Association of SMAD7 genetic markers and haplotypes with colorectal cancer risk.

PURPOSE: Colorectal cancer (CRC) is one of the common cancers with a high mortality rate worldwide. In Iran, there has been a trend of increased incidence of colorectal cancer in the last three decades that necessitates the early diagnosis. Genetic factors have an influential role in its etiology along with the conventional risk factors such as age, diet, and lifestyle. Results from GWAS have shown significant associations between SMAD7 gene variants and risk of CRC. This study aimed to assess the association of certain polymorphisms as well as haplotypes of this gene and risk of colorectal cancer. METHODS AND MATERIALS: This study was designed as a case-control association study. After obtaining ethical approval and informed consent, blood samples from 209 patients with colorectal cancer were collected and DNA was extracted. Four variants: rs4939827, rs34007497, rs8085824 and rs8088297 were genotyped using ARMS-PCR method. RESULTS: SMAD7 rs4939827 in the recessive and co-dominant models was associated with colorectal cancer risk [TT/CT + CC: OR = 2.90, 95%CI (1.38-6.09), p = 0.005; CC + TT/CT: OR = 1.66, 95%CI (1.00-2.75), p = 0.01]. Haplotype analysis indicated that some SNP combinations including two for-SNPs haplotypes of T-T-C-C and T-C-C-A were significantly associated with CRC risk. CONCLUSION: Based on the identified association of SMAD7 gene variations and haplotypes with colorectal cancer risk in our population, genetic variations in this gene region may have a role in CRC development. This data may shed light on the genetic predisposition of CRC which involves different pathways including TGF-ß.

Mutation Screening of KCNQ1 and KCNE1 Genes in Iranian Patients With Jervell and Lange-Nielsen Syndrome.

Background: Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive genetic disease with deafness and QT prolongation. Mutations in KCNQ1 and KCNE1 genes are a cause of JLNS. Our objective was to perform mutational analysis of the KCNQ1 and KCNE1 genes to determine the frequency of mutations in the Iranian population. Material and methods: Fourteen patients and their families were investigated. Mutational screening of the KCNQ1 and KCNE1 genes was performed by a polymerase chain reaction (PCR) followed by direct Sanger sequencing. Results: We identified two frameshift mutations in the KCNQ1 gene, including a novel mutation, c.1356 1356delG, and a known mutation, c.1534_1534delG. A common single nucleotide polymorphism (SNP), c.112G > A, was also found in KCNE1 in seven probands. Conclusion: A novel mutation in the KCNQ1 gene is described. There may be less frequency of mutations in the KCNQ1 and of KCNE1 genes in Iranian JLNS patients compared with other populations.

Polymorphisms in non-coding RNAs and risk of colorectal cancer: A systematic review and meta-analysis.

Colorectal cancer (CRC) has been regarded as a common cancer due to its prevailing incidence in both males and females. Recently, non-coding RNAs used as biomarkers for screening, diagnosis and prognosis of different cancers have been under the focus of attention. As a result of this, the aim of this study was to systematically review articles that investigated the SNPs in genes related to microRNAs and long non-coding RNAs to assess the genetic susceptibility of colorectal cancer risk. The outcome is presented as the results of a meta-analysis. We systematically searched PubMed, Web of Science, and Scopus to identify relevant studies published up to 20/5/2017. These included eligible studies consisting of 23,581 patients and 22,697 controls. The conferred risk was estimated and presented using odds ratios (ORs) and 95% confidence intervals (CI). The Hardy-Weinberg equilibrium (HWE) was assessed by the goodness-of-fit chi-square test in all studies. The power of each study was also calculated based on the available results. Out of 27 different microRNAs which had published results, although most of the studies were under powered, miR-146a and miR-196a were amongst the most studied microRNAs. For five miRNAs (miR-196a, miR-146a, miR-27a, miR-499 and miR-149) which we performed a meta-analysis, miR-27a and miR-149 gene polymorphisms were associated with susceptibility to CRC. Other miRNAs did not show any effect on the CRC risk. Overall, significant association between miR-149 rs2292832 and susceptibility to cancer was identified in a recessive genetic model, TT/ (TC + CC) (OR = 1.19, 95% CI = 1.02-1.39, P = 0.02). On the other hand, rs895819 (miR-27a) GG carriers were more susceptible to CRC (OR = 1.47, 95% CI = 1.21-1.78, P = <0.05) in a recessive genetic model. Analysis of the data based on race revealed that rs2910164 (miR-146a) polymorphism may decrease the risk of CRC among Europeans, in a co dominant model [OR = 0.81, 95% CI 0.66-0.99, p = 0.04], but not among Asians. In conclusion, certain miRNAs (miR-27a and miR-149) may affect the CRC risk and can be regarded as genetic markers amongst different populations. LncRNAs still have to be studied more to reach a conclusion for their association with CRC risk.

Common KRAS and NRAS gene mutations in sporadic colorectal cancer in Northeastern Iranian patients.

OBJECTIVES: Mutation analysis of the Epidermal Growth Factor Receptor downstream has been a main part of colorectal carcinoma evaluation. Large prospective clinical trials have shown only colorectal cancer (CRC) with wild-type KRAS and NRAS responds to anti-Epidermal Growth Factor Receptor treatment. Hence, mutation analysis is necessary prior to treatment. It is essential to conduct studies to learn about the mutation signature of such tumors. The aim of this study was to evaluate the frequency of hotspot mutations in KRAS and NRAS genes in Iranian CRC patients and to explore their correlations with clinicopathologic parameters. METHODS: We detected mutations in exon 2 (codons 12 and 13) of the KRAS and NRAS genes using high resolution melting analysis, Intplex design and Sanger sequencing in 87 Iranian CRC patients. Genomic DNA was isolated from fresh tissue samples of CRC patients. RESULTS: From 87 eligible cases, 51 were male and 36 were females. KRAS mutations in codons 12 and 13 were present in 28.7% of all analyzed CRCs. Our findings suggested that the tumors with KRAS mutations are not with well- and moderately differentiated tumors compared to poorly differentiated tumors (P value = 0.32). The most frequent types of mutations were glycine to aspartate on codon 12 (p.G12D), and glycine to aspartate on codon 13 (p.G13D). No mutation was found in the NRAS gene in our patients. CONCLUSIONS: Based on this study, the frequency of KRAS mutations seems to be in the spectrum of frequencies of other countries such as China, Japan, India, USA, France, and Germany and NRAS was similar to the West of Iran.

The versatile role of curcumin in cancer prevention and treatment: A focus on PI3K/AKT pathway.

Despite significant advances in treatment modalities, millions of cancer-related deaths continue to occur annually, often as a consequence of developing resistance against the range of available chemotherapeutic drugs. Furthermore, available anti-cancer chemotherapeutic agents show limited efficacy, often have severe side effects, and are expensive. Thus, the discovery of pharmacological agents that do not have these disadvantages is necessary. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa L.), is one such agent that has been widely studied for its anti-inflammatory and/or anti-cancer effects. Curcumin exerts its anti-cancer effect by suppressing the initiation, progression, and metastasis of a variety of cancers and appears to inhibit carcinogenesis by affecting two main processes: angiogenesis and tumor growth. These anti-cancer effects are largely mediated via negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. The PI3K/AKT pathway is commonly activated in cancer initiation and progression. Considered to be the key signaling pathway, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway therefore represents a key target for cancer therapeutics. In the current review, we focus upon curcumin's targeting of PI3K/AKT in different malignancies to effect inhibition of cancer development and progression.

Dickkopf homolog 3 (DKK3): A candidate for detection and treatment of cancers?

Wnt signaling is an evolutionary highly conserved pathway that is modulated by several inhibitors and activators, and plays a key role in numerous physiological processes. One of the extracellular Wnt inhibitors is the DKK (Dickkopf Homolog) family which has four members (Dkk1-4) and a unique Dkk3-related gene, Dkkl1 (soggy). DKK3 is a divergent member of the DKK protein family. Evidence suggests that DKK3 may serve as a potential therapeutic target in several types of human cancers. We review here the biological role of DKK3 as a tumor suppressor gene (TSG) or oncogene, and its correlation with various miRNAs. In addition, we discuss the role of polymorphisms and promoter methylation of the DKK3 gene, and of its expression in regulating cancer cell proliferation. Finally, we propose that DKK3 may be considered as both a biomarker and a therapeutic target in different cancers.

Colorectal Cancer Screening: A Comprehensive Review to Recent Non-Invasive Methods.

Colorectal cancer (CRC) is one of the most common cancers worldwide and considered to be one of the hassles in medical communities. CRC develops from precancerous polyps in the colon or rectum and is preventable and curable by an early diagnosis and with the removal of premalignant polyps. In recent years, scientists have looked for inexpensive and safe ways to detect CRC in its earliest stages. Strong evidence shows that screening for CRC is a crucial way to reduce the incidence and mortality of this devastating disease. The main purpose for screening is to detect cancer or pre-cancer signs in all asymptomatic patients. In this review, we holistically introduce major pathways involved in the initiation and progression of colorectal tumorgenesis, which mainly includes chromosome instability (CIN), microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and we then will discuss different screening tests and especially the latest non-invasive fecal screening test kits for the detection of CRC.