Mutational and expressional association of the PIK3CA gene with the risk of breast cancer in the Pakistani population.

PI3K pathway is a very important pathway that is reported to be involved in breast cancer. Mutation of PI3K and p110 alpha-catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) is of high predictive and prognostic values in breast cancer. The purpose of the current study was to screen the hotspot mutations of the PIK3CA gene i.e. rs2677760, rs3806685, rs121913273 & rs121913279 along with expressional analysis of PI3K and PIK3CA genes in breast cancer female patients. For mutational analysis, TaqMan assay & Sanger sequencing were performed while for expressional analysis real-time PCR was carried out. Mutant allele C of rs2677760 was observed to be high in postmenopausal patients. The frequency of mutant allele G of rs3806685 was significantly high in breast cancer patients. All diseased and control samples were of wild type for the hotspot rs121913273 and rs121913279 with allele G for rs121913273 and A for rs121913279. Expression of the PI3K was high in breast cancer tissue samples as compared to the adjacent controls. While the expression of the thePIK3CA gene was significantly high in premenopausal breast cancer patients. It was concluded that the mutant allele C of rs2677760 might have some sort of association with the menopausal status and it could be used as a diagnostic marker in post-menopausal women if studied further. Mutant allele G of rs3806685 was also found to be associated with breast cancer. While multiallelic rs121913273 and rs121913279 showed a different trend for the studied population. For expressional analysis, PI3K showed over-expression in the cases while PIK3CA gene expression was observed to be significantly associated with pre-menopausal status.

Genetic predisposition of SNPs in miRNA-149 (rs2292832) and FOXE1 (rs3758249) in thyroid Cancer.

BACKGROUND: Many efforts have been made in recent years to investigate the alterations in protein-coding genes as well as non-coding RNAs that are playing an emerging role in the development and progression of cancers. These miRNAs are short non-coding functional RNAs that are involved in the regulation of transcriptome. In different studies, it was found that human miRNA-149 is an important microRNA that is functioning either as onco-miRNAs or acting as tumor suppressors, in different conditions. RATIONALE: Many of the miRNAs are regulating different SNPs of FOXE1 in different studies which are causing low-to-moderate penetrance of genes that initiates the development of thyroid cancer. The involvement of SNPs in miRNA-149 gene rs2292832 and FOXE1 rs3758249 with PTC for better disease prognosis and management was determined in this study and the relation between these SNPs at the genotypic level was also evaluated. MATERIALS AND METHODS: PTC patients with age and gender-matched controls were recruited in the present study. Blood samples were collected in EDTA vacutainer followed by DNA extraction by the organic method. Genotyping of rs2292832 and rs3758249 was done by ARMS-PCR and PCR- RFLP respectively. Statistical analyses were carried out by using SPSS software (version 20). RESULTS: The mutation T>C in miRNA-149 rs2292832 was significantly associated with thyroid cancer (p-value 0.0004, < 0.05) while rs3758249 G>C did not show significant association with the disease (p-value 0.124244, > 0.05). Moreover, no correlation of rs2292832 at the genotype level was observed with rs3758249. CONCLUSIONS: miRNA-149 gene SNP rs2292832 was observed in strong association with thyroid cancer. Lack of genetic association of rs3758249 of FOXE1 gene has been ruled for the disease. The statistically significant association of rs2292832 with thyroid cancer depicts its mechanistic involvement at the cellular level in Papillary Thyroid Carcinoma.

Identification of transcriptional level variations in microRNA-221 and microRNA-222 as alternate players in the thyroid cancer tumor microenvironment.

Thyroid cancer (TC) is caused by genetic factors and or their cross talk with lifestyle and environment. An important role of miRNA involvement has been identified in different human diseases alongside the cancer. The growing cloud of miRNA discoveries narrates miRNA-221 and miRNA-222 as key elements of ready arsenal in the cancer micro-niches. The aim of present study was to identify the variations of miRNA-221 and miRNA-222 expression in TC tissues and their likely association with TC. miRNA-221 and miRNA-222 were investigated for their expressional alterations in TC tissue samples and healthy thyroid tissue. Expression of miRNA-221 and -222 was analyzed through real time PCR. The relative gene expression of both the miRNA was quantified and statistically evaluated. miRNA-221 and miRNA-222 were found to be highly over expressed when compared with samples of multinodular goiter (MNG) and normal controls. Interestingly, it was also noted that miRNA-221 and miRNA-222 expression is working in a cluster in thyroid cancer patients. So, it can be concluded that the expressional alterations of miRNA-221 and -222 are playing their potential role in the development of thyroid cancer.

Analysis of Rare Alleles of miRNA-146a (rs2910164) and miRNA-34b/c (rs4938723) as a Prognostic Marker in Thyroid Cancer in Pakistani Population.

Background: Rationale: The miRNAs are short non-coding functional RNAs that are involved in the regulation of transcriptomes. It was found that human miRNA-146a and miRNA34b/c are important microRNAs and are functioning either as onco-miRNAs, or acting as tumor suppressors, in different conditions. To date, no study has been performed to evaluate the alterations of miRNA-146ars2910164 and miRNA34b/crs4938723 polymorphism as a risk factor in the development of thyroid cancer in the Pakistani population. Mutational analysis of rs2910164 and rs4938723 of miRNA-146a and miRNA-34b/c was carried out to check their association with the development of thyroid carcinogenesis. Material and Methods: Papillary thyroid cancer (PTC) patients with age and gender-matched controls were recruited for the present study. DNA extraction, genotyping of rs2910164 and rs4938723 was carried out by ARMS-PCR. Statistical analyses were carried out using SPSS software (version 20). Results: The odds ratio for risk allele C of rs2910164 for patients and controls was 23.0168 (3.0321−174.7208) with a p-value of <0.0001, showing that the frequency of the major allele G was lower in patients while the frequency of minor allele C was higher in patients. Similarly, the odds ratio for risk allele C of rs4938723 was 1.8621 (1.0321−3.3596) with a p-value of <0.03788 showing significant association with the development of thyroid cancer. Conclusions: The study highlights the significant association of miRNAs SNPs as one of the genetic risk factor for PTC. It was concluded that miRNA-146a (rs2910164) showed higher frequency of minor allele C in patients. Similarly in miRNA-34b/c gene SNP rs4938723 was observed to have a strong association with the development of thyroid cancer as the frequency of rare allele C was higher in patients.

Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter.

The sodium iodide symporter (NIS) functions to transport iodide and is critical for successful radioiodide ablation of cancer cells. Approaches to bolster NIS function and diminish recurrence post-radioiodide therapy are impeded by oncogenic pathways that suppress NIS, as well as the inherent complexity of NIS regulation. Here, we utilize NIS in high-throughput drug screening and undertake rigorous evaluation of lead compounds to identify and target key processes underpinning NIS function. We find that multiple proteostasis pathways, including proteasomal degradation and autophagy, are central to the cellular processing of NIS. Utilizing inhibitors targeting distinct molecular processes, we pinpoint combinatorial drug strategies giving robust >5-fold increases in radioiodide uptake. We also reveal significant dysregulation of core proteostasis genes in human tumors, identifying a 13-gene risk score classifier as an independent predictor of recurrence in radioiodide-treated patients. We thus propose and discuss a model for targetable steps of intracellular processing of NIS function.