Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients.

TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.

The Association of SNPs Located in the CDKN2B-AS1 and LPA Genes With Carotid Artery Stenosis and Atherogenic Stroke.

Introduction: The aim of this project was to assess the prevalence of four selected SNPs rs4977574 and rs7857345 (CDKN2B-AS1 gene) and rs3798220 and rs10455872 polymorphisms (the LPA gene) in the subpopulation of patients with symptomatic and asymptomatic carotid stenosis. Material and Methods: This study included 623 individuals (244 patients with symptomatic carotid artery stenosis, 176 patients with asymptomatic carotid artery stenosis and 203 healthy people. All the participants underwent neurological examination, duplex Doppler ultrasound examination and molecular procedures. Results: In the first part of the analysis the assiociation of SNPs with stroke/TIA was investigated. The association was seen in symptomatic vs. control group for two SNPs: rs4977574 and rs7857345 (CDKN2B-AS1 gene); genotype distributions for rs4977574 and rs7857345 showed the statistically significant differences between patients and controls (p = 0.043 and 0.017, respectively). No association was observed for rs3798220 and rs10455872 located in the LPA gene. There were statistically significant differences between asymptomatic patients vs. control group in genotype distribution for the SNPs located in CDKN2B-AS1: rs4977574 and rs7857345 (p = 0.031 and 0.0099, respectively); and for the rs3798220 (LPA gene; p = 0.003); however, statistically significant differences did not occur for the rs10455872 polymorphism located in the LPA gene. In the next part of the evaluation, a comparison between symptomatic and asymptomatic patients was performed. Significant differences in genotype distribution were seen only for the rs3798220 polymorphism located in the LPA gene (p = 0.0015). The analysis of the prevalence of the polymorphisms in the total group (symptomatic and asymptomatic) patients in comparison with the control group showed significant differences for three polymorphisms: rs4977574 and rs7857345 (CDKN2B-AS1 gene; p = 0.015 and 0.0046, respectively) and rs3798220 (LPA gene, p = 0.044). Conclusions: The present research on the carotid artery stenosis patient cohort suggests the significant association between the rs4977574, rs7857345 and rs3798220 polymorphisms and carotid artery stenosis as well as between the rs4977574 and rs7857345 polymorphisms and atherogenic stroke. The rs4977574 and rs7857345 polymorphisms in patients with carotid artery stenosis appear to affect a person's susceptibility to atherogenic brain ischemia. Our results need to be replicated in future studies.

BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma.

BACKGROUND: The molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation--its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior. METHODS: In order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset. RESULTS: Most of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(-) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project. CONCLUSION: The study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.