Impact of CYP1A1 variants on the risk of acute lymphoblastic leukemia: evidence from an updated meta-analysis.

OBJECTIVE: Our study aimed to investigate the association between cytochrome P450 1A1 (CYP1A1) polymorphisms (T3801C and A2455G) and acute lymphoblastic leukemia (ALL) risk, considering genetic models and ethnicity. MATERIALS AND METHODS: PubMed, Embase, Web of Knowledge, Scopus, and the Cochrane electronic databases were searched using combinations of keywords related to CYP1A1 polymorphisms and the risk of ALL. Studies retrieved from the database searches underwent screening based on strict inclusion and exclusion criteria. RESULTS: In total, 2822 cases and 4252 controls, as well as 1636 cases and 2674 controls of the C3801T and A2455G variants of CYP1A1, respectively, were included in this meta-analysis. The T3801C polymorphism of CYP1A1 significantly increases the risk of ALL, particularly those observed in Asian and Hispanic populations, independent of age. Similarly, the A2455G polymorphism of CYP1A1 plays a significant role in the susceptibility to ALL in all genetic models, except the heterozygous form. This association was observed mainly in mixed populations and in both children and adults (except in the heterozygous model). CONCLUSION: Our comprehensive analysis indicates that the T3801 and A2455G polymorphisms of CYP1A1 may increase the risk of ALL depending on ethnicity. Therefore, both variants should be considered promising biomarkers for ALL risk. Further large-scale investigations are necessary to assess other factors, such as gene-gene or gene-environment interactions.

Maternal inherited thrombophilia and recurrent pregnancy loss: a Tunisian study and review of literature.

Background: Inherited thrombophilia, mainly the Factor V Leiden (FVL) and Prothrombin mutation (PTM) are the most risk factors for venous thrombosis especially during pregnancy and was strongly associated with recurrent pregnancy loss (RPL), a devastating reproductive problem that affects more than 1% of couples who are trying to conceive. The frequencies also the correlation among these polymorphisms and RPL have been reported controversially in various populations. Objectives: In this study we evaluated the presence inherited thrombophilia amongst 35 Tunisian women with more than 2 miscarriages, referred to our genetic counseling. Methods: DNA was extracted from peripheral blood samples and PCR-RFLP was performed for the molecular diagnosis of mutation. Results: FVL and PTM were detected in 5.7 % and 2.9% respectively; in women with a particular history of early fetal loss and thrombotic events. Conclusion: This study emphasizes the importance of testing for FVL and FIIM in women with RPL; mainly in the context of thrombotic events. Multi-center collaboration is necessary to clarify the real impact of thrombotic molecular defects on the pregnancy outcome, to ascertain the effect of inherited thrombophilia on recurrent pregnancy loss and then to evaluate the appropriate therapeutic approach.

Update meta-analysis from biomedical literature about MTHFR'polymorphisms and the CML' risk.

BACKGROUND: The MTHFR gene polymorphisms are closely related to the chronic myeloid leukemia (CML). Case-control studies have associated the MTHFR polymorphisms and susceptibility to CML but the results were not conclusive. AIM: To assess this association through an update meta-analysis. METHODS: A descriptive and qualitative study was conducted among students in the 6th year of the faculty during the academic year 2020/2021. The data were collected through a questionnaire written in french evaluating the teaching methods. A focus group of ten persons was led to understand better student's opinions. RESULTS: Totally, 17 and 12 case-control studies including CML cases and controls were enrolled in the meta-analysis respectively for C677T and A1298C polymorphism and CML risk. A poor association between the C677T (T vs C ; OR= 1,28; IC95%= [1,01;1,63]; p=0,04) and the one not significant between the A1298C (C vs A ; OR= 1,52; IC95%= [0,92; 2,51]; p= 0,1) polymorphisms and the CML risk for overall population were found. CONCLUSION: The results of this meta-analysis suggested no significant association between C677T and A1298C polymorphisms and CML risk leading to consider other factors such us folic acid intake, gene-gene and gene- environment interactions.

Cytogenetic Screening in Couples with Recurrent Pregnancy Loss: A Single-Center Study and Review of Literature.

CONTEXT: Recurrent pregnancy loss (RPL) is a devastating reproductive problem that affects more than 2% of couples who are trying to conceive. Chromosomal rearrangements in either carrier are a major cause of clinically recognized abortion. AIMS: The purpose of this study is to report the prevalence of chromosome abnormalities in RPL and provide clinical characteristics of couples with two and more miscarriages. SETTINGS AND DESIGN: Genetic counseling in laboratory of histology housed in a Faculty of Medicine of Sfax. MATERIALS AND METHODS: Karyotype was generated from the peripheral blood lymphocyte cultures and the cytogenetic analysis was performed using R-bands after heat denaturation and Giemsa (RHG) banding. A multiplex polymerase chain reaction wherever necessary was done. STATISTICAL ANALYSIS USED: SPSS version 17. RESULTS: A total of 104 couples with RPL were carried out in this study. The frequency of chromosomal rearrangements was 11.5%, three times more prevalent in men than women (P = 0.08). In addition, the prevalence of chromosomal anomalies increases according to the number of miscarriages (from 4.8% to 7.6%, with 2 or ≥3 miscarriages, respectively; P = 0.9). Finally, a particular familial adverse reproductive background was found in these carriers (P = 0.03). CONCLUSIONS: These data highlight that an RPL evaluation is appropriate after the second miscarriage and that cytogenetic evaluation is necessary for an accurate approach to elucidate the causes of RPL. Moreover, familial adverse reproductive backgrounds have an impact of being carrier of chromosome abnormalities and a larger study is mandatory to define reproductive characteristics of carriers.

Co-existence of BCR-ABL and JAK2V617F mutation in resistant chronic myeloid leukemia in the imatinib era: Is there a correlation?

INTRODUCTION: Diagnoses of myeloproliferative disorder is based on molecular marker. Chronic Myeloid Leukemia and Myeloproliferative neoplasms were considered mutually exclusive and co-existence of BCR/ABL1 and JAK2 mutation is a rare phenomenon. CASE REPORT: Here, we present two cases of co-existence of BCR-ABL and JAK2V617F positivity. We characterize the course of the disease, mainly the minimal residual disease.Management and outcome: The two cases was initially managed as Chronic Myeloid Leukemia and treated by TKI inhibitors. The first one was diagnosed in 2010. He started the first line of TKI, and then switched to second line without obtaining a major molecular response. Hence he was tested for JAK2V617F mutation and positivity was diagnosed. The second patient showed Chronic Myeloid Leukemia phenotype with coexistence of BCR/ABL1 and JAK2 mutation at diagnosis. Molecular monitoring reveals a high BCR-ABL1 transcript level (20%) at the last follow-up (12 months). DISCUSSION: Ours results highlight that JAK2V617F/BCR-ABL double positivity may be a potential marker of resistance in Chronic Myeloid Leukemia and clonal molecular analysis is mandatory to elucidate the mechanism. Moreover, the combination of JAK and TKI inhibitors might be effective and potentially be guided by molecular monitoring of minimal residual disease.

Involvement of MTHFR rs1801133 in the Susceptibility of Acute Lymphoblastic Leukemia: A Preliminary Study.

BACKGROUND: Acute lymphoblastic leukemia (ALL), a common blood cancer, is characterized by the interaction between genetic and environmental factors. Several variants of the Methylenetetrahydrofolate reductase (MTHFR), mainly the C677T (rs1801133), may affect susceptibility to ALL. AIM OF THE STUDY: The authors conducted this case-control study to evaluate the relationship between this variant of the MTHFR gene and the risk of ALL. MATERIALS AND METHODS: Forty-one patients with ALL and 35 non-ALL controls recruited in this study were genotyped utilizing polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The MTHFR 677CT genotype was significantly more frequently found in patients with ALL having a 2-fold increase in risk (P <0.01). CONCLUSION: Our results suggest that rs1801133 of MTHFR is a predictive risk marker to ALL in Tunisian ALL.

Left-sided congenital heart lesions in mosaic Turner syndrome.

In the era of the diseasomes and interactome networks, linking genetics with phenotypic traits in Turner syndrome should be studied thoroughly. As a part of this stratagem, mosaicism of both X and Y chromosome which is a common finding in TS and an evaluation of congenital heart diseases in the different situations of mosaic TS types, can be helpful in the identification of disturbed sex chromosomes, genes and signaling pathway actors. Here we report the case of a mosaic TS associated to four left-sided CHD, including BAV, COA, aortic aneurysms and dissections at an early age. The mosaicism included two cell lines, well-defined at the cytogenetic and molecular levels: a cell line which is monosomic for Xp and Xq genes (45,X) and another which is trisomic for pseudoautosomal genes that are present on the X and Y chromosomes and escape X inactivation: 45,X[8]/46,X,idic(Y)(pter→q11.2::q11.2→pter)[42]. This case generates two hypotheses about the contribution of genes linked to the sex chromosomes and the signaling pathways involving these genes, in left-sided heart diseases. The first hypothesis suggests the interaction between X chromosome and autosomal genes or loci of aortic development, possibly dose-dependent, and which could be in the framework of TGF-ß-SMAD signaling pathways. The second implies that left-sided congenital heart lesions involve sex chromosomes loci. The reduced dosage of X chromosome gene(s), escaping X inactivation during development, contributes to this type of CHD. Regarding our case, these X chromosome genes may have homologues at the Y chromosome, but the process of inactivation of the centromeres of the isodicentric Y spreads to the concerned Y chromosome genes. Therefore, this case emerges as an invitation to consider the mosaics of Turner syndrome and to study their phenotypes in correlation with their genotypes to discover the underlying developmental and genetic mechanisms, especially the ones related to sex chromosomes.

Neonatal lupus erythematosus with congenital heart block in twins.

Background - Neonatal lupus erythematosus is an uncommon acquired autoimmune disease caused by transplacental passage of maternal antibodies SSA/Ro, SSB/La or U1 ribonucleoproteins. The most common clinical manifestations are skin rash, cardiac lesions, thrombocytopenia, anemia and hepatosplenomegaly. Complete congenital heart block is usually irreversible needing a pacemaker implantation in two-thirds of cases. Cases report - We report neonatal lupus erythematosus with complete congenital heart block in twins. Newborns were delivered by caesarean section at week 38 of gestation with a heart rate regular at 70 beats per minute. Both twins and mother were positive for antinuclear, anti-SSA, and anti-SSB antibodies. Twins received single-chamber pacemaker implants at day 12 of life. The evolution was immediately favorable with a heart rate around 110 beats per minute. The follow-up was 2 years. The twins are currently asymptomatic. Conclusion - Complete congenital heart block is the most serious manifestation of the neonatal lupus erythematosus associated with significant morbidity and mortality.