The Role of DNA Repair (XPC, XPD, XPF, and XPG) Gene Polymorphisms in the Development of Myeloproliferative Neoplasms.

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15-2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42-0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19-0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development.

Analysis of Mutational Status of IGHV, and Cytokine Polymorphisms as Prognostic Factors in Chronic Lymphocytic Leukemia: The Romanian Experience.

The aim of the current study was to assess the associations between genetic risk factors (such as the mutational status of the IGHV gene and polymorphisms of the IL-10 and TNF-α genes) and CLL risk, prognosis, and overall survival. Another goal of this study was to evaluate the multivariate effect of the combination of multiple genetic risk factors (mutational status of the IGHV gene, somatic mutations, DNA CNVs, and cytokine SNPs) on the clinical characteristics and survival of patients. A total of 125 CLL patients and 239 healthy controls were included for comparative SNP analysis. IL-10 (rs1800896 and rs1800872) and TNF-α (rs361525 and rs1800750) SNPs and haplotypes were not associated with CLL risk. The absence of hypermutation in the IGHV gene was shown to be of important prognostic value, being associated with short OS. Further individual risk factors for short OS were an age above 65 years at diagnosis and the presence of somatic mutations and/or CNVs. In our multivariable analysis, the presence of somatic mutations and the IL-10 rs1800872 variant allele, and the association of CNVs with the IL-10 rs1800896 variant allele, were identified as risk factors for short OS. Moreover, the OS in unmutated IGHV patients was additionally affected (decreased) by the presence of CNVs and/or somatic mutations. Similarly, IL-10 rs1800896 modulated the OS in unmutated IGHV patients with CNVs.

Impact of BRAFV600E Mutation on Event-Free Survival in Patients with Papillary Thyroid Carcinoma: A Retrospective Study in a Romanian Population.

We aimed to evaluate the prognostic value of BRAFV600E mutation in a series of 127 papillary thyroid carcinoma (PTC) cases as a single factor, and in synergic interaction with other standard risk factors. BRAFV600E mutation was assessed by real-time PCR. Event-free survival (EFS) was calculated between the date of the first evaluation and the date of occurrence of an adverse event or the date of the last known status. The prevalence of BRAFV600E mutation was 57.2%. The Kaplan-Meier analysis showed a significant reduction of EFS among cases harboring BRAFV600E mutation compared to non-mutated cases (p = 0.010). In addition, BRAFV600E mutation was found to better predict adverse outcomes when associated with the following risk factors: age ≥ 55 years old (p < 0.001), male gender (p < 0.001), conventional (p = 0.005) and tall cell (p = 0.014) histology, tumor size > 40 mm (p = 0.001), extrathyroidal extension (p = 0.001), multifocality (p = 0.001) and lymph node metastasis (p < 0.001). In univariate analysis, a 3.74-fold increased risk for a reduced EFS (p = 0.018) was found for BRAFV600E-mutated cases, but no increased risk was further confirmed by multivariate analysis. Our results highlight that BRAFV600E mutation cannot be used alone as an independent predictive factor in PTC patients, but is prognostically valuable if integrated in the context of other clinicopathological risk factors.

Copy Number Variations and Gene Mutations Identified by Multiplex Ligation-Dependent Probe Amplification in Romanian Chronic Lymphocytic Leukemia Patients.

Chronic lymphocytic leukemia (CLL) is known for its wide-ranging clinical and genetic diversity. The study aimed to assess the associations between copy number variations (CNVs) and various biological and clinical features, as well as the survival rates of CLL patients and to evaluate the effectiveness of the multiplex ligation-dependent probe amplification (MLPA) technique in CLL patients.DNA was extracted from 110 patients, and MLPA was performed. Mutations in NOTCH1, SF3B1, and MYD88 were also analyzed. A total of 52 patients showed at least one CNV, 26 had at least one somatic mutation, and 10 presented both, CNVs, and somatic mutations. The most commonly identified CNVs were del(114.3), del(11q22.3), and dup(12q23.2). Other CNVs identified included del(17p13.1), del(14q32.33), dup(10q23.31), and del(19p13.2). One patient was identified with concomitant trisomy 12, 13, and 19. NOTCH1 and SF3B1 mutations were found in 13 patients each, either alone or in combination with other mutations or CNVs, while MYD88 mutation was identified in one patient. Forty-two patients had normal results. Associations between the investigated CNVs and gene mutations and patients' overall survival were found. The presence of NOTCH1 and SF3B1 mutations or the combination of NOTCH1 mutation and CNVs significantly influenced the survival of patients with CLL. Both mutations are frequently associated with different CNVs. Del(13q) is associated with the longest survival rate, while the shortest survival is found in patients with del(17p). Even if MLPA has constraints, it may be used as the primary routine analysis in patients with CLL.

The Role of Galectin-3 in Predicting Congenital Heart Disease Outcome: A Review of the Literature.

Galectin-3 (Gal-3) is a novel pro-fibrotic biomarker that can predict both right and left cardiac dysfunction caused by various cardiovascular conditions. Its expression seems to be progressively altered with evolving cardiac remodeling processes, even before the onset of heart failure. Hence, Gal-3 has been found to be an individual predictor of acute and chronic heart failure or to serve as part of an integrated biomarker panel that can foresee adverse cardiac outcomes. In congenital heart disease (CHD), Gal-3 correlates with cardiac mortality and complications in both children and adults and is proposed as a therapeutic target in order to reverse the activation of pro-fibrosis pathways that lead to heart failure. Positive associations between serum Gal-3 levels, post-operatory hospitalization rates, complications and ventricular dysfunction have also been reported within studies conducted on patients with CHD who underwent corrective surgery. Thus, this review tried to address the potential utility of Gal-3 in patients with CHD and particularly in those who undergo corrective surgery. The heterogeneity of the literature data and the lack of validation of the results obtained by the current studies on larger cohorts cannot be neglected, though. Further longitudinal research is required to establish how Gal-3 can relate to long-term outcomes in pediatric CHD.

Role of salivary miRNAs in the diagnosis of gastrointestinal disorders: a mini-review of available evidence.

MiRNAs are short, non-coding RNA molecules, which are involved in the regulation of gene expression and which play an important role in various biological processes, including inflammation and cell cycle regulation. The possibility of detecting their extracellular expression, within body fluids, represented the main background for their potential use as non-invasive biomarkers of various diseases. Salivary miRNAs particularly gained interest recently due to the facile collection of stimulated/unstimulated saliva and their stability among healthy subjects. Furthermore, miRNAs seem to represent biomarker candidates of gastrointestinal disorders, with miRNA-based therapeutics showing great potential in those conditions. This review aimed to highlight available evidence on the role of salivary miRNAs in different gastrointestinal conditions. Most salivary-based miRNA studies available in the literature that focused on pathologies of the gastrointestinal tract have so far been conducted on pancreatic cancer patients and delivered reliable results. A few studies also showed the diagnostic utility of salivary miRNAs in conditions such as esophagitis, esophageal cancer, colorectal cancer, or inflammatory bowel disease. Moreover, several authors showed that salivary miRNAs may confidently be used as biomarkers of gastric cancer, but the use of salivary miRNA candidates in gastric inflammation and pre-malignant lesions, essential stages of Correa's cascade, is still put into question. On the other hand, besides miRNAs, other salivary omics have shown biomarker potential in gastro-intestinal conditions. The limited available data suggest that salivary miRNAs may represent reliable biomarker candidates for gastrointestinal conditions. However, their diagnostic potential requires validation through future research, performed on larger cohorts.

The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia.

Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed.

Helicobacter pylori-Positive Gastric Biopsies-Association with Clinical Predictors.

Introduction: Although Helicobacter pylori's role in gastric oncogenesis is well-known, only a fraction of infected patients develop cancer. Hence, more factors are supposed to be involved. The objectives of the present study were to investigate the impact of clinicopathological parameters on Helicobacter pylori status. Methods: The study included 1522 patients referred for endoscopy: study group consisted of 557 patients with Helicobacter pylori-positive biopsies confirmed using histochemical stains or immunohistochemistry methods; and the control group consisted of 965 patients with Helicobacter pylori-negative status on histology. Results: Severe endoscopic lesions were more frequent in the Helicobacter pylori group (p < 0.001), with no difference noticed in the distribution of premalignant gastric lesions (p = 0.82). Anemia and dyslipidemia were independent factors associated with Helicobacter pylori-positive biopsies (p < 0.05). Non-steroidal anti-inflammatory therapy was more frequently administered in the study group, while proton-pump inhibitors had an anti-Helicobacter pylori activity on histology (p < 0.0001). Conclusion: In the studied population, patients with Helicobacter pylori-positive biopsies had a more frequent history of gastrotoxic medication, severe endoscopic lesions, and anemia. Helicobacter pylori was unpredictable by gastrointestinal symptoms. The frequency of premalignant gastric lesions was similar irrespective of the actual status of infection, underlining the importance of unintentional clearance of bacteria in old infection and the remaining risk for cancer in this population.

Oxidative-Stress Related Gene Polymorphism in Endometriosis-Associated Infertility.

Background and Objectives: Endometriosis is a benign inflammatory disease associated with infertility and chronic pelvic pain, estimated to affect 7−10% of reproductive-age women, with the possibility of malignant transformation. Recent studies focus on oxidative stress and genetic mutations as risk factors in the pathophysiology of endometriosis-associated infertility. Materials and Methods: This case-control study is the first in Eastern European women that aimed to investigate four genes' genetic polymorphisms that encode antioxidant enzymes involved in oxidative stress (glutathione peroxidase 1, GPX1 198Pro > Leu, catalase CAT-262C > T, glutathione S-transferase M1, and T1 null genotype) and their association with endometriosis-related infertility. We compared 103 patients with endometriosis-associated infertility with 102 post-partum women as the control group. Results: The endometriosis group had a mean age of 34.5 +/− 6.12 years, while the control group's mean age was 35.03 +/− 5.95 years. For CAT-262C > T polymorphism, the variant genotypes were significantly more frequent in the endometriosis group. Moreover, for the GPX1 198Pro > Leu, the endometriosis group had significantly more frequent CT and TT genotypes. The null genotype of GSTM1 was detected significantly higher in the endometriosis group. No significant differences were found in the frequency of GSTT1 between the two groups. This study suggests that GPX1 198Pro > Leu, CAT-262C > T, and GSTM1 polymorphisms may be risk factors and that the association between the GSTM1-GSTT1 null genotype may play a significant role in endometriosis-associated infertility. Moreover, this study suggests that the GSTT1 null genotype does not influence the disease. Visual identification of endometriotic lesions with microscopic confirmation is the accepted gold standard for diagnosing endometriosis, but general anesthesia and laparoscopy are required. Conclusions: In this regard, a panel of genetic or laboratory markers is needed for the early diagnostics of this prevalent disease, especially in the case of young patients with future pregnancy intention.

Clinical Characteristics, Renal Involvement, and Therapeutic Options of Pediatric Patients With Fabry Disease.

Inherited renal diseases represent 20% of the causes of end-stage renal diseases. Fabry disease, an X-linked lysosomal storage disorder, results from α-galactosidase A deficient or absent activity followed by globotriaosylceramide (Gb3) accumulation and multiorgan involvement. In Fabry disease, kidney involvement starts early, during intrauterine life by the Gb3 deposition. Even if chronic kidney disease (CKD) is discovered later in adult life in Fabry disease patients, a decline in glomerular filtration rate (GFR) can occur during adolescence. The first clinical sign of kidney involvement is represented by albuminuria. So, early and close monitoring of kidneys function is required: albuminuria and proteinuria, urinary albumin-to-creatinine ratio, serum creatinine, or cystatin C to estimate GFR, while urinary sediment with phase-contrast microscopy under polarized light may be useful in those cases where leucocyte α-Gal A activity and GLA genotyping are not available. Children with Fabry disease and kidney involvement should receive enzyme replacement therapy and nephroprotective drugs (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) to prevent or slow the progressive loss of kidney functions. Early diagnosis of Fabry disease is important as enzyme replacement therapy reduces symptoms, improves clinical features and biochemical markers, and the quality of life. More importantly, early treatment could slow or stop progressive organ damage in later life.

Association of TLR4 Rs4986791 Polymorphism and TLR9 Haplotypes with Acute Myeloid Leukemia Susceptibility: A Case-Control Study of Adult Patients.

Toll-like receptors (TLRs) have an important role in innate immunity, and single nucleotide polymorphisms (SNPs) of TLR genes influence the risk of developing hematological malignancies. We aimed to evaluate the effect of TLR2 (rs5743708), TLR4 (rs11536889, rs4986790, rs4986791), TLR9 (rs187084, rs352140, rs5743836) on AML risk, the relation between investigated SNPs and somatic mutations, clinical features, and the overall survival of adult AML patients. All mentioned SNPs were genotyped in 511 AML cases and 503 healthy controls. DNMT3A (R882), FLT3 (D835, ITD), and NPM1 mutations' status were investigated in AML patients. TLR4 rs4986791 was associated with an increased risk of AML under the dominant model (OR = 1.61, 95% CI: 1.001-2.59). Variant genotypes of the TLR4 rs4986790 or rs4986791 were associated with the odds of developing AML in the codominant model (OR = 3.14; 95% CI: 1.12-8.84; p = 0.032). The TLR9 rs5743836 variant genotype was associated with the NPM1 mutation (p = 0.002). The investigated SNPs were not associated with the DNMT3A, FLT3 mutations and had no significant contribution to the hazard of death after adjusting for covariates. Our findings suggest that TLR4 rs4986791 is associated with AML susceptibility. The combined variant genotypes of TLR4 rs4986790 and rs4986791 increase AML risk, the TLR9 C-G-A haplotype may represent a promising approach to predict a person's risk for developing AML.

Innate Immune Responses in Pediatric Patients with Gastritis-A Trademark of Infection or Chronic Inflammation?

The aim of this study was to define the relationship between several environmental, laboratory, and genetic factors, i.e., TLR2 and NLRP3 polymorphisms, and Helicobacter pylori (H. pylori) infection in children, by comparing three different groups of pediatric subjects: H. pylori-induced gastritis, non-H. pylori gastritis, and healthy controls. Our final study sample included 269 children, which were divided into three groups according to the histopathological exam: group 1 with 51 children with H. pylori-induced gastritis, group 2 with 103 children with H. pylori-negative gastritis, and group 3 (control group) with 115 children without any histopathological changes. All children underwent a thorough anamnesis, clinical exam, laboratory tests, and upper digestive endoscopy with gastric biopsy for rapid urease test, histopathological exam, and genetic analysis of TLR2 rs3804099, TLR2 rs3804100, and NLRP3 rs10754558 gene polymorphisms. We noticed a significant association between living conditions and the type of gastritis (p < 0.0001). Both rapid urease and serological tests were significantly associated with the presence of H. pylori (p < 0.0001). The CT variant genotype of TLR2 rs380499 was significantly associated with neutrophil count (p = 0.0325). We noticed a significant association between the CC variant genotype of NLRP3 rs10754558 and leucocytes, neutrophils, eosinophils, as well as ALT (p = 0.0185, p = 0.0379, p = 0.0483, p = 0.0356). Based on these findings, we state that poor living conditions and rural areas represent risk factors for H. pylori infection. The rapid urease test is a reliable diagnostic tool for this infection. CT and TT carriers of TLR2 rs3804099, as well as CC carriers of NLRP3 rs10754558, might display a more severe degree of systemic inflammation.

Factors associated with gastro-duodenal ulcer in compensated type 2 diabetic patients: a Romanian single-center study.

INTRODUCTION: Helicobacter pylori infection is accepted as the leading cause of chronic gastritis, ulcer disease and gastric cancer, with an important impact on health care burden, especially in countries with a high prevalence of infection. The aim of the study was to investigate the influence of H. pylori infection, medication, associated medical conditions or social habits on endoscopic ulcer occurrence in the compensated type 2 diabetic population. MATERIAL AND METHODS: Two hundred and sixty type 2 diabetic patients investigated on endoscopy (57 patients with peptic ulcer and 203 controls) with a complete set of biopsies, demographic and medical data were enrolled. RESULTS: On univariate regression analysis, H. pylori infection (42.1% vs. 35.5%, p = 0.359) or a history of peptic ulcer (61.4% vs. 61.6%, p = 0.981) was not a predictor for ulcer on endoscopy in the diabetic population, and heartburn was more frequent in diabetics without ulcer (21.2% vs. 8.8%, p = 0.033). Anemia was the best predictor for ulcer on endoscopy in both diabetics with (p < 0.001, OR = 4.77, 95% CI: 2.02-11.28) and without (p = 0.027, OR = 2.76, 95% CI: 1.10-6.91) chronic proton pump inhibitor (PPI) therapy. In diabetic patients on PPI more than 1 month anticoagulants - acenocoumarol or low-weight molecular heparin (p = 0.038, OR = 2.37, 95% CI: 1.04-5.40), low-dose aspirin 75-125 mg/day (p = 0.029, OR = 2.61, 95% CI: 1.08-6.28) and alcohol consumption (p = 0.015, OR = 2.70, 95% CI: 1.19-6.13) were predictors for ulcer on endoscopy. CONCLUSIONS: In diabetic patients, anemia is the most important predictor for ulcer on endoscopy, but not H. pylori or digestive symptoms, while low-dose aspirin or anticoagulant therapy and alcohol consumption are the most important predictors for ulcer in diabetics on chronic proton pump inhibitor therapy.

TERT rs2853669 as a predictor for overall survival in patients with acute myeloid leukaemia.

INTRODUCTION: the aim of the study was to investigate the contribution of TERT rs2736100 and rs2853669 gene polymorphisms in defining the genetic predisposition to acute myeloid leukaemia (AML), their association with different prognostic markers, and their impact on survival, outcome, and the prognosis of affected patients. Also, we investigated the association of TERT SNPs in AML in the presence or absence of DNMT3A (R882), NPM1, and FLT3 mutations. MATERIAL AND METHODS: A total of 509 participants were enrolled in our study, consisting of 146 AML patients and 363 healthy participants, with no history of malignancy. TERT rs2736100 and rs2853669 polymorphisms were genotyped by using TaqMan SNP genotyping assay FLT3 (ITD, D835), DNMT3A (R882), and NPM1 c.863_864insTCTG (type A) mutations were analised in each AML case. RESULTS: TERT rs2736100 and rs2853669 were not associated with AML risk in the codominant, dominant, recessive, or allelic models. Multivariate Cox regression showed that TERT rs2853669 was a significant predictor for overall survival in AML patients. After adjusting for age, gender, cytogenetic risk group, ECOG status, FLT3, DNMT3A, NPM1 mutation, AML subtype, and treatment, the estimated adjusted hazard ratio (HR adjusted = 1.54, 95% CI: 1.01-2.35) showed that the TERT rs2853669 variant genotype had a negative influence on survival time. CONCLUSIONS: TERT rs2853669 and rs2736100 polymorphisms were not risk factors for developing AML in the Romanian population, but the TERT rs2853669 variant genotype had a negative effect on AML patients' overall survival in the presence of other known prognostic factors.

From Descriptive to Functional Genomics of Leukemias Focusing on Genome Engineering Techniques.

Genome engineering makes the precise manipulation of DNA sequences possible in a cell. Therefore, it is essential for understanding gene function. Meganucleases were the start of genome engineering, and it continued with the discovery of Zinc finger nucleases (ZFNs), followed by Transcription activator-like effector nucleases (TALENs). They can generate double-strand breaks at a desired target site in the genome, and therefore can be used to knock in mutations or knock out genes in the same way. Years later, genome engineering was transformed by the discovery of clustered regularly interspaced short palindromic repeats (CRISPR). Implementation of CRISPR systems involves recognition guided by RNA and the precise cleaving of DNA molecules. This property proves its utility in epigenetics and genome engineering. CRISPR has been and is being continuously successfully used to model mutations in leukemic cell lines and control gene expression. Furthermore, it is used to identify targets and discover drugs for immune therapies. The descriptive and functional genomics of leukemias is discussed in this study, with an emphasis on genome engineering methods. The CRISPR/Cas9 system's challenges, viewpoints, limits, and solutions are also explored.

Cytokine TGF-ß1, TNF-α, IFN-γ and IL-6 Gene Polymorphisms and Localization of Premalignant Gastric Lesions in Immunohistochemically H. pylori-negative Patients.

Background: Cytokines and their gene variants are proven to play a role in pathogenic gastritis and carcinogenesis. The study assesses associations of the cytokine gene polymorphisms with extension of atrophic gastritis/intestinal metaplasia (AGIM) in patients without Helicobacter pylori infection on immunohistochemistry study. Methods: 224 adult consecutive patients undergoing an upper digestive endoscopy were included and grouped according to localization of AGIM: 37 patients with antrum-limited AGIM, 21 corpus-limited AGIM, 15 extended-AGIM (antrum and corpus) and 151 patients had no AGIM. Medical records of the patients were checked and a structured direct interview was applied in order to collect clinical data, including digestive symptoms. In all cases, IFN-γ +874T>A, TGF-ß1 +869T>C, TNF-α-308G>A and -238G>A, and IL-6 -174C>G polymorphisms were genotyped. Results: The mean age was significantly higher in the AGIM group, while the comorbidies were similar among patients with different localization of lesions or in patients without AGIM. There were no significant differences in digestive symptoms, nor in the consumption of non-steroidal anti-inflammatory drugs or proton pump inhibitor with the different extensions of AGIM. There was a significant association between oral anticoagulant consumption and localization of AGIM (P = 0.042), frequency being higher among patients with corpus-limited AGIM than those with no AGIM (P = 0.007, adjusted P = 0.041). TGF-ß1 +869T>C was less frequent among patients with corpus-limited AGIM (n=7, 33.3%) and extended AGIM (n=5, 33.3%) than in antrum-limited AGIM (n=25, 67.6%). There were no other significant differences regarding variant and wild genotype frequencies of IFN-γ +874T>A (86.5%, 81.0%, 86.7%, p=0.814), TNF-α-308G>A (35.1%, 28.6%, 53.3%, p=0.48) and IL-6 -174C>G (70.3%. 61.9%, 73.3% p=0.656) among patients with antrum-limited, corpus-limited or extended AGIM. TGF-ß1 +869T>C was associated with a decreased risk for corpus-affected AGIM (adjusted odds ratio: 0.42, 95% confidence interval: 0.19-0.93, P = 0.032). The dominant inheritance models no revealed significant association for IFN-γ +874T>A, TNF-α-308G>A and IL-6 -174C>G gene polymorphism and the risk of localization of AGIM. Conclusion: TGF-ß1 +869T>C gene polymorphism is associated with a decreased risk for corporeal localization of premalignant lesions, while IFN-γ +874T>A, TNF-α-308G>A and IL-6 -174C>G are not associated with the risk for AGIM in immunohistochemically H. pylori negative patients.

TET2 rs1548483 SNP Associating with Susceptibility to Molecularly Annotated Polycythemia Vera and Primary Myelofibrosis.

BACKGROUND: The complexity of myeloproliferative neoplasms (MPNs) cannot be characterized by acquired somatic mutations alone. Individual genetic background is thought to contribute to the development of MPNs. The aim of our study was to assess the association between the TET2 rs1548483 single nucleotide polymorphism (SNP) and the susceptibility to polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) or chronic myeloid leukemia (CML). METHODS: We evaluated the TET2 rs1548483 SNP through real-time PCR in 1601 MPN patients out of which 431 with PV, 688 with TE, 233 with PMF, 249 with CML and 197 controls. We included only patients with a molecularly proven driver mutation, such as JAK2 V617F, CALR or BCR-ABL1. RESULTS: Significant association between TET2 rs154843 variant allele and JAK2 V617F-positive PV and PMF (OR = 1.70; 95% CI: 1.01-2.91; p-value = 0.046, and OR = 2.04; 95% CI: 1.10-3.77; p-value = 0.024, respectively), and type 2 CALR-positive PMF (OR = 2.98; 95% CI: 1.12-7.93; p-value = 0.035) was noted. CONCLUSIONS: The TET2 rs1548483 SNP is associated with the susceptibility to molecularly annotated PV and PMF.

Exon 21 deletion in the OPHN1 gene in a family with syndromic X-linked intellectual disability: Case report.

INTRODUCTION: The oligophrenin-1 (OPHN1) gene, localized on the X chromosome, is a Rho-GTPase activating protein that is related to syndromic X-linked intellectual disability (XLID). XLID, characterized by brain anomalies, namely cerebellar hypoplasia, specific facial features, and intellectual disability, is produced by different mutations in the OPHN1 gene. PATIENT CONCERNS: In this report, we present the clinical and molecular findings of a family affected by a mild XLID due to a deletion in the OPHN1 gene, exon 21, Xq12 region using Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. The clinical features present in the family are a mild developmental delay, behavioral disturbances, facial dysmorphism, pes planus, nystagmus, strabismus, epilepsy, and occipital arachnoid cyst. INTERVENTIONS: The MLPA analysis was performed for investigation of the copy number variations within the X chromosome for the family. DIAGNOSIS AND OUTCOME: The MLPA analysis detected a deletion in the OPHN1 gene, exon 21 for the proband, and a heterozygous deletion for the probands mother. The deletion of the Xq12 region of maternal origin, including the exon 21 of the OPHN1 gene, confirmed for the probands nephew. LESSONS: Our findings emphasize the utility of the MLPA analysis to identify deletions in the OPHN1 gene responsible for syndromic XLID. Therefore, we suggest that MLPA analysis should be performed as an alternative diagnostic test for all patients with a mild intellectual disability associated or not with behavioral disturbances, facial dysmorphism, and brain anomalies.

Association Analysis of TP53 rs1042522, MDM2 rs2279744, rs3730485, MDM4 rs4245739 Variants and Acute Myeloid Leukemia Susceptibility, Risk Stratification Scores, and Clinical Features: An Exploratory Study.

This study aimed to explore the associations between the TP53 rs1042522 (TP53 Arg72Pro), MDM2 rs2279744 (MDM2 309T>G), rs3730485 (MDM2 del1518), MDM4 rs4245739 (MDM4 34091 C>A) variants and odds of developing acute myeloid leukemia (AML) in a cohort of 809 adult subjects, consisting of 406 healthy controls and 403 AML patients. Model-based multifactor dimensionality reduction (MB-MDR) framework was used to identify the interactions of the mentioned variants and their association with AML risk. Associations of the mentioned variants with clinical features of AML, somatic mutations, and response to treatment were also evaluated. Significant associations between TP53 rs1042522 and MDM4 rs4245739 variants and AML susceptibility were noticed. MB-MDR and logistic regression analysis revealed an interaction between MDM2 rs2279744 and TP53 rs1042522, between MDM4 rs4245739 and MDM2 rs3730485, as well as significant associations with AML susceptibility. Several associations between the mentioned variants and clinical features of AML and somatic mutations were also noticed. Individually, the variant genotypes of TP53 rs1042522 and MDM4 rs4245739 were associated with AML susceptibility, but their interaction with MDM2 rs2279744 and rs3730485 modulated the risk for AML. The variant genotypes of TP53 rs1042522 were associated with adverse molecular and cytogenetic risk and also with NPM1 mutations.