In accordance with our previous reports, we found that observation of concomitant CD26-positive and PTEN-negative status in cases of follicular adenoma suggests a state close to follicular carcinoma or progression to cancer, thus warranting careful follow-up.
CS/CS-like patients have elevated risks of follicular thyroid cancer due to PTEN pathogenic mutations and of papillary thyroid cancer from SDHx and KLLN alterations.
The authors found PTEN methylation to become progressively higher from benign thyroid adenoma to follicular thyroid cancer and to aggressive anaplastic thyroid cancer, which harbored activating genetic alterations in the PI3K/AKT pathway correspondingly with a progressively higher prevalence.
We found PIK3CA copy gain (defined as four or more copies) in nine of 31 FTC (29%), 20 of 141 PTC (14%), and five of 62 FTA (8%); PIK3CA gene mutations in four of 31 FTC (13%), one of 141 PTC (1%), and none of 62 FTA (0%); Ras mutations in three of 31 FTC (10%) and none of the 141 PTC and 62 FTA; and PTEN mutations in two of 31 FTC (6%) and none of 62 FTA (0%).
Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC).
Caveolin-1 is of particular functional interest because it has been shown to interact with PTEN, the tumor suppressor gene mutated in Cowden syndrome, an inherited multiple hamartoma syndrome that includes predisposition to FTC.
In the present study, we aimed to investigate the clinicopathological aspects of a large series of follicular thyroid carcinomas (FTCs) in paediatric patients and to analyse the point mutations in codons 12, 13 and 61 of NRAS, HRAS and KRAS genes and the rearrangements of PAX8-PPARG.
In follicular thyroid carcinoma, NRAS was the most frequently observed mutation (4/9 patients), followed by HRAS (two patients) and KRAS (one patient).
A total of 37 thyroid aspirates, including benign hyperplastic nodules (HBN, N = 16) and follicular thyroid carcinomas (FTC, N = 21) were analyzed for the presence of NRAS(61) and KRAS(13) mutations.
Finally, KRAS2 was found to be differentially expressed (P<0.05) when comparing the papillary thyroid carcinoma and follicular thyroid carcinoma groups.
Thyroid growth is driven by the TSH/cAMP/PKA signaling pathway, and it has previously been shown that activation of PKA through genetic ablation of the regulatory subunit Prkar1a (Prkar1a KO) is sufficient to cause follicular thyroid cancer in mouse models. cAMP also activates the Epac proteins and their downstream effectors, Rap1a and Rap1b.
We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors.
Altogether, our findings provide insight into the role of SOSTDC1 as a novel functional tumor suppressor in follicular thyroid cancer through modulating the activities of PI3K/Akt and MAPK/Erk signaling pathways.
Single nucleotide polymorphism (SNP) rs17849071 was recently reported to be inversely associated with PIK3CA amplification in follicular thyroid cancer, but the main function of this SNP remains unclear.
These results provide in vivo evidence for CD147 upregulation in FTC and in vitro evidence for EGF-stimulated CD147 induction via the PI3K, ERK, and JNK pathways.