Evaluation of the Copy Number Variants and Single-Nucleotide Polymorphisms of ABCA3 in Newborns with Respiratory Distress Syndrome-A Pilot Study.

Background and Objectives: Respiratory distress syndrome (RDS) in preterm infants commonly occurs due to the immaturity-related deficiency of pulmonary surfactant. Beyond prematurity, various environmental and genetic factors can influence the onset and progression of RDS. This study aimed to analyze three single-nucleotide polymorphisms (SNPs) of the ABCA3 gene to assess the ABCA3 gene as a candidate gene for susceptibility to RDS and overall survival in newborns and to evaluate the utility of MLPA in RDS neonatal patients. Materials and Methods: Three SNPs were chosen and genotyped in a cohort of 304 newborns. Data analysis and statistical tests were employed to examine allele frequencies, haplotypes, and measures of pairwise linkage disequilibrium. Results: There was no observed haplotype association with SNPs rs13332514 (c.1059G>A) and rs170447 (c.1741+33T>C) among newborns, both with and without RDS (p > 0.05). The minor C allele frequency of the ABCA3 rs323043 (c.1755G>C) SNP showed a significant increase in preterm infants with RDS. MLPA results indicated that the predominant findings were normal, revealing no CNVs in the genes ABCA3 and SFTPC that were investigated in our patients. Conclusions: The presence of the variant C allele in the rs323043 (c.1755G>C) SNP may be a risk factor for RDS in premature newborns.

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.

Descriptive and Functional Genomics in Neonatal Respiratory Distress Syndrome: From Lung Development to Targeted Therapies.

In this up-to-date study, we first aimed to highlight the genetic and non-genetic factors associated with respiratory distress syndrome (RDS) while also focusing on the genomic aspect of this condition. Secondly, we discuss the treatment options and the progressing therapies based on RNAs or gene therapy. To fulfill this, our study commences with lung organogenesis, a highly orchestrated procedure guided by an intricate network of conserved signaling pathways that ultimately oversee the processes of patterning, growth, and differentiation. Then, our review focuses on the molecular mechanisms contributing to both normal and abnormal lung growth and development and underscores the connections between genetic and non-genetic factors linked to neonatal RDS, with a particular emphasis on the genomic aspects of this condition and their implications for treatment choices and the advancing therapeutic approaches centered around RNAs or gene therapy.

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 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.

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.

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review.

ECHS1 gene mutations are known to cause mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, a neurodegenerative disorder characterized by psychomotor development delay, lactic acidosis, and basal ganglia lesions resembling Leigh syndrome. Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency is a very rare and new disorder, with a wide phenotypic spectrum and different outcomes ranging from neonatal death to survival into adulthood. Since the identification of ECHS1 deficiency in 2014, almost 63 patients with pathogenic mutations in the ECHS1 gene have been described to date. This paper focuses on the clinical and molecular findings as well as the evolution of a Caucasian girl diagnosed with ECHS1 deficiency who carries a new compound heterozygous mutation in the ECHS1 gene. Polymorphic symptoms, namely failure to thrive, significant global developmental delay/regression, movement disorders, ocular abnormalities, hearing loss, seizure, and cardiac myopathy, may be a challenge in mitochondrial disorder suspicion. Early diagnosis, an appropriate diet with valine restriction, and trigger avoidance are essential, as there is no effective therapy for the disease. This disorder influences life quality in these patients and their caregivers, and it has the potential to be fatal.

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.

Antibody Protection against Long-Term Memory Loss Induced by Monomeric C-Reactive Protein in a Mouse Model of Dementia.

Monomeric C-reactive protein (mCRP), the activated isoform of CRP, induces tissue damage in a range of inflammatory pathologies. Its detection in infarcted human brain tissue and its experimentally proven ability to promote dementia with Alzheimer's disease (AD) traits at 4 weeks after intrahippocampal injection in mice have suggested that it may contribute to the development of AD after cerebrovascular injury. Here, we showed that a single hippocampal administration of mCRP in mice induced memory loss, lasting at least 6 months, along with neurodegenerative changes detected by increased levels of hyperphosphorylated tau protein and a decrease of the neuroplasticity marker Egr1. Furthermore, co-treatment with the monoclonal antibody 8C10 specific for mCRP showed that long-term memory loss and tau pathology were entirely avoided by early blockade of mCRP. Notably, 8C10 mitigated Egr1 decrease in the mouse hippocampus. 8C10 also protected against mCRP-induced inflammatory pathways in a microglial cell line, as shown by the prevention of increased generation of nitric oxide. Additional in vivo and in vitro neuroprotective testing with the anti-inflammatory agent TPPU, an inhibitor of the soluble epoxide hydrolase enzyme, confirmed the predominant involvement of neuroinflammatory processes in the dementia induced by mCRP. Therefore, locally deposited mCRP in the infarcted brain may be a novel biomarker for AD prognosis, and its antibody blockade opens up therapeutic opportunities for reducing post-stroke AD risk.

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.

Significant Associations between AXIN1 rs1805105, rs12921862, rs370681 Haplotypes and Variant Genotypes of AXIN2 rs2240308 with Risk of Congenital Heart Defects.

This study aimed to investigate possible associations of the susceptibility to congenital heart defects (CHDs) with AXIN1 rs1805105, rs12921862 and rs370681 gene variants and haplotypes, and AXIN2 rs2240308 gene variant. Significant associations were identified for AXIN1 rs370681 and AXIN2 rs2240308 variants. AXIN1 rs370681 variant was significantly associated with decreased odds of CHDs (adjusted OR varying from 0.13 to 0.28 in codominant, dominant and recessive gene models), while the AXIN2 rs2240308 variant was associated with increased odds of CHD in the dominant model. The haplotype-based generalized linear model regression of AXIN1 rs1805105, rs12921862 and rs370681 variants revealed that C-C-C and C-C-T haplotypes significantly increased the risk of CHDs (p < 0.05). No significant second order epistatic interactions were found between investigated variants (AXIN1 rs1805105, rs12921862, rs370681, and AXIN2 rs2240308). Our conclusion is that AXIN1 rs1805105, rs12921862, and rs370681 (C-C-C and C-C-T) haplotypes and AXIN2 rs2240308 contribute to CHDs susceptibility.

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.

Pitt-Hopkins Syndrome: Clinical and Molecular Findings of a 5-Year-Old Patient.

Pitt Hopkins syndrome (PTHS) is a very rare condition and until now, approximately 500 patients were reported worldwide, of which not all are genetically confirmed. Usually, individuals with variants affecting exons 1 to 5 in the TCF4 gene associate mild intellectual disability (ID), between exons 5 to 8, moderate to severe ID and sometimes have some of the characteristics of PTHS, and variants starting from exon 9 to exon 20 associate a typical PTHS phenotype. In this report, we describe the clinical and molecular findings of a Caucasian boy diagnosed with PTHS. PTHS phenotype is described including craniofacial dysmorphism with brachycephaly, biparietal narrowing, wide nasal bridge, thin and linear lateral eyebrows, palpebral edema, full cheeks, short philtrum, wide mouth with prominent and everted lips, prominent Cupid's bow, downturned corners of the mouth, microdontia and also the clinical management of the patient. The previously and the current diagnosis scores are described in this report and also the challenges and their benefits for an accurate and early diagnosis.

Co-occurrence of PML-RARA gene fusion, chromosome 8 trisomy, and FLT3 ITD mutation in a young female patient with de novo acute myeloid leukemia and early death: A CARE case report.

RATIONALE: Co-occurrence of cytogenetic and molecular abnormalities is frequently seen in patients with acute myeloid leukemia (AML). The clinical outcome and genetic abnormalities of AML may vary; therefore, genetic investigation must be complex, using several techniques, to have an appropriate characterization of the AML genome and its clinical impact. The available molecular markers can predict prognosis only partially. Acute promyelocytic leukemia subtype M3 (AML M3) is a subtype of AML characterized by the presence of promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) genes fusion. Targeted treatment with all-trans-retinoic acid (ATRA) and ATRA combined with arsenic trioxide significantly improved the survival of AML M3 patients. Unknown prognostic factors could contribute to the early death of these patients. PATIENT CONCERNS: We present the case of a young female (20 years old) patient, who presented at the emergency department 5 months after giving birth to her first child, complaining of asthenia, fatigue, general musculoskeletal pain, and fever (38°C), symptoms having been present for the previous 6 days. The patient denied any chronic diseases in her medical and family history. DIAGNOSIS: Laboratory analysis revealed severe pancytopenia. Cytogenetic and molecular analyzes revealed chromosomal abnormalities (trisomy 8), PML-RARA gene fusion, and fms-like tyrosine kinase 3 (FLT3) gene mutation. The immunophenotypic analysis was also suggestive for AML M3 according to the FAB classification. INTERVENTIONS: Specific treatment was initiated for AML M3 and for secondary conditions. Molecular and cytogenetic analyzes were performed to have a more detailed characterization of the patient's genome. OUTCOME: Seventy-two hours after admission, she developed psychomotor agitation, confusion, coma, and convulsion. Subsequent deterioration and early death were caused by intracerebral hemorrhage with multiple localization and diffuse cerebral edema. LESSONS: The presence of FLT3 internal tandem duplication (ITD) mutation may explain the rapid and progressive degradation of this AML M3 case and it may be used as a prognostic marker even when co-occuring with other markers such as PML-RARA gene fusion and trisomy 8. We consider that FLT3 ITD mutation analysis in young patients with AML should be performed as soon as possible. New strategies for patients' education, AML (or cancers in general) prevention, and treatment are needed.

Modelling the Effects of MCM7 Variants, Somatic Mutations, and Clinical Features on Acute Myeloid Leukemia Susceptibility and Prognosis.

The main objective of the study was to evaluate the associations between MCM7 rs2070215, rs1527423, and rs1534309 single nucleotide polymorphisms (SNPs) and acute myeloid leukemia (AML) risk and prognosis. The secondary objectives were to assess if any relationships existed between the mentioned SNPs and FLT3, DNMT3A, NPM1 mutations with clinical outcomes and overall survival (OS) in AML patients. We investigated 281 AML cases and 405 healthy subjects. The results showed a significant association between a variant allele of rs2070215 (p = 0.007), CAT haplotype (p = 0.012), and AML susceptibility. No significant association was found between MCM7 variant genotypes and overall survival of AML patients (p > 0.05), while several associations between somatic mutations, clinical and biological features, and poor OS were noticed. Lactate dehydrogenase (LDH) level ≥ 600 IU/L had a significant effect on the hazard of death (p = 0.004, HR = 1.49, 95% CI: 1.13-1.95). Our study showed that the variant allele of rs2070215, in the allelic model, and CAT haplotype were associated with AML susceptibility. The investigated FLT3, DNMT3A, and NPM1 mutations were associated with the clinical and biological features and poor OS. LDH level ≥ 600 IU/L was associated with an increased hazard of death and this association remained significant when quantifying for effect modification by FLT3 mutation status.