The C allele of the GNB3 C825T polymorphism of the G protein β3‐subunit is associated with an increased risk for the development of oncocytic thyroid tumours

Abstract

Carriers of the C allele of the common C825T polymorphism in the GNB3 gene of the G protein have been associated with the development of follicular thyroid adenomas. Since the C allele of this polymorphism is related to a lower signalling capacity, it was speculated whether the C825T polymorphism may play a particular role in oncocytic thyroid tumours, which are recognized for their reduced ability to synthesize thyroid-specific proteins and hormones, although they possess an intact thyroid-stimulating hormone receptor-adenylyl cyclase system. Using pyrosequencing, both the genotype distribution and the allele frequency of the C825T polymorphism were investigated in a series of 104 patients with oncocytic thyroid tumours of follicular cell origin [58 adenomas, 41 follicular thyroid carcinomas (FTCs), and five papillary thyroid carcinomas (PTCs)]; the results were compared with those obtained from 321 age and gender-matched healthy blood donors and a series of 327 non-oncocytic thyroid tumours of follicular cell origin (119 adenomas, 80 FTCs, and 186 PTCs). Analysis of the genotype distribution (comparing oncocytic with non-oncocytic tumours of the present series) revealed a significantly increased odds ratio (OR) for CC versus TT (OR = 4.22; p = 0.011) and CC versus CT (OR = 1.62; p = 0.049) carriers to develop an oncocytic thyroid tumour; ORs to develop an oncocytic thyroid tumour were also increased comparing the genotype distribution between the group of oncocytic tumours and healthy controls for CC versus TT (OR = 3.73; p = 0.017) and CC versus all T carriers (OR = 1.56; p = 0.034). Oncocytic thyroid tumours as a group showed a statistically significant increase of the C-allele frequency when compared with all non-oncocytic tumours (p = 0.0039) as well as healthy blood donors (p = 0.017). The results strongly suggest that the C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. This polymorphism may thus be considered a (co)factor favouring the development of oncocytic thyroid tumours, although the biological mechanism(s) underlying this association remain obscure.

Novel somatic mutations in heterotrimeric G proteins in melanoma

“…This polymorphism has been associated with oncogenesis and increased metastases in a variety of cancers, including breast, colorectal, head and neck squamous cell, and thyroid cancers. [19][20][21][22][23] The results of these studies, combined with our data showing a mutation in malignant melanoma in GNB3, suggest that further examination of pathway is warranted.…”

Association of the GNB3 825T-allele with better survival in patients with glioblastoma multiforme

“…The modulatory eVects upon G protein-mediated signal transduction pathways have been associated with various clinically important disorders (SiVert 1996a, b;SiVert 1998). Recently, genotypes of the C825T polymorphism in GNB3 were shown to be associated with the prognosis of diVerent malignancies, such as bladder cancer, bone metastasis in breast cancer, and diVerentiated thyroid carcinomas of follicular cell origin (Clar et al 2008;Eisenhardt et al 2005;Sheu et al 2005Sheu et al , 2007.…”

“…The GNB3 825T-allele has been associated with enhanced signal transduction and the occurrence of an alternative splice variant referred to as G 3s (SiVert 1998(SiVert , 2003SiVert et al 2000). Genotypes of this polymorphism have been shown to be associated with the prognosis of diVerent malignomas, such as bladder cancer, bone metastasis in breast cancer, diVerentiated thyroid carcinomas of follicular cell origin and head and neck squamous cell carcinoma, respectively (Clar et al 2008;Eisenhardt et al 2005;Lehnerdt et al 2008;Sheu et al 2007). Thus, we investigated a potential association of genotypes of the GNB3 C825T polymorphism as a possible parameter for survival in patients with GBM.…”

The alternate GNB3 splice variant, Gβ3s, exhibits an altered signalling response to EGF stimulation, which leads to enhanced cell migration

“…This study revealed a shorter time for metastasis in 825T-allele carriers compared to individuals that were homozygous for the GNB3 825C allele. In subsequent studies, it was found that individuals who were suffering from either oncocytic thyroid tumours, head and neck squamous cell carcinoma or bladder carcinoma, were at a significantly higher risk for tumour relapse and death when they were homozygous for the GNB3 825T allele [20,21]. On the contrary, a different study found that the GNB3 825T allele appears to be protective against the development of bone metastasis in breast cancer patients when compared to individuals homozygous for the 825C allele [22].…”