Association between Vitamin D Receptor Polymorphism and Susceptibility to Oral Lichen Planus and Oral Squamous Cell Carcinoma.

Introduction: Oral squamous cell carcinomas (OSCC) comprise 90-95% of oral cancers. Early diagnosis improved the survival rate of OSCC patients to 80-90%. Oral lichen planus (OLP) is a chorionic inflammatory disease with malignancy potential. The vitamin D receptor (VDR) plays a critical role in the pathogenesis of oral cancer. This study aimed to determine the association between VDR rs7975232 (Apa I) polymorphism and potential susceptibility to OLP and OSCC risks. Materials and Methods: In this prospective case-control study, a total of 120 blood samples were obtained from OSCC patients (n=29), OLP (n=50), and controls (n=40). VDR rs7975232 polymorphism was studied using the Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) method. Statistical analysis was performed with SPSS Version 23 software. Data were expressed as means ± standard deviation (SD). Age, sex, allelic frequency, and genotyping were compared using the chi-square test. A p-value of less than 0.05 was regarded as statistically significant. The disease risk was estimated by Odds ratio (OR) with a 95% confidence interval. Results: A significant age difference was observed between the controls and the OSCC group (p=0.001). A significant difference was observed in Aa and aa genotypes compared with AA between OSCCs and controls. Moreover, dominant (p<0.001), additive (p<0.001), and allelic (p=0.001) models were different between groups. Conclusion: There was a positive association between rs7975232 VDR polymorphism and susceptibility to OSCC. More experimental evidence must reveal the possible association between rs7975232 and the risk of OLP in a larger cohort.

Potential Role of Zinc Finger 365 rs10822013 and rs10995190 in Mammographic Density, Sporadic Breast Cancer Risk, and Prognosis.

Background: Despite suggesting many genetic risk markers as the outcome of Genome-wide association studies (GWAS) for breast cancer, replicating the results in different populations has remained the main issue. In this regard, this study assessed the association of two variations in Zinc Finger 365 (ZNF365) in an Iranian population. Methods: In a case-control study conducted at Mashhad University of Medical Sciences, Mashhad, Iran, between 2017 and 2020, ZNF365-rs10822013 and rs10995190 were genotyped using Allele-Specific PCR (AS-PCR). Breast density was assessed using mammography images. PHASE software module version 2 and SPSS version 16.0 were used for haplotype and statistical analyses. Quantitative and qualitative variables were compared between groups using independent t tests and Chi square tests, respectively. Binary logistic regression analysis was performed to calculate odds ratios. Multivariate analysis was then undertaken for the baseline variables, with a P<0.05 in the univariate analysis. The survival analysis was performed using the Kaplan-Meier method and the log-rank test. Results: In this survey, 732 females, including 342 breast cancer patients and 390 healthy subjects, were enrolled. rs10822013-T allele (P=0.014), rs10995190-G allele (P=0.003), and TG haplotype (P=0.002) were significantly associated with the increased risk of breast cancer. Moreover, rs10995190-GG genotype (P=0.042) and C-G haplotype (P=0.019) revealed a significant association with better overall survival. However, considered polymorphisms and their haplotypes indicated no association with breast density and clinical features of breast cancer. Conclusion: ZNF365 variants might be a potential risk marker of breast cancer in the Iranian population. The interaction between alleles in haplotypes may modulate the amount of the risk conferred by these variants. Further studies on different ethnic groups can validate these results.

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.

Genetic architecture of mammographic density as a risk factor for breast cancer: a systematic review.

BACKGROUND: Mammography Density (MD) is a potential risk marker that is influenced by genetic polymorphisms and can subsequently modulate the risk of breast cancer. This qualitative systematic review summarizes the genes and biological pathways involved in breast density and discusses the potential clinical implications in view of the genetic risk profile for breast density. METHODS: The terms related to "Common genetic variations" and "Breast density" were searched in Scopus, PubMed, and Web of Science databases. Gene pathways analysis and assessment of protein interactions were also performed. RESULTS: Eighty-six studies including 111 genes, reported a significant association between mammographic density in different populations. ESR1, IGF1, IGFBP3, and ZNF365 were the most prevalent genes. Moreover, estrogen metabolism, signal transduction, and prolactin signaling pathways were significantly related to the associated genes. Mammography density was an associated phenotype, and eight out of 111 genes, including COMT, CYP19A1, CYP1B1, ESR1, IGF1, IGFBP1, IGFBP3, and LSP1, were modifiers of this trait. CONCLUSION: Genes involved in developmental processes and the evolution of secondary sexual traits play an important role in determining mammographic density. Due to the effect of breast tissue density on the risk of breast cancer, these genes may also be associated with breast cancer risk.

2q35-rs13387042 variant and the risk of breast cancer: a case-control study.

BACKGROUND: Breast Cancer is the most frequent neoplasm diagnosed among women worldwide. Genetic background and lifestyle/environment play a significant role in the disease etiology. According to Genome-wide association studies, some single-nucleotide polymorphisms such as 2q35-rs13387042-(G/A) have been introduced to be associated with breast cancer risk and features. In this study, we aimed to evaluate the association between this variant and the risk of breast cancer in a cohort of Iranian women. METHODS: Demographics and clinical information were collected by interview and using patients' medical records, respectively. DNA was extracted from 506 blood samples, including 184 patients and 322 controls, and genotyping was performed using allele specific-PCR. SPSS v16 was used for statistical analysis. RESULT: Statistically significant association was observed between AA genotype and disease risk in all patients [padj = 0.048; ORadj = 2.13, 95% CI (1.01-4.50)] and also ER-positive breast cancers [padj = 0.015; ORadj = 2.12, 95% CI (1.16-3.88)]. There was no association between rs13387042 and histopathological characteristics of the disease. Furthermore, overall survival was not statistically associated with genotype and allelic models even after adjustment for stage and receptor status (p > 0.05). CONCLUSION: There is a statistically significant association between 2q35-rs13387042 and breast cancer risk. rs13387042-AA genotype might be a risk-conferring factor for breast cancer development in the Iranian population. However, further consideration is suggested to confirm its role in risk assessment and probable association with other genetic markers.

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.

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 CYP19A1 variants and haplotypes on breast cancer risk, clinicopathological features and prognosis.

BACKGROUND: Different genetic variants in hormone-regulating pathways have been identified to influence the risk of breast cancer. This study aimed to evaluate the association of CYP19A1 rs10046 and rs700519 polymorphisms with the risk, clinicopathological factors and prognosis of breast cancer. METHODS: In a case-control study, rs10046 and rs700519 polymorphisms were genotyped using ARMS-PCR and high-resolution melting (HRM), respectively, in a total of 702 females. Statistical analysis and evaluation of haplotypes and linkage disequilibrium were performed using SPSS v16, PHASE and 2LD. RESULTS: Although no association of rs700519 with breast cancer was observed, rs10046 in different genetic models as well as C-C/C-T and C-C/C-C diplotypes, revealed the association with the risk of breast cancer (p < 0.05). Moreover, the rs700519-C allele was shown to be associated with longer overall survival. In contrast, the T-T haplotype conferred s a shorter overall survival. rs700519-C allele was also significantly associated with menarche age. CONCLUSION: Based on the identified independent association between CYP19A1 diplotypes and rs700519-C allele with the risk and prognosis of the disease, the gene region and its genetic variants may have a diagnostic and prognostic role in breast cancer development. Further confirmation using other variants in this locus can validate these findings.

GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients.

The effect of somatic mutations and the gene expression profiles on the prognosis is well documented in cancer research. This study was conducted to evaluate the association of GATA3 somatic mutations with tumor features, survival, and expression profiles in breast cancer. Clinicopathological information was compared between TCGA-BRCA patients with GATA3-mutant and non-mutant tumors in all patients as well as in ER-positive subgroup. Cox-regression method was used to evaluate the association of the GATA3 mutation status with overall survival time. Differential gene expression, functional annotation, and protein-protein interaction analyses were performed using edgeR, Metascape, DAVID, STRING and CytoNCA. GATA3-mutant and non-mutant samples had significantly different clinicopathological features (p < 0.05). While GATA3 mutation status was not associated with the overall survival in the entire cohort (padj = 0.52), the GATA3-wild type ER-positive cases had a better prognosis than mutant ones (padj = 0.04). GATA3 expression was higher in tumors than normal tissues. Several pathways were different between mutant and non-mutant groups (p < 0.05). Interleukin-6 was found as the highest scored gene in both comparisons (normal vs. mutant and normal vs. non-mutant groups) in the entire patient and in the ER-positive subgroup, suggesting the association of IL6 with breast tumorigenesis. These findings suggest that GATA3 mutations can be associated with several tumor characteristics and influence the pattern of gene expression. However, GATA3 mutation status seems to be a prognostic factor for the disease only in ER-positive patients.

ESR1 gene variants, haplotypes and diplotypes may influence the risk of breast cancer and mammographic density.

Breast cancer as the most common cancer worldwide is influenced by genetic and physiological factors. Based on some evidence indicating the role of estrogen receptor 1 gene (ESR1) in breast cancer development, in this study, the association of three common variations in ESR1 gene with breast cancer and density in an Iranian population was evaluated. In a case-control study, 400 blood samples were collected for DNA extraction and genotyping. Breast density was assessed using mammography. ESR1 rs6915267 (G/A), rs2077647 (C/T) and rs1801132 (C/G) were genotyped using ARMS-PCR method. PHASE program was used to estimate the haplotypes frequencies. Our data analysis showed rs6915267 GA genotype in the heterozygous (GA) as well as co-dominant models was associated with lower mammographic density. None of the three variations were associated with the breast cancer risk. Haplotype analysis indicated G-T-C haplotype of rs6915267, rs2077647 and rs1801132 [OR = 0.54, 95% CI (0.31-0.92), p = 0.025] and G-T/G-T diplotype of rs6915267-rs2077647 [OR = 0.38, 95% CI (0.17-0.86), p = 0.019] were associated with a decreased risk of breast cancer. ESR1 may affect density of the breast and its haplotypes may modulate breast cancer risk.

The Dilemma of TP53 Codon 72 Polymorphism (rs1042522) and Breast Cancer Risk: A Case-Control Study and Meta-Analysis in The Iranian Population.

OBJECTIVE: Mutations of TP53 as a tumor suppressor gene are frequently observed in different types of cancer. A codon 72 polymorphism located on exon 4 with two alleles encoding either Proline (CCC) or Arginine (CGC) has been indicated as a common variation in association with cancers. Controversial results have been reported regarding the association of allelic polymorphism of codon 72 of TP53 gene and breast cancer risk in Iranian patients. Therefore, a case-control study was designed. A meta-analysis was also carried out to provide evidence of association between this variation and breast cancer in Iran, based on all available published data. MATERIALS AND METHODS: In this case-control study, blood sample of 622 participants, including 308 breast cancer cases and 314 controls were collected. Genotyping for rs1042522 was conducted by Allele Specific polymerase chain reaction (AS-PCR). In order to set a meta-analysis study, PubMed, Scopus and ISI Web of Knowledge and Persian databases were searched to explore relevant studies, published up to September 2018, containing information on TP53 polymorphism and the risk of breast cancer in Iran. Statistical analysis was performed using SPSS 16.0 and MetaGenyo. RESULTS: All retrieved available data as well as the results of our current study were consisted of 1965 breast cancer cases and 1999 healthy controls. No significant difference was observed in allele frequencies between groups (P=0.90) in our study. The cumulative results did not also show any association between rs1042522 and breast cancer risk on the dominant (P=0.61) and recessive (P=0.89) models. CONCLUSION: These findings cannot support contribution of rs1042522 polymorphism to breast cancer risk in an Iranian population. Future larger studies may help confirm this finding with a greater power.

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.

Association of caspase 8 promoter variants and haplotypes with the risk of breast cancer and its molecular profile in an Iranian population: A case-control study.

Caspase 8 (CASP8) gene plays a key role in the regulation of apoptotic cell death. Expression variation in this gene has been associated with the risk of breast cancer. The aim of this study was to investigate the association of rs3834129 and rs3769821, as functional variants, and their haplotypes with molecular profile as well as the risk of breast cancer in an Iranian population. A case-control study was conducted on 812 participants including 293 breast cancer patients and 519 healthy controls. Genotyping was performed by polymerase chain reaction-based methods. Statistical analysis was performed using SPSS Ver16. The association between polymorphisms and haplotypes with the risk of breast cancer was estimated by calculating odds ratios (OR) and chi-square (χ2 ) tests. In comparison with ins allele (I) of rs3834129, carriers of del allele (D) showed a lower risk of breast cancer (OR, 0.65; 95% confidence interval [CI], 0.49-0.87; P = 0.004). The multivariate logistic regression model indicated DD genotype as an independent factor for a decreased risk of breast cancer in our population (OR, 0.18; 95% CI, 0.06-0.58; P = 0.004). Also, the C allele of rs3769821 was associated with a 43% increased risk of breast cancer (P = 0.005); however, after adjustment for confounding factors, no association with rs3769821 and breast cancer was observed. In addition, D-T haplotype and diplotype presented protective effects (P < 0.05). Our results indicate that genetic variations in the promoter region of CASP8 gene, especially rs3834129, may serve as a genetic risk factor for breast cancer in an Iranian population.

Targeted therapies in pancreatic cancer: Promises and failures.

Pancreatic ductal adenocarcinoma (PDAC) is an incidence rate nearly equal to its mortality rate. The poor prognosis of the disease can be explained by the absence of effective biomarkers for screening and early detection, together with the aggressive behavior and resistance to the currently available chemotherapy. The therapeutic failure can also be attributed to the inter-/intratumor genetic heterogeneity and the abundance of tumor stroma that occupies the majority of the tumor mass. Gemcitabine is used in the treatment of PDAC; however, the response rate is less than 12%. A recent phase III trial revealed that the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin could be an option for the treatment of metastatic PDAC patients with good performance status, although these approaches can result in high toxicity level. Further investigations are required to develop innovative anticancer agents that either improve gemcitabine activity, within novel combinatorial approaches or acts with a better efficacy than gemcitabine. The aim of the current review is to give an overview of preclinical and clinical studies targeting key dysregulated signaling pathways in PDAC.

Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives.

Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to stimulate breast cancer cell growth and metastasis via tyrosine kinase receptors TrkA, TrkB, and the p75NTR death receptor. The aberrant activation of BDNF/TrkB pathways can modulate several signaling pathways, including Akt/PI3K, Jak/STAT, NF-kB, UPAR/UPA, Wnt/ß-catenin, and VEGF pathways as well as the ER receptor. Several microRNAs have been identified that are involved in the modulation of BDNF/TrkB pathways. These include miR-206, miR-204, MiR-200a/c, MiR-210, MiR-134, and MiR-191; and these may be of value as prognostic and predictive biomarkers for detecting patients at high risk of developing breast cancer. It has been also been demonstrated that a high expression of genes involved in the BDNF pathway in breast cancer is associated with poor clinical outcome and reduced survival of patients. Several approaches have been developed for targeting this pathway, for example TKr inhibitors (AZD6918, CEP-701) and RNA interference. The aim of the current review was to provide an overview of the role of BDNF/TrkB pathways in the pathogenesis of breast cancer and its value as a potential therapeutic target. J. Cell. Biochem. 118: 2502-2515, 2017. © 2017 Wiley Periodicals, Inc.

Ki67 Frequency in Breast Cancers without Axillary Lymph Node Involvement and its Relation with Disease-free Survival.

BACKGROUND: Breast cancer prognosis is influenced by several histopathology and clinical factors including expression of Ki67 which may have a predictive role in lymph node negative breast cancer patients. The aim of this study was to assess Ki67 expression in breast cancers without axillary lymph node involvement and to evaluate its prognostic value with regard to disease-free survival. MATERIALS AND METHODS: Subjects were selected from non-metastatic invasive breast cancer patients who were referred to the oncology department of Ghaem hospital during 1 April 2001 to 1 April 2008. Ki67 levels were measured using immunohistochemistry (IHC) and compared with clinicopathological features. The relation of Ki67 expression with disease-free survival was also analysed. RESULTS: A total of 106 women with a mean age of 49 were examined. Some 94.3% were classified as having invasive ductal carcinomas and the mean tumour diameter at the time of diagnosis was 2.8 cm. Some 50.9% of cases were ER positive and 47.2% were PR positive. P53 expression was positive in 48.1% of the cases. According to the IHC results, only 8.5% of the patients were Her2/neu positive. Ki67 was positive in 66 (62.3%) with a significant relation to lower age (p=0.0229) and P53 positivity (p=0.005). After an average of 40-months follow up, 13 (12.3%) demonstrated recurrence, most commonly systemic. Of 13 cases with relapse, 10 patients (77%) were Ki67 positive. CONCLUSIONS: In our population Ki67 appeared to be an independent prognostic factor for three-year survival. However, we stress that a survival study with a bigger sample size would help to support this conclusion.