Identifying novel regulatory effects for clinically relevant genes through the study of the Greek population.

BACKGROUND: Expression quantitative trait loci (eQTL) studies provide insights into regulatory mechanisms underlying disease risk. Expanding studies of gene regulation to underexplored populations and to medically relevant tissues offers potential to reveal yet unknown regulatory variants and to better understand disease mechanisms. Here, we performed eQTL mapping in subcutaneous (S) and visceral (V) adipose tissue from 106 Greek individuals (Greek Metabolic study, GM) and compared our findings to those from the Genotype-Tissue Expression (GTEx) resource. RESULTS: We identified 1,930 and 1,515 eGenes in S and V respectively, over 13% of which are not observed in GTEx adipose tissue, and that do not arise due to different ancestry. We report additional context-specific regulatory effects in genes of clinical interest (e.g. oncogene ST7) and in genes regulating responses to environmental stimuli (e.g. MIR21, SNX33). We suggest that a fraction of the reported differences across populations is due to environmental effects on gene expression, driving context-specific eQTLs, and suggest that environmental effects can determine the penetrance of disease variants thus shaping disease risk. We report that over half of GM eQTLs colocalize with GWAS SNPs and of these colocalizations 41% are not detected in GTEx. We also highlight the clinical relevance of S adipose tissue by revealing that inflammatory processes are upregulated in individuals with obesity, not only in V, but also in S tissue. CONCLUSIONS: By focusing on an understudied population, our results provide further candidate genes for investigation regarding their role in adipose tissue biology and their contribution to disease risk and pathogenesis.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) expression in human benign and malignant thyroid lesions.

BACKGROUND: The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that contributes to tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of RCAS1 expression in human benign and malignant thyroid lesions. MATERIAL/METHODS: RCAS1 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 121 patients with benign and malignant lesions and was associated with type of thyroid histopathology and tumor stage parameters such as tumor size, lymph node metastases, capsular, lymphatic and vascular invasion. RESULTS: RCAS1 positivity, overexpression and staining intensity provided a distinct discrimination between benign and malignant thyroid cases (p=0.0006, p=0.0001 and p=0.0001, respectively), as well as between hyperplastic nodule and papillary carcinoma cases (p=0.0229, p=0.0001 and p=0.0001, respectively). RCAS1 positivity, overexpression and staining intensity also provided distinct discrimination between cases with Hashimoto thyroiditis and those with hyperplastic nodule (p=0.0221, p=0.0001 and p=0.0019, respectively). In the subgroup of malignant thyroid lesions, RCAS1 overexpression was significantly associated with large tumor size (p=0.0246), the presence of lymph node metastases (p=0.0351) and capsular invasion (p=0.0397). CONCLUSIONS: RCAS1 protein may participate in thyroid neoplastic transformation and could be considered as a useful biomarker to improve diagnostic scrutiny.

Human kallikrein-related peptidase 12 (KLK12) splice variants discriminate benign from cancerous breast tumors.

OBJECTIVES: As kallikrein-related peptidase 12 (KLK12) has been implicated in the cancer progression and alternative splicing plays significant role in this disease, the aim of this study was to examine the expression profile and the clinical impact of the KLK12 splice variants in breast cancer. DESIGN AND METHODS: Total RNA was isolated and reverse transcripted from 141 tissues. Afterwards, quantitative real-time PCR were conducted, followed by the performance of the comparative CT (2-ΔΔCT) method for relative quantification, whilst their correlation with the clinicopathological features of breast malignancies were assessed by statistical analysis. RESULTS: Both KLK12sv1/2 and KLK12sv3 showed higher expression in non-cancerous than in cancerous samples. KLKsv1/2 (P = 0.001) upregulated and KLK12sv3 (P < 0.001) downregulated in the malignant compared to the benign tumors and their discriminative ability was verified by ROC curve analysis. Moreover, KLK12sv3 was associated with grade (P = 0.012) and hormonal receptor status (P = 0.001). Furthermore, Kaplan-Meier and Cox regression analyses showed that patients with positive KLK12sv1/2 and KLK12sv3 levels presented a significantly longer disease-free survival (P = 0.014 and P = 0.013, respectively) and overall survival (P = 0.062 and P = 0.004, respectively). CONCLUSIONS: Our results demonstrate the discriminative value of KLK12sv1/2 and KLK12sv3 between benign and malignant breast tumors as well as their potential favorable prognostic significance in breast adenocarcinoma.