Project 2 takes a clinical and translational genetics approach to identify and characterize genes and their pathways that play a role In the initiation of differentiated thyroid cancer (DTC) for the purposes of the eariiest diagnosis via gene-enabled cancer risk assessment. We will utilize human Cowden syndrome (CS), and a mouse model of human Carney Complex (CNC), as our models epitomizing germline (inherited) predisposition as the first event in initiation in a heritable thyroid neoplasia disorder. CS is a difficult-to- recognize, under-diagnosed heritable disorder characterized by follicular thyroid adenomas (FA), DTC and breast cancer. We found that germline PTEN mutations cause finite subsets of CS and other clinical syndromes, which we collectively term PTEN hamartoma-tumor syndrome (PHTS). Germline PRKR1A mutations associate with CNC. In the first grant period, we have prospectively accrued >3,000 probands from community and academic medical centers who meet CS or CS-like (CSL) criteria and created a web- based PTEN risk calculator based on presence/absence of pathogenic PTEN mutations and clinical characteristics;and showed 32% lifetime risk of DTC in PHTS. We found functional germline variants in SDHB and SDHD, encoding 2 subunits of succinate dehydrogenase, resulting in destabilization of p53 via NQ01 and decreasing ATP levels associated with PTEN nuclear trapping, we developed mouse models of the spectrum of FTC, including FA (thyroid-specific Pten knock-out), locally invasive FTC (Prkaria KO), and metastatic FTC (Pten/Prkaria double KO);preliminary data Indicating downregulation of Sdhb and other Sdh subunits in the FTC models, we broadly hypothesize that Interactions of PTEN, SDHx and PRKR1A play a role in thyroid neoplasia initiation by modulating ROS and other mitochondria-associated energetics. We will (1) analyze SDHx and PRKARIA germline variants In modifying the risk and sub-histology of DTC and of other component cancers in PTEN mutation positive CS/CSL patients;(2) mitochondrial energetics-relevant in vitro functional assays to analyse the interaction of PTEN and SDHx;and (3) physiological validate our human in vivo and in vitro observations in murine models.

Public Health Relevance

Compared to 1 % lifetime risk of developing thyroid cancer, individuals who are at genetic risk carry markedly increased (but never 100%) lifetime risks, often eariy-onset, multifocal and aggressive, and more importantly, almost always carry risks of other extra-thyroldal cancers. However, what remains elusive is the ability to predict which individual carrying predisposition alleles will develop a component malignancy, in this case, DTC. We propose to study energetics for modifying heritable thyroid cancer risk and histology

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
United States
Zip Code
Mahdi, Haider; Mester, Jessica L; Nizialek, Emily A et al. (2015) Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study. Cancer 121:688-96
Lakshmanan, Aparna; Doseff, Andrea I; Ringel, Matthew D et al. (2014) Apigenin in combination with Akt inhibition significantly enhances thyrotropin-stimulated radioiodide accumulation in thyroid cells. Thyroid 24:878-87
Wójcicka, Anna; Czetwerty?ska, Ma?gorzata; ?wierniak, Micha? et al. (2014) Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma. Genes Chromosomes Cancer 53:516-23
Pringle, Daphne R; Vasko, Vasily V; Yu, Lianbo et al. (2014) Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice. J Clin Endocrinol Metab 99:E804-12
McCarty, Samantha K; Saji, Motoyasu; Zhang, Xiaoli et al. (2014) BRAF activates and physically interacts with PAK to regulate cell motility. Endocr Relat Cancer 21:865-77
Lakshmanan, Aparna; Scarberry, Daniel; Shen, Daniel H et al. (2014) Modulation of sodium iodide symporter in thyroid cancer. Horm Cancer 5:363-73
Wojcicka, A; de la Chapelle, A; Jazdzewski, K (2014) MicroRNA-related sequence variations in human cancers. Hum Genet 133:463-9
Stechschulte, Lance A; Wuescher, Leah; Marino, Joseph S et al. (2014) Glucocorticoid receptor ? stimulates Akt1 growth pathway by attenuation of PTEN. J Biol Chem 289:17885-94
Ngeow, Joanne; Stanuch, Kim; Mester, Jessica L et al. (2014) Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol 32:1818-24
Medici, Marco; Porcu, Eleonora; Pistis, Giorgio et al. (2014) Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet 10:e1004123

Showing the most recent 10 out of 58 publications