Ozlem Timirci Kahraman

Association between PTEN IVS4 polymorphism and development of colorectal cancer in a Turkish population.

Background: Phosphatase and tensin homolog (PTEN) is one of the most frequently mutated suppressor genes in human cancers. However, there are no data about the role of PTEN IVS4 polymorphism in development of colorectal cancer (CRC). The authors aimed to determine the role of PTEN IVS4 variants in the etiology of CRC. Patients and methods: A hospital-based case–control study was conducted in 203 patients with CRC (127 colon, 76 rectum) and 245 healthy controls. The frequencies of PTEN IVS4 (rs 3830675) genotypes were determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results: The (-/-) genotype of PTEN IVS4 that absence of ATCTT insertion at downstream of exon 4 in intron 4 of PTEN gene was found to be associated with 1.55-fold increased risk of colon cancer (p < 0.005; OR: 1.55, 95% CI: 1.24 – 1.94) and 1.4-fold increased risk of rectum cancer (p < 0.005; OR: 1.4, 95% CI: 1.08 – 1.82). Subgroup analyses showed that PTEN IVS4 genotypes were not associated with any clinicopathological characteristics of patients with CRC (p > 0.05). Conclusion: The (-/-) genotype of PTEN IVS4 gene might be associated with increased risk for development of CRC in a Turkish population. Further studies will clarify the exact role of PTEN IVS4 polymorphism in the etiology of CRC.

Investigation of ICAM-1 and β3 integrin gene variations in patients with brain tumors.

BACKGROUND Primary brain tumors constitute a small percent of all malignant cancers, but their etiology remains poorly understood. β3 integrin (ITGB3) has been recognized to play influential roles in angiogenesis, tumor growth and metastasis. Intercellular adhesion molecule-1 (ICAM-1) is a surface glycoprotein important for tumor invasion and angiogenesis. The aim of this study was to investigate whether specific genetic polymorphisms of ICAM-1 and ITGB3 could be associated with brain cancer development and progression in a Turkish population. Our study is the first to our knowledge to investigate the relationship between brain tumor risk and ICAM-1 and β3 integrin gene polymorphisms. MATERIALS AND METHODS The study covered 92 patients with primary brain tumors and 92 age-matched healthy control subjects. Evaluation of β3 integrin (Leu33Pro (rs5918)) and ICAM-1 (R241G (rs1799969) and K469E (rs5498)) gene polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS According to results of our research, the A allele of the ICAM-1 R241G gene polymorphism appeared to be a risk factor for primary brain tumors (p<0.001). Similarly, the frequency of the A mutant allele of ICAM-1 R241G was statistically significant in patients with brain tumors classified as glioma (p<0.001). When allele and genotype distributions of ICAM- 1 K469E, ICAM-1 R241G and β3 integrin Leu33Pro gene polymorphisms were evaluated with age, sex, and smoking, there were no statistically significant differences. Haplotype analysis revealed that the frequencies of GAC (rs1799969-rs5498-rs5918) and GAT (rs1799969-rs5498-rs5918) haplotypes were significantly lower in patients as compared with controls (p=0.001; p=0.036 respectively). CONCLUSIONS This study provides the first evidence that ICAM-1 R241G SNP significantly contributes to the risk of primary brain tumors in a Turkish population. In addition, our results suggest that ICAM-1 R241G in combination ICAM-1 K469E may have protective effects against the development of brain cancer.

Increased Gastric Cancer Risk with PTEN IVS4 Polymorphism in a Turkish Population

We aimed to investigate the association of the phosphatase and tensin homolog (PTEN) IVS4 polymorphism with a gastric cancer (GC) risk in the Turkish population. A hospital-based case-control study was conducted in 93 patients with GC, and 113 healthy controls. The PTEN IVS4 (rs no: 3830675) polymorphism was determined by using polymerase chain reaction-restriction fragment length polymorphism analysis. The PTEN IVS4 (-/-) genotype exhibited a significantly elevated risk for GC compared to controls (p<0.005; odds ratio: 1.6, 95% confidence interval: 1.19-2.14). Analyses on clinicopathological parameters showed that PTEN IVS4 genotypes were not associated with any of the variables of patients with GC (p>0.05). In conclusion, the PTEN IVS4 polymorphism might contribute to the development of GC in a Turkish population. Further studies, including comparison of the PTEN IVS4 polymorphism with plasma and tissue expressions of PTEN in larger study size groups will provide a further assessment of the PTEN IVS4 polymorphism in GC patients.

Association between Laryngeal Squamous Cell Carcinoma and Polymorphisms in Tumor Necrosis Factor Related Apoptosis Induce Ligand (TRAIL), TRAIL Receptor and sTRAIL Levels

The laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors occurring in the head and neck. Tumor necrosis factor related apoptosis induce ligand (TRAIL) and TRAIL-receptors (DR4, DR5, DcR1, DcR2) are known as important members of TRAIL-mediated biochemical signaling pathway. Associations between polymorphisms in these genes and clinicopathological characteristics of human laryngeal carcinoma are not well defined. This study therefore aimed to investigate a possible relationship among the TRAIL and TRAIL-DR4 polymorphisms and sTRAIL levels in the risk or progression of LSCC. A total of 99 patients with laryngeal cancer and 120 healthy subjects were enrolled in the study. DR4 C626G and TRAIL 1595 C/T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and sTRAIL levels were measured by ELISA. There were significant differences in the distribution of DR4 C626G genotypes and frequencies of the alleles between laryngeal cancer patients and controls (p<0.001) but not in TRAIL 1595 C/T. We found the increased frequency of the DR4 C626G homozygote CC genotype in patients than in controls (p<0.001). Haplotype analysis revealed that there was also a statistically significant relationship between TRAIL and TRAIL-DR4 polymorphisms and laryngeal cancer. Serum sTRAIL levels in the laryngeal patients with CC genotype who had advanced tumour stage were lower than those of patients with early tumor stage (p=0.014). Our findings suggest that DR4 C626G genotypes and sTRAIL levels might be associated with progression of laryngeal cancer in the Turkish population.

MCP-1 and CCR2 Gene Variants and the Risk for Osteoporosis and Osteopenia

AIM In this study, we investigated whether monocyte chemotactic protein 1 (MCP-1) and CC chemokine receptor 2 (CCR2) gene polymorphisms account for an increased risk of osteoporosis or osteopenia. METHODS Three hundred three postmenopausal women, 80 osteoporotic, 123 osteopenic, and 100 unrelated age-matched healthy controls, were included in the study. Genotyping of MCP-1 A2518G and CCR2 V64I gene polymorphisms were detected by PCR-RFLP. RESULTS We, for the first time, demonstrated the positive association of MCP-1 GG, CCR2 Val/Ile, and CCR2 Val+ genotype with osteoporosis risk. However, CCR2 Ile/Ile genotype frequencies were high in the control group compared with those of the patients with osteoporosis and osteopenia. Haplotype analysis confirmed the association of MCP-1/CCR2 gene variants with osteopenia and revealed that the frequency of MCP-1 A:CCR2 Val haplotype was significantly higher in patients when compared with controls. CONCLUSIONS In conclusion, our findings have suggested that MCP-1 and CCR2 gene variants were risk factors for osteoporosis and osteopenia.

Lack of influence of the ACE1 gene I/D polymorphism on the formation and growth of benign uterine leiomyoma in Turkish patients.

Uterine leiomyomas (ULM), are benign tumors of the smooth muscle cells of the myometrium. They represent a common health problem and are estimated to be present in 30-70% of clinically reproductive women. Abnormal angiogenesis and vascular-related growth factors have been suggested to be associated with ULM growth. The angiotensin-I converting enzyme (ACE) is related with several tumors. The aim of this study was to identify possible correlation between ULM and the ACE I/D polymorphism, to evaluate whether the ACE I/D polymorphism could be a marker for early diagnosis and prognosis. ACE I/D was amplified with specific primer sets recognizing genomic DNA from ULM (n=72) and control (n=83) volunteers and amplicons were separated on agarose gels. The observed genotype frequencies were in agreement with Hardy-Weinberg equilibrium (χ2=2.162, p=0.339). There was no association between allele frequencies and study groups (χ2=0.623; p=0.430 for ACE I allele, χ2=0.995; p=0.339 for ACE D allele). In addition, there were no significant differences between ACE I/D polymorphism genotype frequencies and ULM range in size and number (χ2=1.760; p=0.415 for fibroid size, χ2=0.342; p=0.843 for fibroid number). We conclude that the ACE gene I/D polymorphism is not related with the size or number of ULM fibroids in Turkish women. Thus it cannot be regarded as an early diagnostic parameter nor as a risk estimate for ULM predisposition.

Does DRD2 polymorphism influence the clinical characteristics of prolactinoma

OBJECTIVES Genetic alterations explaining the clinical variability of prolactinomas still could not be clarified and dopamine D2 receptor (DRD2) polymorphism is a putative candidate for the variable response to dopaminergic treatment. The present study was conducted to investigate the influence of DRD2 TaqI A polymorphism on initial and follow-up characteristics of prolactinoma. PATIENTS AND METHODS Seventy-two patients with prolactinoma and 98 age and gender matched control subjects were recruited to the case-control study. Serum prolactin levels were assessed by enzyme-linked immunosorbent assay and DRD2 polymorphism was determined by polymerase chain reaction and restriction length polymorphism analysis. RESULTS Decrease of prolactin levels and the tumor shrinkage after cabergoline treatment were 93.9±5.9% and 58.3±33.1% in microadenomas and 96.1±6.1% and 51.7±29.3 in macroadenomas (P=0.02 and P>0.05, respectively). We observed no significant difference for DRD2 genotypes and the alleles between the patients and healthy group (P>0.05). Prolactin levels before treatment were correlated with tumor diameter before and after treatment and the percentage of prolactin decrease with treatment (P<0.001 r=0.58, P<0.001 r=0.40 and P<0.001 r=0.47, respectively). Tumor diameter before the treatment was also correlated with the tumor diameter after the treatment (P<0.001 r=0.64) and the percentage of prolactin decrease (P=0.01 r=0.30). However, no significant association was found between characteristics of prolactinoma and DRD2 genotypes and alleles (P>0.05). CONCLUSION This study revealed that DRD2 TaqI A receptor polymorphism was not associated with the development of prolactinoma and its clinical characteristics. Future studies are needed to clarify the clinical implications of genetic alterations in prolactinoma.

Plasma fibrinogen-like protein 2 levels in patients with non-alcoholic fatty liver disease.

BACKGROUND/AIMS Fibrinogen-like protein 2 (fgl2), has recently been identified as a new member of the fibrinogen-like family of proteins. In this study we assayed plasma levels of fgl2 in patients with biopsy proven non-alcoholic fatty liver disease (NAFLD) and examined their association with clinical, biochemical and histological phenotypes. METHODOLOGY Levels of plasma fgl2 were measured by enzyme linked immunosorbent assay and compared between the study groups. Moreover, concentrations of fgl2 were assessed in relation to the general characteristics of the study participants and the results of the liver biopsy. RESULTS Levels of fgl2 were significantly higher in patients with definite non-alcoholic steatohepatitis (NASH) (788±190pg/mL, p<0.001) and borderline NASH (710 ± 140pg/mL, p<0.001) compared with controls (515±174pg/mL). No significant differences were found in patients with simple steatosis (649 ± 162pg/mL) as compared with controls. There were no associations between the plasma fgl2 levels with the fibrosis stage and steatosis grade. CONCLUSIONS Although subject to future confirmation, our data suggest that fgl2 levels are elevated in the more severe forms of NAFLD.

LGALS3 and AXIN1 gene variants playing role in the Wnt/β-catenin signaling pathway are associated with mucinous component and tumor size in colorectal cancer

The Wnt pathway alterations have been identified in colorectal and many other cancer types. It has been reported that galectin-3 (which is encoded by the LGALS3 gene) alters the signaling mechanism in the Wnt/β-catenin pathway by binding to β-catenin in colon and other cancers. AXIN1 is mainly responsible for the assembly of the β-catenin destruction complex in the Wnt pathway. This study investigated the relationship of rs4644 and rs4652 variants of the LGALS3 gene and rs214250 variants of the AXIN1 gene to histopathological and clinical properties. Our study included a total of 236 patients, of whom 119 had colorectal cancer (42 women, 77 men) and 117 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and allele-specific oligonucleotide (ASO) PCR methods were used. In addition, the serum galectin-3 level was studied with the enzyme-linked immunosorbent assay (ELISA) method. For the rs4644 variant of the LGALS3 gene, the CC genotype a mucinous component was significantly more common than those without a mucinous component (p=0.026). C allele frequency of the rs214250 variant of the AXIN1 gene was significantly correlated to tumor size in the advanced tumor stage (p=0.022). The CCAACT haplotype was more common in colorectal cancer patients (p=0.022). Serum galectin-3 level was higher in the patient group compared to the control group (5.9± 0.69 ng/ml vs. 0.79±0.01 ng/ml; p<0.001). In conclusion, variants of LGALS3 and AXIN1 genes affect tumor sizes and the mucinous component via Wnt/β-catenin pathway in the pathogenesis of colorectal cancer.