RAS Gene Mutations in Thyroid Cancer

The RAS genes (HRAS, KRAS and NRAS) encode highly related G-proteins that play a central role in the intracellular transduction of signals arising from cell membrane receptors.

In its inactive state, RAS protein is bound to GDP. Upon activation, it releases GDP and binds GTP, thereby activating the MAPK and other signaling pathways, such as PI3K / AKT. Normally, the activated RAS-GTP protein becomes quickly inactive due to its intrinsic GTPase activity and the action of cytoplasmic GTPase-activating proteins.

Point mutations in the discrete domains of the RAS gene either increase its affinity for GTP (mutations in codons 12 and 13) or inactivate its autocatalytic GTPase function (mutation in codon 61). As a result, the mutant protein becomes permanently switched in the active position and continuously activates its downstream targets.

Point mutations involving several specific sites (codons 12, 13 and 61) of the NRAS, HRAS or KRAS genes are found in 10% to 20% of papillary thyroid carcinomas. Papillary thyroid carcinomas harboring RAS mutation almost always have follicular variant histology; this mutation also correlates with significantly less prominent nuclear features of papillary thyroid carcinoma, more frequent encapsulation and low rate of lymph node metastases.

Some studies have reported the association between RAS mutations and more aggressive behavior of papillary thyroid carcinoma, such as a higher frequency of distant metastases. Mutations of the RAS gene are not restricted to papillary thyroid carcinoma and also found in other benign and malignant thyroid neoplasms, as well as in tumors from other tissues.

The molecular pathogenesis of thyroid cancer involves dysregulation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/AKT pathways. Common activating mutations in the MAPK pathway include RET / PTC and NTRK rearrangements, and RAS and BRAF mutations. Common genetic alterations in the PI3K pathway include RAS mutations, PTEN mutations or deletions, PIK3K mutations or amplifications, and AKT1 mutations. PAX8 / PPARG fusions are common in FTC. Activation of Wnt/b-catenin pathway, inactivating mutations in TP53, and activating mutations in TERT promoter are frequent in undifferentiated thyroid cancer.
#Arrangoiz #ThyroidSurgeon

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