X-Inactive-Specific Transcript: Review of Its Functions in the Carcinogenesis.

X-inactive-specific transcript (XIST) is one of the firstly discovered long non-coding RNAs with prominent roles in the process of X inactivation. Moreover, this transcript contributes in the carcinogenic process in different tissues. In addition to interacting with chromatin modifying molecules, XIST can be served as a molecular sponge for miRNAs to modulate expression of miRNA targets. Most of the studies have indicated an oncogenic role for XIST. However, in prostate cancer, a single study has indicated a tumor suppressor role for this lncRNA. Similar result has been reported for XIST in oral squamous cell carcinoma. In hepatocellular carcinoma, breast cancer, ovarian cancer, osteosarcoma, and renal cell carcinoma, different studies have reported inconsistent results. In the present manuscript, we review function of XIST in the carcinogenesis.

BCYRN1: An oncogenic lncRNA in diverse cancers.

Brain cytoplasmic 200 (BC200) or alternatively named as brain cytoplasmic RNA 1 (BCYRN1) is a long non-coding RNA (lncRNA) primarily identified in the neurons. In addition to its participation in the pathogenesis of neurodegenerative disorders, it partake in the carcinogenesis process. Numerous in vitro studies have reported elevation of expression of BCYRN1 in cancer cell lines. Short hairpin-RNA-mediated silencing of BCYRN1 has attenuated growth of tumors in the animal models. Independent studies in esophageal squamous cell cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma and non-small cell lung cancer have demonstrated association between elevated BCYRN1 levels and poor survival of patients. Taken together, BCYRN1 is an appropriate candidate for targeted therapies in the field of cancer.

A review on the role of oncogenic lncRNA OIP5-AS1 in human malignancies.

OIP5-AS1 is a long non-coding transcript with high expression in nervous system, but crucial functions in the neoplastic transformation. This lncRNA partake in the regulation of cell cycle transition at different points. Moreover, it acts a competing endogenous RNA for tens of microRNAs among them are miR-338-3p, miR-204-5p, miR-641, miR-422a, miR-367-3p, miR-153-3p, miR-186, miR-369-3p, miR-137, miR-342-3p, miR­429, miR-3163, miR-363-3p, miR-186a-5p, hsa-miR-26a-3p, miR­300, miR-217, miR-378a-3p and miR-448. OIP5-AS1 influence the carcinogenesis via different routes among them is modulation of epithelial-mesenchymal transition. Expression of OIP5-AS1 has been elevated in nearly all kinds of neoplastic tissues except for multiple myeloma. Moreover, in bladder, gastric cancer and lung cancers, assessment of its expression in clinical samples has led to conflicting results. In the current paper, we have provided a comprehensive collection of research papers that evaluated function of OIP5-AS1 in diverse cancer types.

Deleted in lymphocytic leukemia 2 (DLEU2): An lncRNA with dissimilar roles in different cancers.

Deleted in lymphocytic leukemia 2" (DLEU2) is a long non-coding transcript with several splice variants. It has been identified through a comprehensive sequencing of a commonly deleted region in leukemia i.e. the 13q14 region. Afterwards, different investigations reported up-regulation of this long non-coding RNA in several types of cancers. Up-regulation of DLEU2 has been shown to determine poor survival in esophageal, pancreatic, laryngeal, renal, cervical and lung cancers. However, the diagnostic power of DLUE2 has only assessed in two studies; only one them exhibiting promising results. A limitation of most of studies is that they did not differentiate between transcript variants of this lncRNA. Therefore, it is not possible to attribute the observed functions to a certain alternate transcript. In this manuscript, we discuss the results of these studies in three different sections based on the type of experiments.

HOX transcript antisense RNA: An oncogenic lncRNA in diverse malignancies.

HOX transcript antisense RNA (HOTAIR) is a transcript produced from the antisense strand of the HOXC gene cluster and influencing expression of genes from the HOXD locus. HOTAIR has prominent roles in different aspects of carcinogenic process from cancer initiation to metastasis. A number of in vitro, in vivo and human investigations have confirmed the oncogenic impacts of HOTAIR. The diagnostic power of HOTAIR in distinguishing cancer status from healthy status has been optimal in gastric cancer, pancreatic adenocarcinoma and colorectal cancer. The most important achievement in this regard has been provided by studies that verified diagnostic value of this lncRNA in the serum samples, potentiating its application in non-invasive diagnosis of cancer. Moreover, HOTAIR has a crucial role in determination of response of cancer cells to therapeutic modalities. The current review aims to explain the outlines of these studies to emphasize its potential as a biomarker and therapeutic target for these conditions.

An in-silico method leads to recognition of hub genes and crucial pathways in survival of patients with breast cancer.

Breast cancer is a highly heterogeneous disorder characterized by dysregulation of expression of numerous genes and cascades. In the current study, we aim to use a system biology strategy to identify key genes and signaling pathways in breast cancer. We have retrieved data of two microarray datasets (GSE65194 and GSE45827) from the NCBI Gene Expression Omnibus database. R package was used for identification of differentially expressed genes (DEGs), assessment of gene ontology and pathway enrichment evaluation. The DEGs were integrated to construct a protein-protein interaction network. Next, hub genes were recognized using the Cytoscape software and lncRNA-mRNA co-expression analysis was performed to evaluate the potential roles of lncRNAs. Finally, the clinical importance of the obtained genes was assessed using Kaplan-Meier survival analysis. In the present study, 887 DEGs including 730 upregulated and 157 downregulated DEGs were detected between breast cancer and normal samples. By combining the results of functional analysis, MCODE, CytoNCA and CytoHubba 2 hub genes including MAD2L1 and CCNB1 were selected. We also identified 12 lncRNAs with significant correlation with MAD2L1 and CCNB1 genes. According to The Kaplan-Meier plotter database MAD2L1, CCNA2, RAD51-AS1 and LINC01089 have the most prediction potential among all candidate hub genes. Our study offers a framework for recognition of mRNA-lncRNA network in breast cancer and detection of important pathways that could be used as therapeutic targets in this kind of cancer.

TINCR: An lncRNA with dual functions in the carcinogenesis process.

Long non-coding RNAs (lncRNAs) have prominent roles in the pathogenesis of human cancers. Several studies have shown oncogenic or tumor suppressor roles of lncRNAs in different human tissues. Thus, these transcripts have been regarded as putative targets in treatment of cancer. The lncRNA terminal differentiation-induced non-coding RNA (TINCR) has an especial position in this regard, as it exerts different opposite roles in the pathogenesis of different human cancers. While it is up-regulated in gastric, esophageal, bladder and breast cancer; it is down-regulated in glioma, retinoblastoma and prostate cancer. Notably, data regarding expression profile of this lncRNA in a number of human cancers such as colon cancer, squamous cell carcinoma, non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are controversial. Expression level of this lncRNA has been associated with clinical outcome in patients with gastric cancer, colorectal cancer, NSCLC and head and neck squamous cell carcinoma. Moreover, Kaplan-Meier analyses have shown correlation between expression levels of TINCR and patients survival in patients with lung cancer and HCC. A number of cellular pathways such as Wnt/ß-catenin, ERK1/2-SP3 and MAPK signaling pathways have been identified as targets of this lncRNA in different cancers. Moreover, the rs8113645, rs2288947 and rs8105637 within this lncRNA have been associated with risk of gastric and colorectal cancer. In conclusion, although the role of TINCR in the carcinogenesis is essential, based on the conflicting data regarding the direction of effect of this lncRNA, therapeutic targeting of this lncRNA is a complicated issue which should be considered in a tissue-specific or even individualized manner.

The role of long non-coding RNA CASC2 in the carcinogenesis process.

The lncRNA cancer susceptibility candidate 2 (CASC2) has been initially discovered in a genomic area on 10q26 that is commonly lost in human endometrial cancer. Subsequent assessments revealed its down-regulation in almost all kinds of cancer including glioma, breast cancer, colorectal cancer, lung cancer, ovarian cancer and hepatocellular carcinoma. Yet, it has been shown to be up-regulated in astrocytoma and in paclitaxel (PTX) resistant breast cancer tissues. In vitro studies have shown the role of this lncRNA in suppression of cell proliferation and induction of apoptosis. Animal studies have shown that over-expression of CASC2 suppresses tumorigenesis of human cancer cells in xenograft models. Diagnostic power of CASC2 levels has been evaluated in a number of human cancers and the best parameters have been demonstrated in pituitary adenomas and oral squamous cell carcinoma. Taken together, the main body of evidence show a tumor suppressor role of CASC2 and indicate up-regulation of this lncRNA as a putative therapeutic modality for human cancers. In this review, we summarize the data regarding expression pattern, function and diagnostic role of CASC2 in human cancer based on the results of cell line studies, animal investigations and human studies.

Expression profile of lncRNAs and miRNAs in esophageal cancer: Implications in diagnosis, prognosis, and therapeutic response.

Esophageal cancer is the seventh most common cancer worldwide. Although a number of environmental and lifestyle-related risk factors have been identified for this kind of cancer, the exact molecular mechanisms of tumor evolution have not been clarified yet. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) as important regulators of gene expression and chromatin configuration have essential roles in the pathogenesis of esophageal cancer. They have been shown to alter the function of cancer-related signaling pathways such as phosphoinositide 3-kinase/protein kinase B and Wnt pathway, thus they might modulate the response of patients to pathway-targeted therapies. Moreover, a number of lncRNAs, such as AFAP1-AS1, UCA1, HOTAIR, LOC285194, and TUSC7, are involved in conferring chemoresistant/radioresistant in esophageal cancer cells. A complex network of interaction exists between lncRNAs and miRNAs in the context of esophageal cancer. Finally, various panels of lncRNAs and miRNAs have been introduced that can predict the survival of esophageal cancer patients. In this review article, we summarize the recent findings regarding the role of miRNAs and lncRNAs in the pathogenesis of esophageal cancer with the special focus on their regulatory roles on signaling pathways, their potential as diagnostic/prognostic markers, and their relevance with therapeutic response.

In silico identification of MAPK14-related lncRNAs and assessment of their expression in breast cancer samples.

Mitogen-activated protein kinase (MAP kinase) pathways participate in regulation of several cellular processes involved in breast carcinogenesis. A number of non-coding RNAs including both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate or being regulated by MAPKs. We performed an in-silico method for identification of MAPKs with high number of interactions with miRNAs and lncRNAs. Bioinformatics approaches revealed that MAPK14 ranked first among MAPKs. Subsequently, we identified miRNAs and lncRNAs that were predicted to be associated with MAPK14. Finally, we selected four lncRNAs with higher predicted scores (NORAD, HCG11, ZNRD1ASP and TTN-AS1) and assessed their expression in 80 breast cancer tissues and their adjacent non-cancerous tissues (ANCTs). Expressions of HCG11 and ZNRD1ASP were lower in tumoral tissues compared with ANCTs (P values < 0.0001). However, expression levels of MAPK14 and NORAD were not significantly different between breast cancer tissues and ANCTs. A significant association was detected between expression of HCG11 and estrogen receptor (ER) status in a way that tumors with up-regulation of this lncRNA were mostly ER negative (P value = 0.04). Expressions of ZNRD1ASP and HCG11 were associated with menopause age and breast feeding duration respectively (P values = 0.02 and 0.04 respectively). There was a trend towards association between ZNRD1ASP expression and patients' age of cancer diagnosis. Finally, we detected a trend toward association between expression of NORAD and history of hormone replacement therapy (P value = 0.06). Expression of MAPK14 was significantly higher in grade 1 tumors compared with grade 2 tumors (P value = 0.02). Consequently, the current study provides evidences for association between lncRNA expressions and reproductive factors or tumor features.

Expression analysis of vimentin and the related lncRNA network in breast cancer.

Vimentin (VIM) is a mesenchymal marker which is expressed in some cancer types including breast cancer. A long non-coding RNA (lncRNA) has been identified to be transcribed from VIM gene locus and positively regulate expression of VIM. This lncRNA has been named as VIM-antisense 1 (VIM-AS1). Expression of VIM is also regulated by another lncRNA namely AGAP2-antisense RNA 1 (AGAP2-AS1). In the current study, we aimed at identification of the expression pattern of VIM, VIM-AS1, AGAP2 and AGAP2-AS1 in 78 breast cancer samples and their paired adjacent non-cancerous tissues (ANCTs) by means of real time PCR. All mentioned genes were significantly down-regulated in tumoral tissues compared with ANCTs (P values less than 0.000). Relative expression of VIM-AS1 in tumoral tissues versus ANCTs was associated with menopause age (P = .02) in a way that this gene was down-regulated in most of patients whose menopause age was between 40 and 50 years. Moreover, AGAP2-AS1 relative expression was associated with patients' body mass index (P = .03). There were trends toward association between VIM relative expression and tumor size (P = .07) and association between VIM-AS1 relative expression and obesity (P = .06). Expression of VIM was significantly higher in tumoral tissues of patients who had history of hormone replacement therapy compared with those without such history (P = .03). Moreover, expression levels of both VIM and AGAP2-AS1 were lower in patients whose menarche age was between 10 and 12 years old compared with those whose menarche age was between 13 and 15 years old (P values = .01 and 0.04, respectively). Transcript quantities of VIM, VIM-AS1, AGAP2 and AGAP2-AS1 were correlated with each other both in tumoral tissues and in ANCTs. Among four assessed genes, AGAP2 had the best diagnostic power for discrimination of tumoral tissues from ANCTs (AUC value = 0.87). Combination of four genes led to enhancement of AUC value to 0.94. The current study shows the importance of VIM and its associated lncRNAs in breast cancer and potentiates these genes as biomarkers for this malignancy. Moreover, these lncRNAs might be regarded as therapeutic targets in breast cancer.

The HOTTIP (HOXA transcript at the distal tip) lncRNA: Review of oncogenic roles in human.

HOXA transcript at the distal tip (HOTTIP) is a 3764 nucleotide long non-coding RNA (lncRNA) encoded from a genomic region in the 5' tip of the HOXA locus. This lncRNA has a role in transmission of signals from higher order chromosomal configuration into chromatin codes. HOTTIP directly binds with the WDR5 protein and recruits the WDR5/MLL complexes across the HOXA locus which leads to H3K4 methylation and activation of the transcription of HOXA genes. This lncRNA has a prominent role in the pathogenesis of almost all kinds of cancers. Apart from a single study in glioma cells, all in vitro studies have emphasized on oncogenic roles of HOTTIP in different malignancies. In vivo studies also showed the effect of HOTTIP silencing in reduction of tumorigenicity in all cancer types except from glioma. Results of clinical studies mostly demonstrated up-regulation of this lncRNA in cancer samples compared with non-malignant tissues of the same origin and correlation between its expression levels and patients' outcome. Taken together, HOTTIP is regarded as an oncogenic lncRNA in almost all kinds of cancers and a putative biomarker and therapeutic target in human malignancies.

PCAT1: An oncogenic lncRNA in diverse cancers and a putative therapeutic target.

The critical roles of long non-coding RNAs (lncRNAs) in the regulation of diverse biological functions has potentiated them as cancer biomarkers. Among these transcripts is the prostate cancer associated transcript 1 (PCAT1) which has been initially shown to exert oncogenic roles in prostate cancer. Further studies revealed its similar roles in various kinds of human malignancies including both solid tumors and hematological malignancies. Animal studies have shown that down-regulation of this lncRNA can attenuate tumor growth in a wide array of cancers including prostate cancer, colorectal cancer, squamous cell carcinoma lung cancer and hepatocellular carcinoma. Studies aimed at identification of diagnostic value of this lncRNA in human cancers reported various values ranging from 0.66 to 0.89 in diverse cancers with the best value reported in multiple myeloma. This lncRNA has a number of putative functional genomic variants such as rs1902432, rs2632159, rs1026411, rs710886, rs16901904 and rs710886 which can modify expression or function of PCAT1 thus altering the risk of human cancers. Based on aberrant expression of PCAT1 in malignancies of diverse origins, this lncRNA can be regarded as a therapeutic target in a vast array of cancers. Thus, modalities for efficient reduction of its expression would be beneficial for several patients.

Expression analysis of growth arrest specific 8 and its anti-sense in breast cancer tissues.

The Growth arrest specific 8 (GAS8) and its anti-sense transcript (GAS8-AS1) are located in a genomic region that is frequently mutated in breast cancer. These transcripts have established tumor suppressor effects in some human malignancies. In the current investigation, we aimed at identification of the role of GAS8 and GAS8-AS1 in breast cancer. We measured gene expression of GAS8 and GAS8-AS1 in paired tumoral and non-tumoral tissues obtained from 88 breast cancer patients by means of real time PCR. No significant differences were identified in expressions of GAS8 and GAS8-AS1 in tumoral samples compared with non-tumoral tissues (Fold changes = 1.53 and 1.71; P values = .28 and 0.14 respectively). Transcript levels of GAS8-AS1 was significantly correlated with estrogen receptor (ER) status (P = .01). Expression of GAS8 gene was associated with history of oral contraceptive use (P = .04). The similar expressions of GAS8 and GAS8-AS1 genes in tumoral and non-tumoral tissues of breast in spite of previous reports regarding their fundamental tumor suppressor roles in other tissues show that these genes are not involved in the pathogenesis of breast cancer. So, these genes have distinct roles in diverse tissues.

Gene expression of indoleamine and tryptophan dioxygenases and three long non-coding RNAs in breast cancer.

The kynurenine pathway (KP) has a principal role in the metabolism of tryptophan. This pathway is also involved in the pathogenesis of cancer. We evaluated expression of two rate limiting enzymes from this pathway (IDO1 and TDO2) as well as three long non-coding RNAs (lncRNAs) that have been predicted to alter expression of IDO1 (ITGB2-AS1, HCP5 and MIR155HG) in 82 breast cancer tissues and their adjacent non-cancerous tissues (ANCTs). While IDO1 expression levels were not significantly different between malignant tissues and ANCTs (expression ratio = 0.56, P = .21), TDO2 was significantly down-regulated in malignant tissues compared with ANCTs (Expression ratio = 0.001, P < .001). Among lncRNAs, expression of HCP5 was significantly lower in malignant tissues compared with ANCTs (Expression ratio = 0.17, P < .001). However, expression of ITGB2-AS1 was higher in malignant tissues compared with ANCTs (Expression ratio = 3.38, P = .01). Expressions of genes were not associated with any of clinical or demographic data of patients. However, there were trends towards association between IDO1 expression and tumor size as well as estrogen receptor (ER) status (P values 0.09 and 0.08 respectively). Significant pairwise correlations were found between expression levels of genes especially in ANCTs. Notably, TDO2 expression levels were correlated with expression of all other genes in ANCTs but none of them in tumor tissues. Based on the area under curve (AUC) values, HCP5 and TDO2 had "fair" diagnostic power (AUC values of 0.73 and 0.72). Notably, combination of HCP5, ITGB2-AS1 and TDO2 genes increased the diagnostic power to the level of "good". The current investigation underscores the role of KP in breast cancer and potentiates some genes within this pathway as diagnostic markers in breast cancer.

Assessment of anti-cancer effects of koenimbine on colon cancer cells.

BACKGROUND: Recent studies have highlighted the role of natural elements in reduction of cancer cell growth and apoptosis. Koenimbine, a natural product isolated from Murraya koenigii (L) Spreng is a substance with cytotoxic effects on cancer cells. AIM: The effects of koenimbine on HT-29 and SW48 colon cancer cells were evaluated by MTT and Annexin V assays. Expression levels of Wnt/ß-catenin pathway genes were quantified by real time PCR. RESULTS: The IC50 values of koenimbine in HT-29 and SW48 was calculated to be 50 µg/ml based on the results of MTT assay. This value was 75 µg/ml in IEC-18 cells which were used as normal control. Annexin V assays revealed induction of cell apoptosis and necrosis in HT-29 and SW48 cells but not IEG18 cells by koenimbine. Koenimbin treatment resulted in significant down-regulation of CYCLD1 expression in SW48 cell line, but up-regulation of this gene in HT29 cell line. Expression of TBLR1, DKK1, GSK3B and ß-catenin was significantly decreased after koenimbin treatment in HT-19 cell line. Moreover, expression of DKK1 and GSK3B was significantly decreased after koenimbin treatment in SW-40 cell line. TCF4 expression was not detected in any of cell lines either before or after treatment with koenimbin. CONCLUSION: The current in vitro study showed the cytotoxic effects of koenimbin on two colon cancer cell lines and the effects of this substance on expression of selected genes from Wnt-ß catenin pathway. Future in vivo studies are needed before suggestion of this substance as an anti-cancer drug.

Expression analysis of NF-κB interacting long noncoding RNAs in breast cancer.

The nuclear factor-κB (NF-κB) has a prominent role in development of breast cancer and response of patients to conventional therapies. Several factors regulate the activity of this transcription factor. In the current investigation, we compared expression levels of five long non-coding RNAs (lncRNAs) with putative interactions with NF-κB namely CHAST, ADINR, DICER1-AS1, HNF1A-AS1 and NKILA between 78 breast cancer tissues and their paired adjacent non-cancerous tissues (ANCTs). We also assessed expression levels of ATG5 and CEBPA mRNA coding genes that are functionally linked with NF-κB signaling in these two sets of samples. All assessed genes except for NKILA were significantly down-regulated in tumoral tissues compared with ANCTs. Expression of NKILA was not significantly different between tumoral tissues and ANCTs. Expression levels of CEBPA and HNF1A-AS were significantly associated with cancer stage (P values of 0.03 and 0.02 respectively). Expression levels of ATG5 tended to be associated with mitotic rate (P = .05). The association between expression levels of ATG5 and tumor size was also significant (P = .02). Expression of CHAST was significantly associated with PR status (P = .04) and tended to be associated with ER status (P = .05). Finally, expression of NKILA was significantly associated with first pregnancy age (P = .01). No other significant association was detected between expression levels of assessed genes and clinical parameters. Expression levels of mentioned genes were significantly correlated with each other. The most significant correlations were found between CHAST and ADINR (correlation coefficients of 0.78 and 0.69 in tumoral tissues and ANCTs respectively). Based on the area under curve (AUC) values, DICER1-AS and CEBPA had the best performance in differentiation of tumoral tissues from ANCTs (AUC values of 0.92 and 0.90 respectively. Combination of transcript quantities of six genes could differentiate these two sets of samples with 92.3% sensitivity, 91% specificity and diagnostic power of 95%. The current project highlights dysregulation of NF-κB-associated genes in breast cancer tissues and suggests them as potential diagnostic markers in breast cancer.

Cellular immune responses against cancer-germline genes in cancers.

BACKGROUND: Cancer-germline genes are a class of genes that are normally expressed in testis, trophoblast and few somatic tissues but abnormally expressed in tumor tissues. Their expression signature indicates that they can induce cellular immune responses, thus being applied as targets in cancer immunotherapy. OBJECTIVES: To obtain the data of cellular immune responses against cancer-germline genes in cancer. METHODS: We searched PubMed/Medline with the key words cancer-germline antigen, cancer-testis antigen, CD4+ T cell, CD8+ T cell and cancer. RESULTS: About 40 cancer-germline genes have been shown to induce T cell specific responses in cancer patients. Melanoma, lung and breast cancer are among the mostly assessed cancer types. Several epitopes have been identified which can be used in immunotherapy of cancer. CONCLUSION: Cellular immune responses against cancer-germline genes are indicative of appropriateness of these genes as therapeutic targets.

Associations between XRCC3 Thr241Met polymorphisms and breast cancer risk: systematic-review and meta-analysis of 55 case-control studies.

BACKGROUND: The X-ray repair cross-complementing group 3 (XRCC3) is an efficient component of homologous recombination and is required for the preservation of chromosomal integrity in mammalian cells. The association between Thr241Met single-nucleotide polymorphism (SNP) in this gene and susceptibility to breast cancer has been assessed in several studies. Yet, reports are controversial. The present meta-analysis has been designed to identify whether this SNP is associated with susceptibility to breast cancer. METHODS: We performed a systematic review and meta-analysis for retrieving the case-control studies on the associations between T241 M SNP and the risk of breast cancer. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to verify the association in dominant, recessive, and homozygote inheritance models. RESULTS: We included 55 studies containing 30,966 sporadic breast cancer cases, 1174 familial breast cancer cases and 32,890 controls in the meta-analysis. In crude analyses, no association was detected between the mentioned SNP and breast cancer risk in recessive, homozygote or dominant models. However, ethnic based analysis showed that in sporadic breast cancer, the SNP was associated with breast cancer risk in Arab populations in homozygous (OR (95% CI) = 3.649 (2.029-6.563), p = 0.0001) and recessive models (OR (95% CI) = 4.092 (1.806-9.271), p = 0.001). The association was significant in Asian population in dominant model (OR (95% CI) = 1.296, p = 0.029). However, the associations was significant in familial breast cancer in mixed ethnic-based subgroup in homozygote and recessive models (OR (95% CI) = 0.451 (0.309-0.659), p = 0.0001, OR (95% CI) = 0.462 (0.298-0.716), p = 0.001 respectively). CONCLUSIONS: Taken together, our results in a large sample of both sporadic and familial cases of breast cancer showed insignificant role of Thr241Met in the pathogenesis of this type of malignancy. Such results were more conclusive in sporadic cases. In familial cases, future studies are needed to verify our results.

Assessment of the expression pattern of mTOR-associated lncRNAs and their genomic variants in the patients with breast cancer.

The mechanistic target of rapamycin (mTOR) is a fundamental component of a signaling pathway that is involved in the pathogenesis of breast cancer via different mechanisms. This pathway is functionally linked with a number of small nucleolar RNA host genes (SNHGs). In the present project, we have searched for the expression quantitative trait loci (eQTLs) within SNHGs that are possibly involved in the pathogenesis of breast cancer. Following this in silico step, we have assessed expression levels of mTOR and four SNHGs in malignant and nonmalignant samples obtained from 80 patients with breast cancer. We also genotyped rs4615861 of SNHG3 and rs3087978 of SNHG5 in the peripheral blood of patients. SNHG12 expression was not detected in any of the assessed malignant or nonmalignant tissues. So this gene was excluded from further steps. Expression of mTOR and other three long noncoding RNAs (lncRNAs) were significantly increased in the malignant tissues compared with the nonmalignant tissues. When classifying patients into down-/upregulation categorized based on the transcript levels of each gene in malignant tissue versus nonmalignant tissues, we noticed associations between expression of SNHG1 and stage (p = 0.03), expression of SNHG5 and grade (p = 0.05), as well as between expression of SNHG3 and history of oral contraceptive use (p = 0.04). We also detected higher levels of SNHG3 expression in estrogen receptor/progesterone receptor (ER/PR) negative tumors compared with the ER/PR positive tumors (p = 0.003 and p = 0.01, respectively). Moreover, there was a trend toward higher expression of this lncRNA in HER2-positive tumors compared with the HER2-negative ones (p = 0.07). Combination of transcript levels of all genes could differentiate malignant tissues from nonmalignant tissues with the diagnostic power of 69% (p = 0.0001). The rs3087978 was associated with the expression of mTOR in malignant tissues in a way that TT and TG genotypes were associated with the higher and lower levels of expressions, respectively (p = 0.01). The current study underscores the significance of SNHGs in the pathogenesis of breast cancer.