Thyroid cancer is the most rapidly rising incident cancer in women and the second most rapidly risingincident cancer in men in the United States. Project 2 will take a clinical and translational genetics approachto identify and characterize genes and their pathways that play a role in the initiation of heritable andsporadic follicular thyroid cancer (FTC) for the translational purposes of the earliest diagnosis. Towardsthese goals, we will take a 3-pronged approach to examine the earliest events in FTC initiation: germlineinitiating events in human heritable FTC, somatic initiating events in sporadic FTC and finally physiologicvalidation 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 disordercharacterized by follicular thyroid adenomas (FA), FTC and breast cancer. We plan to prospectively accrue1,000 probands by set criteria, perform comprehensive PTEN alteration (DMA, RNA and protein) analysisand find the most parsimonious subset of clinical features by logistic regression analysis that will give a fixedlikelihood of a PTEN alteration for purposes of referral as well as for purposes of correlating PTEN alterationand features associated with FTC vs FA risk. Second, we will identify and characterize the genes whichwhen differentially expressed differentiate sporadic FTC from FA and independently validate our preliminarydata which yielded a 3-gene combination, the latter mandatory before routine clinical application. This willallow the pre-surgical diagnosis of malignancy amongst all follicular thyroid nodules, something whichremains extremely challenging on fine needle cytology. Importantly, if validated, our data would allow thepre-surgical diagnosis of FTC versus FA in the clinical arena. The genes which differentiate FTC from FAmay play a role in the process of initiating sporadic FTC-genesis. Third, we propose a thyroid specific Ptenconditionalknock-out murine model that will allow mechanism resolution for the first 2 aims on humanheritable FTC and sporadic FTC initiation.
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