*3.2. Studies in Humans*

Further evidence to support the involvement of PKA in thyroid tumors was demonstrated by studying the *PRKAR1A* gene in thyroid tissue from patients with CNC [29]. The involvement of the thyroid in the syndrome was reported for the first time twelve years after CNC was first described [88], in 1997 [89]. In a cohort of 53 individuals with familial

CNC, thyroid disease was identified in 11% of patients; of them, three were studied in detail, two with thyroid carcinomas (one PTC, one FTC) and one patient with a benign follicular adenoma. [89]. In addition, 60% of patients with the sporadic form of the complex exhibited thyroid gland lesions of follicular origin [89]. The authors concluded that thyroid carcinomas may develop in situ from precursor benign lesions in these patients. It is important to note that patients' ethnicity does not seem to play a role in CNC phenotype that include thyroid carcinomas.

Since the *PRKAR1A* gene was identified as causal in CNC, many disease-causing mutations have been identified [24,90]. Sandrini et al. showed that in thyroid cancer the activity of PKA is greater than in adenomas, partly due to genetic defects in the *PRKAR1A* gene and/or locus [26]. The region 17q22–24 was frequently lost in cancer but not in benign tumors. In addition, it was shown that RIα, the most abundant regulatory subunit of cAMP-dependent PKA [91], in thyroid cells, possibly exhibits a tumor-suppressor function, as indicated by decreased expression of the RIα subunit in carcinomas and by the losses of *PRKAR1A* 17q22–24 locus in about 50% of all informative cancers. It has been known that the activation of cAMP/PKA pathway is involved in normal thyroid cell growth [92]; the same appears to be true for thyroid adenomas, while in the case of PTCs inhibition is induced [93]. The results suggested that *PRKAR1A* is indeed involved in sporadic thyroid tumors, along with other genes [94–97], some of which could be associated with the PKA pathway [91]. Any disruption of that, because of deficiency of the RIα subunit, could lead to cAMP-dependent PKA mediated cell proliferation and/or stimulation of other pathways linked to proliferation of thyroid cells [91,98].

In a recent series of 353 CNC patients from 185 families, patients from various ethnicities and with a wide range of clinical manifestations were studied [99]. More than 60% of them harbored mutations in the *PRKAR1A* gene. In 25% of patients, thyroid tumors were present while thyroid cancer (either FTC or PTC or both) was present in 2.5% of cases. In addition, thyroid tumors (*p* = 0.016) were more frequent in *PRKAR1A* carriers and presented at a younger age (*p* = 0.03). Moreover, they were more commonly associated with the 'hot spot' c.491–492delTG mutation in comparison with all other *PRKAR1A* defects. It was also observed that patients with no mutations of the *PRKAR1A* gene or its genomic locus 17q22–24, were less likely to develop thyroid tumors. In a review of 26 patients, in 61% of them benign lesions (including follicular adenoma, follicular hyperplasia or nodular hyperplasia) were detected, while 38% of them had thyroid carcinomas (seven with FTC and three with PTC). The majority of patients presented with an asymptomatic thyroid nodule and included middle-aged women [100].
