scholarly journals Association Analysis Between the Functional Single Nucleotide Variants in miR-146a, miR-196a-2, miR-499a, and miR-612 With Acute Lymphoblastic Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Silvia Jiménez-Morales ◽  
Juan Carlos Núñez-Enríquez ◽  
Jazmín Cruz-Islas ◽  
Vilma Carolina Bekker-Méndez ◽  
Elva Jiménez-Hernández ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Gene Interaction ◽  
Control Group ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Mexican Children

BackgroundAcute lymphoblastic leukemia (ALL) is characterized by an abnormal proliferation of immature lymphocytes, in whose development involves both environmental and genetic factors. It is well known that single nucleotide polymorphisms (SNPs) in coding and noncoding genes contribute to the susceptibility to ALL. This study aims to determine whether SNPs in miR-146a, miR-196a-2, miR-499a, and miR-612 genes are associated with the risk to ALL in pediatric Mexican population.MethodsA multicenter case-control study was carried out including patients with de novo diagnosis of ALL and healthy subjects as control group. The DNA samples were obtained from saliva and peripheral blood, and the genotyping of rs2910164, rs12803915, rs11614913, and rs3746444 was performed using the 5′exonuclease technique. Gene-gene interaction was evaluated by the multifactor dimensionality reduction (MDR) software.ResultsmiR-499a rs3746444 showed significant differences among cases and controls. The rs3746444G allele was found as a risk factor to ALL (OR, 1.6 [95% CI, 1.05–2.5]; p = 0.028). The homozygous GG genotype of rs3746444 confers higher risk to ALL than the AA genotype (OR, 5.3 [95% CI, 1.23–23.4]; p = 0.01). Moreover, GG genotype highly increases the risk to ALL in male group (OR, 17.6 [95% CI, 1.04–298.9]; p = 0.00393). In addition, an association in a gender-dependent manner among SNPs located in miR-146a and miR-196a-2 genes and ALL susceptibility was found.ConclusionOur findings suggest that SNP located in miR-499a, miR-146a, and miR-196a-2 genes confer risk to ALL in Mexican children. Experimental analysis to decipher the role of these SNPs in human hematopoiesis could improve our understanding of the molecular mechanism underlying the development of ALL.

scholarly journals Rare single nucleotide variants in COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liubov O. Skorodumova ◽  
Alexandra V. Belodedova ◽  
Elena I. Sharova ◽  
Elena S. Zakharova ◽  
Liliia N. Iulmetova ◽  
...  
Keyword(s):  
Rare Variants ◽  
Snp Array ◽  
Promoter Sequence ◽  
Minor Allele ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Degenerative Disorder ◽  
Pcr Targeting

Abstract Background Keratoconus is a chronic degenerative disorder of the cornea characterized by thinning and cone-shaped protrusions. Although genetic factors play a key role in keratoconus development, the etiology is still under investigation. The occurrence of single-nucleotide polymorphisms (SNPs) associated with keratoconus in Russian patients is poorly studied. The purpose of this study was to validate whether three reported keratoconus-associated SNPs (rs1536482 near the COL5A1 gene, rs2721051 near the FOXO1 gene, rs1324183 near the MPDZ gene) are also actual for a Russian cohort of patients. Additionally, we investigated the COL5A1 promoter sequence for single-nucleotide variants (SNVs) in a subgroup of keratoconus patients with at least one rs1536482 minor allele (rs1536482+) to assess the role of these SNVs in keratoconus susceptibility associated with rs1536482. Methods This case-control study included 150 keratoconus patients and two control groups (main and additional, 205 and 474 participants, respectively). We performed PCR targeting regions flanking SNVs and the COL5A1 promoter, followed by Sanger sequencing of amplicons. The additional control group was genotyped using an SNP array. Results The minor allele frequency was significantly different between the keratoconus and control cohorts (main and combined) for rs1536482, rs2721051, and rs1324183 (p-value < 0.05). The rare variants rs1043208782 and rs569248712 were found in the COL5A1 promoter in two out of 94 rs1536482+ keratoconus patients. Conclusion rs1536482, rs2721051, and rs1324183 were associated with keratoconus in a Russian cohort. SNVs in the COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482.

scholarly journals Comprehensive Custom NGS Panel Validation for the Improvement of the Stratification of B-Acute Lymphoblastic Leukemia Patients

2020 ◽  
Vol 10 (3) ◽  
pp. 137
Author(s):  
Adrián Montaño ◽  
Jesús Hernández-Sánchez ◽  
Maribel Forero-Castro ◽  
María Matorra-Miguel ◽  
Eva Lumbreras ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Wide Spectrum ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Single Step ◽  
Fusion Genes ◽  
Single Nucleotide Variants ◽  
Single Nucleotide

Background: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations. Methods: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced. Results: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques. Conclusions: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management.

Targeting AKT Signaling in Pediatric Acute Lymphoblastic Leukemia with Sulforaphane

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1521-1521
Author(s):  
Koramit Suppipat ◽  
Evelyn Zhu ◽  
Daniel Lacorazza
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Akt Signaling ◽  
Leukemic Cells ◽  
Control Group ◽  
Dependent Manner ◽  
Phosphorylated Akt ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Survival Signals

Abstract Abstract 1521 Refractory and relapse acute lymphoblastic leukemia (ALL) is one of the leading causes of cancer-related death in children. Novel agents are still in need as a frontline therapy in high risk patients and salvage agent in relapse patients. Leukemic cells acquire a survival advantage over normal blood cells by losing control of the cell cycle and activating pro-survival signals. There are emerging evidences showing that the PI3K/AKT/mTOR pathway is frequently activated in both T cell acute lymphoblastic leukemia (T-ALL) and precursor B cell acute lymphoblastic leukemia (pre-B ALL) (approximately 30% of ALL patients). Thus, drugs able to inhibit AKT signaling are potential candidates for ALL treatment. Sulforaphane (SF) is a dietary compound found in cruciferous vegetables with well-known chemopreventive and chemotherapeutic function in solid tumors by inducing apoptosis and inhibiting survival and cell division. However, the anti-leukemic capacity of SF in hematologic malignancies has not been extensively investigated. In this study, we found increased cleavage of PARP, caspase-3, caspase-8 and caspase-9 by immunoblots in pre-B and T-ALL cell lines treated with SF (5–10 μM) for 24 –48 hours. In addition, we detected increased expression of p21 and cyclin B that correlated with a G2/M block and DNA damage observed in SF treated cells by analysis of DNA content and H2AXγ expression. Noteworthy, SF-treated pre-B and T-ALL cell lines exhibit lower levels of total and phosphorylated AKT in addition to decreased levels of total and phosphorylated mTOR, which was independent of p53 and PTEN activities. Lower survival signals upon SF treatment correlated with a dose- and time-dependent cytotoxicity in pre-B ALL cell lines (Nalm-6, REH and RS-4) and T-ALL cell lines (Jurkat, RPMI, DND-41 and KOPTK1) compared to EBV-transformed lymphoblasts used as a control. Interestingly, SF showed a synergistic effect with vincristine in pre-B and T-ALL cell lines, suggesting a potential use of SF in adjunctive therapy. Aiming to support future clinical trials, we confirmed that SF is effective in lymphoblasts from pediatric patients suffering with ALL, both pre-B and T, in a time- and dose-dependent manner (95% confidence interval IC50: pre-B ALL = 9.9 – 12.13 μM, T-ALL = 8.3 –11.00 μM). To investigate whether SF is effective in vivo in a xenograft mouse model, we injected nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice with Nalm-6 cells transduced with GFP-FFluc for bioluminescent imaging detection. SF treatment (2 mg i.p. daily) significantly reduced tumor burden compared to the control group (injected with vehicle). Collectively, our data show that SF has anti-leukemic properties in ALL, both in primary samples from patients and cell lines, by inducing cell death selectively in leukemic cells likely by inhibiting AKT-dependent survival signals. Disclosures: No relevant conflicts of interest to declare.

MicroRNA 146a Polymorphisms and Expression in Indian Children with Acute Lymphoblastic Leukemia

2018 ◽  
Vol 50 (3) ◽  
pp. 249-253 ◽  
Author(s):  
Helen Jemimah Devanandan ◽  
Vettriselvi Venkatesan ◽  
Julius Xavier Scott ◽  
Latha Sneha Magatha ◽  
Solomon Franklin Durairaj Paul ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Risk Haplotype ◽  
Nucleotide Polymorphisms ◽  
Indian Children ◽  
Single Nucleotide ◽  
Protective Haplotype ◽  
Asian Children

Abstract Background MicroRNAs (miR) have been reported to be involved in hematopoiesis and in the pathogenesis of several hematological malignant neoplasms. Single-nucleotide polymorphisms (SNPs) in human miR genes may alter the expression of those genes and influence the predisposition to childhood leukemia. Objective To evaluate the association of rs2910164 G>C, rs57095329 A>G and the expression of miRNA-146a in ethnic South Asian children with acute lymphoblastic leukemia (ALL). Method Genotyping and expression analysis using TaqMan Small RNA Assay was performed on 71 patients with pathologically confirmed ALL and 74 control individuals. Results No statistically significant association was found between the 2 SNPs, its expression levels, and ALL risk. Conclusion Haplotype analysis indicated a combination of allele A of rs57095329 and allele G of rs2910164 could represent a risk haplotype and an allele combination of G of rs57095329 and G of rs2910164 could represent a protective haplotype for ALL.

scholarly journals Single Nucleotide Polymorphisms and Thromboembolism in Acute Lymphoblastic Leukemia — a NOPHO ALL2008 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 143-143 ◽  
Author(s):  
Kirsten Brunsvig Jarvis ◽  
Marissa Le Blanc ◽  
Morten Tulstrup ◽  
Ellen Ruud ◽  
Ruta Tuckuviene ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Single Nucleotide Polymorphisms ◽  
Risk Score ◽  
Genetic Risk ◽  
Lymphoblastic Leukemia ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Risk Alleles ◽  
All Treatment

Abstract Introduction: Thromboembolism (TE) is a major toxicity of acute lymphoblastic leukemia (ALL) treatment and contributes to substantial morbidity and mortality. Several germline DNA variants have been associated with TE in adults without cancer. A meta-analysis of genome-wide association studies on TE by Germain et al. (Am J Hum Genet 2015) identified single nucleotide polymorphisms (SNPs) in 8 genes that contribute to increased risk of TE in adults (ABO,F2, F5,F11, FGG,PROCR,TSPAN15, and SLC44A2). De Haan et al. (Blood 2012) found that SNPs in 5 of these (F5, F2, F11, FGG, and ABO) predicted TE almost as well as a 31 SNP-based risk score. However, the impact of these SNPs in patients with cancer, particularly in children, remains uncertain. Materials and methods: The Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol for children and adults (1-45 years) included a 3-drug induction (vincristine, doxorubicin, glucocorticosteroid) followed by exposure to asparaginase (1,000 IU/m.sq. i.m.) from week 5 until week 33 (details of therapy in Toft, Leukemia 2018). We collected germline DNA and prospectively registered TE events on 1482 children and adults diagnosed with ALL and treated according to the ALL2008 protocol in seven Nordic and Baltic countries (7/2008-7/2016) (Rank, Blood 2018). Inclusion criteria for TE were i) symptomatic venous or arterial TE confirmed by imaging or by autopsy for TE diagnosed post mortem or ii) asymptomatic TE confirmed by imaging due to other non-TE symptoms and treated with systemic anticoagulation. Based on previously published data and a priori power calculations, we selected and genotyped 5 SNPs: F5 rs6025 (risk allele frequency (RAF) 0.05), F11 rs2036914 (RAF 0.52), FGG rs2066865 (RAF 0.22), and ABO SNPs rs8176719 (RAF 0.39) and rs2519093 (RAF 0.24). Three SNPs (F5 and the two ABO SNPs) were found by imputation, which was done on a subset of patients with European ancestry and included in the NOPHO ALL2008 protocol (N = 1229). We constructed genetic risk scores using a combination of the SNPs. Results: During the ALL treatment period 107 of 1482 patients developed TE (2.5-year cumulative incidence 7.3%, 95% confidence interval (CI) 5.9-8.5). In multivariate Cox regression analysis controlling for age, gender, presence of mediastinal mass and enlarged lymph nodes (N = 1192, whereof TE events 84), we found statistically significant associations with TE development for SNPs F5 rs6025 (hazard ratio (HR) 2.96, 95% CI 1.59-5.48), F11 rs2036914 (HR 1.62, 95% CI 1.18-2.24), and FGG rs2066865 (HR 1.40 95% CI 1.01-1.95), whereas there were no significant associations with ABO SNPs rs8176719 (HR 0.98, 95% CI 0.64-1.51) or rs2519093 (HR 1.06, 95% CI 0.65-1.73). An unweighted 3 SNP risk score based on SNPs F5, F11, and FGG was associated with TE development (HR 1.59, 95% CI 1.27-1.98) (Figure 1). Twenty-six of 217 patients with ≥3 risk alleles developed TE (12.0%, 95% CI 8.1-17.2), compared to 62 of 1007 patients with <3 risk alleles (6.2%, 95% CI 4.8-7.9). The association was strongest in the adolescent age group (10-18 years; HR 1.88, 95% CI 1.35-2.63). Thirteen of 43 adolescents with ≥3 risk alleles developed TE (30.2%, 95% CI 17.8-46.3), compared to 20 of 182 adolescents with <3 risk alleles (11.0%, 95% CI 7.0-16.7) (Figure 2). In adults (>18 years) the proportion who developed TE was quite high in both the group with ≥3 risk alleles (23.5%, 95% CI 7.8-50.2) and with <3 risk alleles (17.6% 95%CI 11.1-26.3). In children (1-10 years) the proportion who developed TE was low in both the group with ≥3 risk alleles (5.7%, 95% CI 2.8-10.9) and with <3 risk alleles (3.2%, 95% CI 2.1-4.8). A weighted 3 SNP genetic risk score based on estimated odds ratios from literature for SNPs F5, F11 and FGG was also associated with TE development (HR 2.84, 95% CI 1.85-4.36). Again, the association was strongest in adolescents (HR 4.20, 95% CI 2.22-7.94). Conclusion: Based on the strong association between F5 rs6025, F11 rs2036914, and FGG rs2066865 and TE development, not least for adolescents, future preventive measures for TE should target adolescents with ≥3 risk alleles as well as any adults ≥18 years. Disclosures No relevant conflicts of interest to declare.

Genetics of Schizophrenia and Bipolar Disorder

2013 ◽  
pp. 232-246 ◽  
Author(s):  
Pamela Sklar
Keyword(s):  
Bipolar Disorder ◽  
Copy Number ◽  
Psychotic Disorders ◽  
De Novo ◽  
Copy Number Variants ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Sequencing Studies ◽  
Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. The explosion of strong and convincing genetic evidence indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. There is a role for rare single nucleotide variation as well as de novo genetic variation being pointed to in new sequencing studies, but their overall contribution to risk is less clear. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, there is evidence for polygenicity and as yet no deep sequencing surveys have been published. Several intriguing biological pathways are suggested by these genetic findings related to microRNAs and calcium channel signaling. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder. Translating these results into biological and etiological understanding has not yet advanced, and will likely only do so when experimental methods are developed than can address the large numbers of genes and variants within them that, along with environmental and stochastic effects, result in the development of disease for a particular person.

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