Polymorphisms and haplotypes of the CYP2B6 detoxification gene in the predisposition of Acute Myeloid Leukemia (AML) and induction of its cytogenetic abnormalities

CYP2B6 is a polymorphic detoxification gene which plays a vital role in the degradation of genotoxic compounds. In this study we hypothesized that inadequate detoxification due to CYP2B6 polymorphisms may contribute to AML. To evaluate the potential impact of CYP2B6 polymorphisms on AML development and induction of its specific chromosomal abnormalities we studied C777A and A785G polymorphisms for the first time in AML. Furthermore, we investigated the co-existence of the above polymorphisms with G516T polymorphism to determine the CYP2B6 high-risk haplotypes in AML susceptibility. Our study included 619 AML patients and 430 healthy donors. Concerning C777A CYP2B6 polymorphism, no significant difference was found between patients and controls. However, A785G CYP2B6 polymorphism showed a statistically higher frequency of the variant genotypes in patients (48.2%), mainly in secondary AML patients (49.1%) than in controls (26.1%). Moreover, an increased frequency of the variant genotypes was found in those with abnormal karyotypes, especially with −7/del(7q), −5/del(5q), +8, inv(16) and t(8;21). The combination of the three CYP2B6 polymorphisms (G516T, C777A & A785G) revealed seven haplotypes. Four out of six haplotypes with at least one mutant allele were significantly associated with an increased risk for AML. Interestingly, T516A777G785 haplotype, where the three mutant alleles co-existed, had ~3-fold increased risk to be found in patients than controls. The association between haplotypes and cytogenetic aberrations revealed a positive correlation between specific CYP2B6 haplotypes and AML cytogenetic abnormalities. Our data suggest that A785G CYP2B6 gene polymorphism and specific CYP2B6 haplotypes may contribute to AML and its specific chromosomal aberrations. © 2016 Elsevier Inc

Effect of parental obesity and gestational diabetes on child neuropsychological and behavioral development at 4 years of age: the Rhea mother-child cohort, Crete, Greece

Studies have suggested an association between maternal obesity pre-pregnancy and gestational diabetes (GDM) with impaired offspring neurodevelopment, but it is not clear if these associations are explained by shared familiar characteristics. We aimed to assess the associations of maternal and paternal obesity, maternal glucose intolerance in early pregnancy and GDM, with offspring neurodevelopment at 4 years of age. We included 772 mother-child pairs from the "Rhea" Mother-Child cohort in Crete, Greece. Data on maternal/paternal body mass index (BMI) and maternal fasting serum samples for glucose and insulin measurements were collected at 12 weeks of gestation. GDM screening was performed at 24-28 weeks. Neurodevelopment at 4 years was assessed using the McCarthy Scales of Children's Abilities. Behavioral difficulties were assessed by Strengths and Difficulties Questionnaire and Attention Deficit Hyperactivity Disorder Test. Multivariate linear regression analyses showed that maternal obesity was associated with a significant score reduction in general cognitive ability (beta-coeff -4.03, 95% CI: -7.08, -0.97), perceptual performance (beta-coeff -4.60, 95% CI: -7.74, -1.47), quantitative ability (beta-coeff -4.43, 95% CI: -7.68, -1.18), and executive functions (beta-coeff -4.92, 95% CI: -8.06, -1.78) at 4 years of age, after adjustment for several confounders and paternal BMI. Maternal obesity was also associated with increased behavioral difficulties (beta-coeff 1.22, 95% CI: 0.09, 2.34) and ADHD symptoms (beta-coeff 4.28, 95% CI: 1.20, 7.36) at preschool age. Paternal obesity maternal glucose intolerance in early pregnancy and GDM was not associated with child neurodevelopment. These findings suggest that maternal obesity may impair optimal child neurodevelopment at preschool age independently of family shared characteristics

The G516T CYP2B6 germline polymorphism affects the risk of acute myeloid leukemia and is associated with specific chromosomal abnormalities

The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The CYP2B6 gene is subjected to a single-nucleotide polymorphism (G516T) with heterozygotes (GT) and homozygotes (TT) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of CYP2B6 G 516T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (GT and TT) in patients compared to the controls (GT:38.8% vs 29.8% and TT:9.3% vs 5.3% respectively) (p<0.001). More specifically, a significantly higher frequency of GT+TT genotypes in de novo AML patients (46.6%) and an immensely high frequency of TT in secondary AML (s-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in de novo and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the TT genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of TT genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the CYP2B6 polymorphism in AML susceptibility and suggest a possible role of the CYP2B6 genetic background on the development of specific chromosomal aberrations. © 2014 Daraki et al

Benefits and Limitations of TKIs in Patients with Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis

Introduction: Tyrosine kinase inhibitors (TKIs) have been used in patients with advanced medullary thyroid carcinoma (MTC); however, data on their effectiveness and safety are limited. The aim of this systematic review and meta-analysis was to document clinical response and toxicities of TKIs in advanced MTC. Methods: We systematically searched major databases for articles or abstracts on TKI use in MTC patients until May 2018. Objective response (OR), defined as the sum of complete + partial response, expressed as percentage, was our primary endpoint, while disease stability, disease progression (DP), median progression-free survival (PFS), and drug discontinuation rate due to adverse events (AEs) were secondary endpoints. Pooled percentages, PFS time, and 95% CIs were reported. Results: Thirty-three publications were finally included in the analysis: 1 phase IV, 2 phase III trials evaluating vandetanib and cabozantinib, respectively, 20 phase I or II studies, and the remaining 10 studies of retrospective-observational nature. OR was documented in 28.6% (95% CI 25.9-31.9) of patients. Stable disease was recorded in 46.2% (95% CI 43.3-49.1). Overall, DP was observed in 22.9% (95% CI 20.4-27.6). Grade 3 or more AEs occurred in 48.5% (95% CI 45.5-51.5) of patients, and drug discontinuation was reported in 44.7% (95% CI 41.7-47.6). In general, use of TKIs conferred a PFS of 23.3 months (95% CI 21.07-25.5). In particular, vandetanib induced an OR in 33.8% (95% CI 29.6-38.0) of patients and cabozantinib in 27.7% (95% CI 22.05-33.4). DP occurred in 23.7% (95% CI 19.9-27.6) with vandetanib use and in 22.6% (95% CI 17.4-27.9) in cabozantinib-treated patients. Sorafenib, the third most frequently studied drug, showed intermediate efficacy, but higher discontinuation rates. Conclusion: Treatment with TKIs in MTC patients with progressive disease is associated with a moderate therapeutic benefit, with achievement of either disease stability or partial response in 73%. The toxicity of these drugs is not negligible, but it is, nonetheless, manageable. © 2020 The Author(s) Published by S. Karger AG, Basel

ASXL1 mutations in AML are associated with specific clinical and cytogenetic characteristics

Mutations of ASXL1 are early events in acute myeloid leukemia (AML) leukemogenesis and have been associated with unfavorable prognosis. In this study, we investigated the type and frequency of ASXL1 mutations in a large cohort of patients with de novo or secondary AML (s-AML) and looked for correlations with cytogenetic findings and disease features. ASXL1 mutations were associated with older age, s-AML and higher peripheral leukocytosis. We observed more frequent co-occurrence of ASXL1 mutations with trisomy 8 and chromosome 11 aberrations but a negative correlation with myelodysplastic syndromes (MDS)-related cytogenetic abnormalities, especially −5/del(5q) and −7/del(7q). ASXL1 mutations were also found in other genetically defined AML subgroups such as those with t(9;22), inv(3)/t(3;3), t(8;21) or t(15;17); however, none of our inv(16) cases carried ASXL1 mutations. We detected two previously unreported ASXL1 mutations, p.IIe593Val and p.Cys688Tyr. Our findings suggest that ASXL1 mutations tend to cluster with specific clinical and cytogenetic profiles of AML patients. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group

Benefits and Limitations of TKIs in Patients with Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis

Introduction: Tyrosine kinase inhibitors (TKIs) have been used in patients with advanced medullary thyroid carcinoma (MTC); however, data on their effectiveness and safety are limited. The aim of this systematic review and meta-analysis was to document clinical response and toxicities of TKIs in advanced MTC. Methods: We systematically searched major databases for articles or abstracts on TKI use in MTC patients until May 2018. Objective response (OR), defined as the sum of complete + partial response, expressed as percentage, was our primary endpoint, while disease stability, disease progression (DP), median progression-free survival (PFS), and drug discontinuation rate due to adverse events (AEs) were secondary endpoints. Pooled percentages, PFS time, and 95% CIs were reported. Results: Thirty-three publications were finally included in the analysis: 1 phase IV, 2 phase III trials evaluating vandetanib and cabozantinib, respectively, 20 phase I or II studies, and the remaining 10 studies of retrospective-observational nature. OR was documented in 28.6% (95% CI 25.9-31.9) of patients. Stable disease was recorded in 46.2% (95% CI 43.3-49.1). Overall, DP was observed in 22.9% (95% CI 20.4-27.6). Grade 3 or more AEs occurred in 48.5% (95% CI 45.5-51.5) of patients, and drug discontinuation was reported in 44.7% (95% CI 41.7-47.6). In general, use of TKIs conferred a PFS of 23.3 months (95% CI 21.07-25.5). In particular, vandetanib induced an OR in 33.8% (95% CI 29.6-38.0) of patients and cabozantinib in 27.7% (95% CI 22.05-33.4). DP occurred in 23.7% (95% CI 19.9-27.6) with vandetanib use and in 22.6% (95% CI 17.4-27.9) in cabozantinib-treated patients. Sorafenib, the third most frequently studied drug, showed intermediate efficacy, but higher discontinuation rates. Conclusion: Treatment with TKIs in MTC patients with progressive disease is associated with a moderate therapeutic benefit, with achievement of either disease stability or partial response in 73%. The toxicity of these drugs is not negligible, but it is, nonetheless, manageable. © 2020 The Author(s) Published by S. Karger AG, Basel

Erdheim–chester disease and acute myeloid leukemia with mutated NPM1 in a patient with clonal hematopoiesis: A case report

Background: Erdheim–Chester Disease (ECD) is a clonal non-Langerhans histiocytosis, classified as a macrophage-dendritic cell neoplasm in the 2016 WHO classification. The exact cell of origin of ECD is unknown, although some limited evidence suggests that it arises from myeloid progenitors. Case Presentation: A 43-year-old patient, diagnosed with BRAFV600E mutated ECD, developed NPM1+/FLT3+ acute myeloid leukemia (AML) with wild-type BRAF, 15 months after the initial ECD diagnosis. The patient received intensive chemotherapy plus midos-taurin, followed by midostaurin maintenance. Six months into maintenance, the patient remains in complete remission with low-level measurable residual disease, whereas ECD shows a sustained partial metabolic response. Molecular karyotype at several distinct time-points, namely ECD diagnosis, AML diagnosis, and following treatment of AML, high-lighted a molecular signature, indicative of a persistent, underlying clonal hematopoiesis. Conclusion: This case report suggests that ECD and AML might represent an expansion of two distinct clones in a background of clonal hematopoiesis, indicating their shared origin. Moreover, molecular karyotype might serve as a strong, inexpensive tool for revealing clonal hematopoiesis in cases of negative targeted next-generation sequencing. Finally, the moder-ate response of ECD to midostaurin suggests that kinase inhibition might have a potential role in ECD treatment. © 2020 Papageorgiou et al