In silico characterization of functional SNP within the oestrogen receptor gene.

Single-nucleotide polymorphism (SNP) association studies have become crucial in uncovering the genetic correlations of genomic variants with complex diseases, quantitative traits and physiological responses to drugs. However, the identification of SNPs responsible for specific phenotypes is a difficult problem to solve, requiring multiple testing of hundreds or thousands of SNPs in candidate genes. In this study, we performed an analysis of the genetic variations that can alter the structure and function of oestrogen receptor α using different computational tools. Among the nonsynonymous SNPs, a total of four SNPs were found to be damaging by both a sequence homology-based tool (SIFT) and a structural homology-based method (polyphen-2, SNAP), as well as by the ESEfinder program, and one nonsense nsSNP was found. For noncoding SNPs, we found that one SNP in 5' UTR may potentially change protein expression level, nine SNPs were found to affect miRNA binding site and 28 SNPs might affect transcriptional regulation of the ESR1 gene. Reviewing the literature, 89 SNPs were found to be functional among which only four were located in exons.

Genetic features of thyroid hormone receptors.

Thyroid hormone receptors (TR) are prototypes of nuclear transcription factors that regulate the expression of target genes. These receptors play an important role in many physiological processes. Moreover, a dysfunction of these proteins is often implicated in several human diseases and malignancies. Here we report genetic variations and alterations of the TRs that have been described in the literature as well as their potential role in the development of some human diseases including cancers. The functional effects of some mutations and polymorphisms in TRs on disease susceptibility, especially on cancer risk, are now established. Therefore, further investigations are needed in order to use these receptors as therapeutic targets or as biological markers to decide on appropriate forms of treatment.

Mutations and polymorphisms of estrogens receptors genes and diseases susceptibility.

BACKGROUND: Estrogen receptors (ER) belong to the super-family of the nuclear hormone receptors which act as ligand-regulated transcription factor to control a diverse set of essentials functions, such as growth development, metabolism, and reproduction. Though, the involvement of these receptors in several diseases including cancer was shown in numerous studies. AIM: Here, we reviewed the literature to report genetic polymorphisms and mutations investigated in the ESR genes (α and ß) and to explore their relationship and their potential role to develop some diseases as well as the ER expression status especially in cancer. METHODS: We searched the MEDLINE database with the keywords of estrogens receptors gene polymorphisms, short tandem repeat (STR) sequences, single-nucleotide polymorphisms (SNPs), cancer risk and diseases susceptibility. RESULTS: The functional effects of some mutations, short nucleotide polymorphisms and STR polymorphisms of ESR gene on susceptibility of multiple diseases, especially on cancer risk, are well approved. CONCLUSIONS: The involvement of genetic variations of the ERs in the risk of multiples diseases is frequently established, which incite to more elucidate the functional role of these markers in cell. Therefore, further investigations are needed to see the impact of these variations in drug response which makes them suitable therapeutic.

HER2 polymorphisms and breast cancer in Tunisian women.

HER2 has been thought to play a critical role in both breast cancer development and progression. Any functional polymorphisms can potentially affect breast cancer risk as well as cancer phenotype and outcome. In our study, we analyzed three polymorphisms in the HER2 gene: the single-nucleotide polymorphism (SNP) HER2 Ile(655)Val as well as another SNP (rs903506) close to it and a new screened dinucleotide repeat H(AC)I4 in intron 4, in a sample of 148 cases and 290 controls from the Tunisian population and investigated their association with breast cancer risk. For the HER2 Ile(655)Val, we found similar allele frequencies between cases and controls (frequency of I allele was 0.92 and 0.91, respectively). The same was observed for the noncoding SNP (rs903506). These two SNPs also showed no association with any clinical parameters, except the association of HER2 Ile(655)Val with tumor size (p = 0.002). But, a significant association was found between the short tandem repeat (STR) [H(AC)I4] and breast cancer risk at both genotypic and allelic levels (p = 0.0004 and p = 0.0001, respectively). Multivariate analysis with binary logistic regression of disease status on genotypes of the three polymorphisms confirmed the association of STR with breast cancer risk (p = 0.016). Therefore, this STR seems to be a promising biomarker in breast cancer and deserves further investigation.

Association of EGFR and HER2 polymorphisms with risk and clinical features of thyroid cancer.

The epidermal growth factor receptor family plays a critical role in the control of many physiological processes. Genetic alterations and/or variations in the gene encoding these receptors have been implicated in a variety of human cancers. In this study we evaluate the association of two single-nucleotide polymorphisms (SNP), R497K and I655V, of the EGFR and HER2 genes, respectively, with thyroid cancer risk. The analysis was performed with 302 healthy individuals and 106 thyroid cancer patients. No significant difference was found in the allelic and genotypic frequency distribution of the SNP R497K between the control and patient groups. While for the SNP I655V, the allele G is more frequent in patients than in controls and was associated with an increased risk of thyroid cancer (odds ratio = 1.88; 95% confidence intervals: 1.18-3.01; p = 0.007). We have also investigated the relationship between these two polymorphic sites and clinicopathological characteristics such as thyroid-stimulating hormone level, off-thyroxin, serum thyroglobulin, tumor histology, metastasis, tumor status, tumor stage, and survival. No significant association was observed. Tumor status was found significantly associated with HER2 I655V as well as with two previously studied markers in the thyroid hormone receptor A and estrogen receptor 1 (ESR1) genes (D17S2189 and D6S440, respectively). We also report a correlation between thyroglobulin level and genotypes for SNP rs2228480 in exon 8 of the ESR1 gene. In conclusion, our results suggest that the SNP HER2 I655V, but not the EGFR R497K, was associated with thyroid cancer risk.

Genetic polymorphisms in the EGFR (R521K) and estrogen receptor (T594T) genes, EGFR and ErbB-2 protein expression, and breast cancer risk in Tunisia.

We evaluated the association of epidermal growth factor receptor (EGFR) 142285G>A (R521K) and estrogen receptor alpha (ESR1) 2014G>A (T594T) single nucleotide polymorphisms with breast cancer risk and prognosis in Tunisian patients. EGFR 142285G>A and ESR1 2014G>A were genotyped in a sample of 148 Tunisian breast cancer patients and 303 controls using PCR-RFLP method. Immunohistochemitsry was used to evaluate the expression levels of EGFR, HER2, ESR1, progesterone receptor and BCL2 in tumors. We found no evidence for an association between EGFR R521K polymorphism and breast cancer risk. However, we found that the homozygous GG (Arg) genotype was more prevalent in patients with lymph node metastasis (P = .03) and high grade tumors (P = .011). The ESR1 2014G allele showed significant association with breast cancer risk (P = .025). The GG genotype was associated with HER2 overexpression and this association withstood univariate and multivariate analyses (P = .009; P = .021, resp.). These data suggest that the R521K might be a prognostic factor, because it correlates with both tumor grade and nodule status. The higher expression of HER2 in ESR1 T594T GG patients suggests the possibility that ESR1 gene polymorphisms accompanied by HER2 expression might influence the pathogenesis of breast cancers.

Association of polymorphisms in estrogen and thyroid hormone receptors with thyroid cancer risk.

The receptors for thyroid hormone (THR) and oestrogen (ESR) are prototypes of nuclear transcription factors that regulate the expression of target genes. Genetic alterations in the genes of these receptors were found to be involved in cancer development. In this study we investigated the association of one SNP (rs2228480, T594T) and one microsatellite marker (D6S440) within the ESR1 gene and a dinucleotide repeat (D17S2189) within the THRA gene, with thyroid cancer risk. A case-control association study was conducted with 299 healthy individuals and 106 patients with thyroid cancer. Genotypic and allelic frequencies for the dinucleotide repeat in the ESR1 gene were similar between thyroid cancer patients and controls. For the AC repeat in the THRA gene, a slightly significant difference was found for the genotype 18/20 between the two groups (P = 0.034), which suggests that alleles with less than 20 repeats might have a protective effect in thyroid cancer risk. For the SNP T594T, the A allele was much more prevalent in patients than in controls and was highly associated with the risk of thyroid cancer (OR: 4,56; IC: 3.23-6.44; P < 10(-18)) and seems to have an additive mode of action. In conclusion, our data suggest that the SNP T594T but not the D6S440 and D17S189 is associated with thyroid cancer risk.

Association analysis of interleukin gene polymorphisms in autoimmune thyroid diseases in the Tunisian population.

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and autoimmune hypothyroidism (AH), are inherited as complex traits. Among the genes contributing to AITDs susceptibility are genes of the IL-1 family. IL-1 regulates T and B lymphocyte maturation, including the induction of several cytokines and cytokine receptors. Therefore, disturbances of this balance may not only play a role in inflammation but also in the pathogenesis of autoimmunity. In order to investigate genetic association of IL-1 gene polymorphisms with AITDs, we performed both a familial study in a large Tunisian pedigree with high prevalence of AITDs (64 patients and 176 controls), and a case-control study (131 GD unrelated patients and 225 healthy controls). PCR and PCR-RFLP methods were used to analyse respectively a VNTR in the IL-1RN gene and three SNPs in both IL-1B genes (-511 C/T and +3954 C/T) and IL-1A (-889 C/T). The family-based association study showed an association of the IL-1B+3954 C/T polymorphism (p=0.02) and two haplotypes IL-1RN*3/C/T/T and IL-1RN*1/C/T/T (p=0.009 and p=0.047 respectively) with AITDs. The case-control study is the first study revealing a significant association of the IL-1A-889 C/T polymorphism (chi2=10.23; p=0.0014) with susceptibility to GD. Our data suggest that the IL-1 gene cluster may harbour susceptibility genes for AITDs and GD pathogenesis in the Tunisian population.

Haplotype structure of five SNPs within the ACE gene in the Tunisian population.

BACKGROUND: The Angiotensin-Converting Enzyme (ACE) is a candidate gene in the aetiology of several common diseases. The study of the haplotype structure of this gene is of interest in diagnosis and in pharmacogenomics. AIM: The study investigated the haplotype profile of single nucleotide polymorphisms (SNPs) within the ACE gene in the Tunisian population and compared it with other populations. SUBJECTS AND METHODS: Five SNPs (rs1800764, rs4291, rs4309, rs4331, rs4340) covering a region of 15.6 kb of the ACE gene were typed by PCR-digestion in a sample of 100 healthy subjects. RESULTS: All SNPs were polymorphic and in Hardy-Weinberg equilibrium. A total of 21 haplotypes were identified but only eight had a frequency of more than 1%. The four most common haplotypes had a cumulative frequency of 87.4%. The 'Yin-Yang' phenomenon (the two major haplotypes are complementary at all sites) was found. Linkage disequilibrium between all pairs of loci was highly significant (p<10-5). A simple and efficient statistical procedure was used to identify three important SNPs. CONCLUSION: The Tunisian population showed a different haplotype structure from the European one for the ACE gene and three important SNPs were identified. These will be very helpful in future association studies in the Tunisian and North African populations.