which novel prognostic and therapeutic strategies may be developed for thyroid cancer.

Public Health Relevance

A subgroup of papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) can become aggressive and incurable, creating significant prognostic and therapeutic challenges, which need novel strategies to overcome. With our recent landmark discovery of TERT promoter mutations in thyroid cancer, we propose here to extensively explore the pathologic role and clinical significance of these novel mutations and the underlying molecular mechanisms involving the cooperation with genetic alterations in the MAP kinase and PI3K pathways in the tumorigenesis and aggressiveness of PTC and FTC. A variety of in vitro and in vivo experiments using our established expertise are designed to pursue these studies and completion of this project will likely have a significant impact on the thyroid cancer field by identifying new genetic mechanisms, based on which novel prognostic and therapeutic strategies can be developed for PTC and FTC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA189224-03
Application #
9205496
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Mckee, Tawnya C
Project Start
2015-03-05
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$330,709
Indirect Cost
$124,834
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Wang, Fei; Zhao, Shihua; Shen, Xiaopei et al. (2018) BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer. J Clin Oncol 36:2787-2795
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
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
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:

Showing the most recent 10 out of 13 publications