Thyroid cancer is the most rapidly rising incident cancer in women and the second most rapidly rising incident cancer in men in the United States. Project 2 will take a clinical and translational genetics approach to identify and characterize genes and their pathways that play a role in the initiation of heritable and sporadic follicular thyroid cancer (FTC) for the translational purposes of the earliest diagnosis. Towards these goals, we will take a 3-pronged approach to examine the earliest events in FTC initiation: germline initiating events in human heritable FTC, somatic initiating events in sporadic FTC and finally physiologic validation and mechanism resolution in a murine model. Specifically, we will utilize germline (inherited) predisposition to reflect the earliest initiating event by utilizing an heritable thyroid neoplasia disorder, Cowden syndrome (CS), which is a difficult-to-recognize, under-diagnosed autosomal dominant disorder characterized by follicular thyroid adenomas (FA), FTC and breast cancer. We plan to prospectively accrue 1,000 probands by set criteria, perform comprehensive PTEN alteration (DMA, RNA and protein) analysis and find the most parsimonious subset of clinical features by logistic regression analysis that will give a fixed likelihood of a PTEN alteration for purposes of referral as well as for purposes of correlating PTEN alteration and features associated with FTC vs FA risk. Second, we will identify and characterize the genes which when differentially expressed differentiate sporadic FTC from FA and independently validate our preliminary data which yielded a 3-gene combination, the latter mandatory before routine clinical application. This will allow the pre-surgical diagnosis of malignancy amongst all follicular thyroid nodules, something which remains extremely challenging on fine needle cytology. Importantly, if validated, our data would allow the pre-surgical diagnosis of FTC versus FA in the clinical arena. The genes which differentiate FTC from FA may play a role in the process of initiating sporadic FTC-genesis. Third, we propose a thyroid specific Ptenconditional knock-out murine model that will allow mechanism resolution for the first 2 aims on human heritable FTC and sporadic FTC initiation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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Ohio State University
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Yu, Wanfeng; Ni, Ying; Saji, Motoyasu et al. (2017) Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells. Hum Mol Genet 26:1365-1375
Gudmundsson, Julius; Thorleifsson, Gudmar; Sigurdsson, Jon K et al. (2017) A genome-wide association study yields five novel thyroid cancer risk loci. Nat Commun 8:14517
Azmat, Umal; Porter, Kyle; Senter, Leigha et al. (2017) Thyroglobulin Liquid Chromatography-Tandem Mass Spectrometry Has a Low Sensitivity for Detecting Structural Disease in Patients with Antithyroglobulin Antibodies. Thyroid 27:74-80
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Rossfeld, Kara K; Justiniano, Steven E; Ding, Haiming et al. (2017) Biological Evaluation of a Fluorescent-Imaging Agent for Medullary Thyroid Cancer in an Orthotopic Model. J Clin Endocrinol Metab 102:3268-3277
Saporito, Donika; Brock, Pamela; Hampel, Heather et al. (2017) Penetrance of a rare familial mutation predisposing to papillary thyroid cancer. Fam Cancer :
Byrd, Victoria; Getz, Ted M; Padmanabhan, Roshan et al. (2017) Microbiome in PTEN hamartoma tumor syndrome. Endocr Relat Cancer :
Tomsic, Jerneja; Fultz, Rebecca; Liyanarachchi, Sandya et al. (2017) Variants in microRNA genes in familial papillary thyroid carcinoma. Oncotarget 8:6475-6482
Ni, Ying; Seballos, Spencer; Fletcher, Benjamin et al. (2017) Germline compound heterozygous poly-glutamine deletion in USF3 may be involved in predisposition to heritable and sporadic epithelial thyroid carcinoma. Hum Mol Genet 26:243-257
Ashtekar, Amruta; Huk, Danielle; Magner, Alexa et al. (2017) Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype. Endocr Relat Cancer 24:579-591

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