*Review PRKAR1A* **and Thyroid Tumors**

**Georgia Pitsava 1,2, Constantine A. Stratakis <sup>2</sup> and Fabio R. Faucz 2,\***


**\*** Correspondence: fabio.faucz@nih.gov; Tel.: +1-301-451-7177

**Simple Summary:** In 2021 it is estimated that there will be 44,280 new cases of thyroid cancer in the United States and the incidence rate is higher in women than in men by almost 3 times. Well-differentiated thyroid cancer is the most common subtype of thyroid cancer and includes follicular (FTC) and papillary (PTC) carcinomas. Over the last decade, researchers have been able to better understand the molecular mechanisms involved in thyroid carcinogenesis, identifying genes including but not limited to *RAS*, *BRAF*, *PAX8/PPARγ* chromosomal rearrangements and others, as well as several tumor genes involved in major signaling pathways regulating cell cycle, differentiation, growth, or proliferation. Patients with Carney complex (CNC) have increased incidence of thyroid tumors, including cancer, yet little is known about this association. CNC is a familial multiple neoplasia and lentiginosis syndrome cause by inactivating mutations in the *PRKAR1A* gene which encodes the regulatory subunit type 1α of protein kinase A. This work summarizes what we know today about *PRKAR1A* defects in humans and mice and their role in thyroid tumor development, as the first such review on this issue.

**Abstract:** Thyroid cancer is the most common type of endocrine malignancy and the incidence is rapidly increasing. Follicular (FTC) and papillary thyroid (PTC) carcinomas comprise the welldifferentiated subtype and they are the two most common thyroid carcinomas. Multiple molecular genetic and epigenetic alterations have been identified in various types of thyroid tumors over the years. Point mutations in *BRAF*, *RAS* as well as *RET/PTC* and *PAX8/PPARγ* chromosomal rearrangements are common. Thyroid cancer, including both FTC and PTC, has been observed in patients with Carney Complex (CNC), a syndrome that is inherited in an autosomal dominant manner and predisposes to various tumors. CNC is caused by inactivating mutations in the tumorsuppressor gene encoding the cyclic AMP (cAMP)-dependent protein kinase A (PKA) type 1α regulatory subunit (*PRKAR1A*) mapped in chromosome 17 (17q22–24). Growth of the thyroid is driven by the TSH/cAMP/PKA signaling pathway and it has been shown in mouse models that PKA activation through genetic ablation of the regulatory subunit *Prkar1a* can cause FTC. In this review, we provide an overview of the molecular mechanisms contributing to thyroid tumorigenesis associated with inactivation of the *RRKAR1A* gene.

**Keywords:** thyroid carcinoma; *PRKAR1A*; PKA; Carney complex; cAMP
