Genetic contribution of caspase-8 variants and haplotypes to breast cancer risk and prognosis: a case-control study in Iran.

PURPOSE: Multiple genome-wide and candidate-gene association studies have been conducted to search for common risk variants of breast cancer. Recent large meta-analyses and consolidating evidence have highlighted the role of the caspase-8 gene in breast cancer pathogenesis. Therefore, this study aimed to identify common variations and haplotypes associated with risk and overall survival of breast cancer with respect to underlying susceptibility variants in the CASP8 gene region in a group of the Iranian population. METHODS: In a case-control study with a total of 1008 samples (455 cases and 553 controls), genotyping of 12 candidate polymorphisms, consisting of rs3834129, rs2037815, rs7608692, rs12990906, rs3769821, rs6435074, rs3754934, rs3817578, rs10931936, rs1045485, rs1045487, and rs13113, were performed using PCR-based methods, including ARMS-PCR, AS-PCR, RFLP-PCR, HRM-PCR, and TaqMan-PCR. RESULTS: rs3834129, rs3754934, rs12990906, and rs10931936 were associated with the risk and overall survival of breast cancer. Several haplotypes were also identified an associated with a higher risk of breast cancer, including a three-SNP haplotype rs3817578-rs10931936-rs1045485 [p < 0.001, OR = 1.78(1.32-2.41)]. rs3754934-C allele showed an association with a lower risk of death in all patients [p = 0.022; HR = 0.46(0.23-0.89)] and in the hormone-receptor-positive group [p = 0.038; HR = 0.37(0.14-0.95)], as well as CC genotype in the hormone-receptor-positive group [p = 0.002; HR = 0.09(0.02-0.43)]. CONCLUSION: The present study suggests a diagnostic and prognostic role of CASP8 gene variations in breast cancer. The risky haplotypes are likely to have one or more underlying breast cancer susceptibility alleles. Understanding the mode of action of these alleles will aid individual-level risk prediction. It also may help identify at-risk patients to provide them with better surveillance.

Evaluating the Association between CCR5delta32 Polymorphism (rs333) and the Risk of Breast Cancer in a Cohort of Iranian Population.

BACKGROUND: CC chemokine receptor 5 (CCR5) is introduced as an immune response modulator. The activity of CCR5 influences breast tumour development in a p53-dependent manner. This study aimed to investigate the frequency of CCR5delta32 and its association with the risk of breast cancer in 1038 blood samples in North East of Iran. METHODS: In this case-control study, we genotyped 570 control samples and 468 breast cancer patients by a gel electrophoresis-based gap-polymerase chain reaction (gap-PCR) method Mashhad, Iran. The data were analyzed using the SPSS software. RESULTS: Of 570 controls included, 542 (95.09%) had CCR5delta32 wild/wild (W/W) genotype, 28 samples (4.91%) had CCR5delta32 wild/deletion (W/D) genotype and none of them were CCR5delta32 deletion/deletion (D/D) genotype (0%). While 428 samples of patients (91.45%) had CCR5delta32 W/W genotype, 40 samples (8.55%) had CCR5delta32 W/D and CCR5delta32 D/D homozygous was nil (0%) amongst cases. All samples were in the Hardy-Weinberg equilibrium (P>0.05). According to the allele frequency, D allele, as a risky allele, in the cases was more than the control samples (0.0427 vs 0.0245, respectively) (P=0.0206). Hence, W/D genotype may confer a risk effect (OR=1.77, CI: 1.09-2.90; P=0.0206) compared with WW genotype between case and control groups. CONCLUSION: There is a statistically significant association between CCR5W/D and breast cancer risk. CCR5 may be regarded as a target for the prevention of breast cancer in certain conditions such as interaction with p53 variants, which remains to be further investigated.

The Impact of CASP8 rs10931936 and rs1045485 Polymorphisms as well as the Haplotypes on Breast Cancer Risk: A Case-Control Study.

INTRODUCTION: Single nucleotide polymorphisms account for most genetic predispositions to breast cancer in the general population. Because of the lack of studies concerning the 2 common polymorphisms in caspase 8 (CASP8), namely rs104548 and rs10931936 in Iranian population, we evaluated the association of these 2 polymorphisms and their haplotypes with breast cancer and molecular profile. MATERIALS AND METHOD: Blood samples were collected from 287 breast cancer patients and 490 controls. Genotyping of rs1045485 and rs10931936 was conducted using an amplification refractory mutation system and polymerase chain reaction restriction fragment length polymorphism, respectively. PHASE version 2 (Matthew Stephens) was used to estimate the frequencies of haplotypes. Statistical analysis was performed using SPSS 16.0 (SPSS Inc). RESULTS: Although hormone receptors and the molecular profile did not indicate any significant association with different genotypes (P > .05), patients with CC genotype of rs1045485 were more likely to have HER2-positive breast cancer than those with GG genotype (odds ratio [OR], 2.93; 95% confidence interval [CI], 1.0 4-8.26). In addition, CC genotype of D302H was associated with a decreased risk of breast cancer to 48% (OR, 0.52; 95% CI, 0.30-0.90) whereas no significant association was found between rs10931936 and breast cancer. Haplotype analysis indicated C-C haplotype is associated with the decreased risk of breast cancer (OR, 0.69; 95% CI, 0.52-0.91). CONCLUSION: Our data showed a protective effect for CC genotype of rs1045485 variant and C-C haplotype of rs10931936-rs104548 in CASP8 in association with the decrease risk of breast cancer whereas rs10931936 showed no significant association. CASP8 rs1045485 polymorphism might be a candidate genetic marker to evaluate risk of breast cancer. However, further larger studies can confirm such findings.

Autologous Bone Marrow Stem Cell Transplantation in Liver Cirrhosis after Correcting Nutritional Anomalies, A Controlled Clinical Study.

OBJECTIVE: Liver transplantation is the gold standard approach for decompensated liver cirrhosis. In recent years, stem cell therapy has raised hopes that adjusting some clinical and laboratory parameters could lead to successful treatments for this disease. Cirrhotic patients may have multiple systemic abnormalities in peripheral blood and irregular cell populations in bone marrow (BM). Correcting these abnormalities before BM aspiration may improve the effectiveness of cell-based therapy of liver cirrhosis. MATERIALS AND METHODS: In this controlled clinical trial study, 20 patients with decompensated liver cirrhosis were enrolled. Patients were randomly assigned to control and experimental groups. Blood samples were obtained to measure vitamin B12, folate, serum iron, total iron bonding capacity (TIBC) and ferritin before any intervention. Furthermore, the iron storage and fibrosis level in BM biopsies, as well as the percentage of different cell populations, were evaluated. Prior to cell isolation for transplantation, we performed palliative supplement therapy followed by a correction of nutritional deficiencies. Mononuclear cells (MNCs) were then isolated from BM aspirates and transfused through peripheral vein in patients in the experimental group. The model of end-stage liver disease (MELD) score, The international normalized ratio (INR), serum albumin and bilirubin levels were assessed at 0 (baseline), 3 and 6 months after cell transplantation. RESULTS: The MELD score (P=0.0001), INR (P=0.012), bilirubin (P<0.0001) and total albumin (P<0.0001) levels improved significantly in the experimental group after cell transplantation compared to the baseline and control groups. Moreover, the increase in serum albumin levels of patients in the experimental group was statistically significant 6 months after transplantation. CONCLUSION: We have successfully improved the conditions of preparing -BM-derived stem cells for transplantation. Although these cells are relatively safe and have been shown to improve some clinical signs and symptoms temporarily, there need to be more basic studies regarding the preparation steps for effective clinical use (Registration number: IRCT2014091919217N1).

Significant association of TOX3/LOC643714 locus-rs3803662 and breast cancer risk in a cohort of Iranian population.

Genome-wide association studies normally focus on low penetrance and moderate to high-frequency single nucleotide polymorphisms (SNPs), which lead to genetic susceptibility to breast cancer. In this regard, the T allele of rs3803662 has been associated with breast cancer risk and with lower expression level of TOX3. We aimed to assess the risk of breast cancer associated with this polymorphism in an Iranian population. Using Tetra Primer ARMS PCR, rs3803662 was analyzed in a total of 943 individuals (430 cases and 513 healthy controls form North East of Iran). Allele frequencies and genotype distribution were analyzed in case and control samples to find out any association using the Chi-squared test and Logistic regression. All cases were pathologically confirmed; all controls were mainly healthy individuals. Genotype frequencies were found to be in agreement with HWE in controls and cases. TOX3-rs3803662 SNP was associated with breast cancer risk in our study (T vs. C allele contrast model: OR 1.36, 95% CI 1.12-1.64, Pvalue = 0.002; TT vs. CT + TT dominant model: OR 0.67, 95% CI 0.51-0.87, Pvalue = 0.003; TT vs. CT + CC recessive model: OR 1.54, 95% CI 1.02-2.30, Pvlue = 0.036). Moreover, after adjusting for age, BMI, history of previous cancer and also family history of cancer, all results, except for the recessive model, were remained significant. TOX3-rs3803662, may confer some degrees of risk of breast cancer in Iranian population. This finding is in line with similar results in other populations. It highlights the importance of TOX3 pathway in tumorigenesis.

Hereditary breast cancer; Genetic penetrance and current status with BRCA.

The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D. Many BC susceptibility genes can be grouped into two classes, high- and low-penetrance genes, each of which interact with multiple genes and environmental factors. However, the penetrance of genes can also be represented by a spectrum, which ranges between high and low. Two of the most common susceptibility genes are BRCA1 and BRCA2, which perform vital cellular functions for repair of homologous DNA. Loss of heterozygosity accompanied by hereditary mutations in BRCA1 or BRCA2 increases chromosomal instability and the likelihood of cancer, as well as playing a key role in stimulating malignant transformation. With regard to pathological features, familial breast cancers caused by BRCA1 mutations usually differ from those caused by BRCA2 mutations and nonfamilial BCs. It is essential to acquire an understanding of these pathological features along with the genetic history of the patient to offer an individualized treatment. Germline mutations in BRCA1 and BRCA2 genes are the main genetic and inherited factors for breast and ovarian cancer. In fact, these mutations are very important in developing early onset and increasing the risk of familial breast and ovarian cancer and responsible for 90% of hereditary BC cases. Therefore, according to the conducted studies, screening of BRCA1 and BRCA2 genes is recommended as an important marker for early detection of all patients with breast or ovarian cancer risk with family history of the disease. In this review, we summarize the role of hereditary genes, mainly BRCA1 and BRCA2, in BC.

Effect of a functional food (vegetable soup) on blood rheology in patients with polycythemia.

OBJECTIVE: Key hemorheological variables are associated with several life-threatening diseases including cardio-cerebro-vascular diseases. A diet can influence the blood rheological variables. To compare the effectiveness of a vegetable soup on blood viscosity (BV), hematocrit (Hct), plasma fibrinogen, lipid profile, fasting blood sugar (FBS), and blood osmolarity in patients with polycythemia in comparison to a control group. MATERIALS AND METHODS: This randomized controlled trial study was conducted at Isar health clinics in Mashhad, Iran, during a 7-month period. Forty male participants (35 to 60 years old) with polycythemia, but without underlying diseases, were included. They randomly assigned to two groups and either received diet/phlebotomy or phlebotomy alone, for 6 weeks. The data were analyzed by SPSS version 16 using parametric tests. RESULTS: A significant reduction in BV at 30s (p ≤ 0.001), BV at 40s (p ≤ 0.001), BV at 50s (p ≤ 0.001), Hct (p ≤ 0.001), plasma fibrinogen (p ≤ 0.001), total cholesterol (p<0.01), LDL-cholesterol (p<0.01), VLDL-cholesterol (p ≤ 0.001), HDL-cholesterol (p ≤ 0.01), osmolarity (p ≤ 0.001), and FBS (p ≤ 0.001) was observed in diet recipients. Following the intervention, there was a significant decrease in triglyceride (intervention group, p<0.05; control group, p<0.05), in both groups. CONCLUSION: This trial showed that the plant-based food used in this study could improve blood rheology.

A Randomized Placebo- Controlled Double Blind Clinical Trial of Quercetin in the Prevention and Treatment of Chemotherapy-Induced Oral Mucositis.

INTRODUCTION: Oral Mucositis (OM) is a serious complication of chemotherapy that results in painful debilitating inflammation that sometimes ends in interruption of treatment. AIM: The study evaluated the effect of quercetin (a natural flavonoid) on preventing and treating chemotherapy induced OM in patients with blood malignancies. Materials and Methods: This double-blind, placebo controlled randomized trial was carried out on 20 adult patients who underwent high dose chemotherapy for blood malignancies. Patients were divided into two groups (10 patients in the intervention group and 10 patients in the control group). Patients in the intervention group were administered 250 mg quercetin capsules twice daily for four weeks. RESULTS: Nine out of 20 patients developed OM (three in the intervention group and six in the control group). The incidence of OM was lower in the intervention group although it was not statistically significant (p=0.189). The mean severity of OM was higher in the intervention group (2.6 vs 2). Healing time, age, gender, type of malignancy, drug type and duration of OM were not different in two groups. CONCLUSION: The incidence of mucositis was lower in the quercetin group, but mucositis was more severe in the intervention group, which may be due to lower oral health status in the intervention group.

Lack of KRAS gene mutations in chronic myeloid leukemia in Iran.

BACKGROUND: The single most common proto-oncogene change in human neoplasms is a point mutation in RAS genes. A wide range of variation in frequency of KRAS mutations has been seen in hematologic malignancies. Despite this, RAS roles in leukemogenesis remain unclear. The frequency of KRAS mutations in CML has been reported to be between zero an 10%. Many attempts have been done to develop an anti-RAS drug as a therapeutic target. . MATERIALS AND METHODS: This cross sectional study was performed in Mashhad University of Medical Sciences, Mashhad, Iran from 2010-2012. In 78 CML patients (diagnosed according to WHO 2008 criteria) in chronic or accelerated phases, KRAS mutations in codons 12 and 13 were analyzed using a modified PCR- restriction fragment length polymorphism (RFLP) method. RESULTS: We did not detect any KRAS mutations in this study. CONCLUSIONS: KRAS mutations are overall rare in early phase CML and might be secondary events happening late in leukemogenesis cooperating with initial genetic lesions.

Genes and SNPs associated with non-hereditary and hereditary colorectal cancer.

BACKGROUND: Colorectal cancer is the third most common cancer in both men and women in the world and the second leading cause of cancer-related deaths. The incidence of colorectal cancer has increased in Iran in the past three decades and is now considered as a serious problem for our society. This cancer has two types hereditary and non-hereditary, 80% of cases being the latter. Considering that the relationship between SNPs with diseases is a concern, many researchers believed that they offer valuable markers for identifying genes responsible for susceptibility to common diseases. In some cases, they are direct causes of human disease. One SNP can increase risk of cancer, but when considering the rate of overlap and frequency of DNA repair pathways, it might be expected that SNP alone cannot affect the final result of cancer, although several SNPs together can exert a significant influence. Therefore identification of these SNPs is very important. The most important loci which include mutations are: MLH1, MSH2, PMS2, APC, MUTYH, SMAD7, STK11, XRCC3, DNMT1, MTHFR, Exo1, XRCC1 and VDR. Presence of SNPs in these genes decreases or increases risk of colorectal cancer. MATERIALS AND METHODS: In this article we reviewed the Genes and SNPs associated with non-hereditary and hereditary of colorectal cancer that recently were reported from candidate gene y, meta-analysis and GWAS studies. RESULTS: As with other cancers, colorectal cancer is associated with SNPs in gene loci. Generally, by exploring SNPs, it is feasible to predict the risk of developing colorectal cancer and thus establishing proper preventive measures. CONCLUSIONS: SNPs of genes associated with colorectal cancer can be used as a marker SNP panel as a potential tool for improving cancer diagnosis and treatment planning.

Identification of germline BRCA1 mutations among breast cancer families in Northeastern Iran.

BACKGROUND: The purpose of this study was to evaluate the prevalence of BRCA1 (MIM: 113705) founder mutations in familial breast cancer (BC) patients with high risks in Iran. BRCA1 is among the cancer susceptibility genes best known for high penetrance mutations. BRCA1 genotyping is now used to determine patient counseling, management decisions, and prognosis of this syndrome. MATERIALS AND METHOD: Thirty nine patients with clinical BC and 29 high risk healthy women, related to the patients, participated in the study. DNA from blood samples was extracted and analyzed by PCR and SSCP methods in order to find 185delAG and 5382insC founder mutations. In addition, a 251bp fragment of BRCA1's exon 11 was amplified and analyzed for determination of new mutations. RESULTS: The data indicated the presence of 185delAG and 5382insC founder mutations in both groups studied. Two out of 39 BC patients (5.1%) and one out of 29 relatives (3.4%) were suspected to be carriers of 185delAG mutations. However, we found only one patient (2.6%) to be a carrier of a 5382insC mutation. Also, 2 women (5.1%) of the patient group and 3 n (10.3%) of relatives group were identified as carriers of unclarified mutations in the 251bp fragment of the BRCA1 gene. The carriers of BRCA1 founder mutations have a high lifetime risk of breast cancer. CONCLUSIONS: Therefore, these data are useful in counseling of individuals with a significant family history of breast cancer.