Pharmacogenetics of ABCB1, CDA, DCK, GSTT1, GSTM1 and outcomes in a cohort of pediatric acute myeloid leukemia patients from Colombia.

BACKGROUND AND AIM: Different studies have shown pharmacogenetic variants related to drug toxicity in acute myeloid leukemia (AML) patients. Our aim was to identify the association between ABCB1, CDA, DCK, GSTT1, and GSTM1 variants with clinical outcomes and toxicity in pediatric patients with AML. METHODS: Fifty-one confirmed de novo AML pediatric patients were included. A SNaPshot™ assay and conventional PCR were used to evaluate ABCB1, CDA, DCK, GSTT1, and GSTM1 variants. Clinical outcomes and toxicity associations were evaluated using odds ratios and Chi-square analysis. RESULTS: Patients carrying ABCB1 (1236C > T, rs1128503) GG genotype in had a 6.8 OR (CI 95% 1.08-42.73, p = .044) for cardiotoxicity as compared to patients carrying either AA or GA genotypes 0.14 OR (CI 95% 0.023-0.92, p = .044). For ABCB1 (1236G > A rs1128503/2677C > A/T rs2032582/3435G > A rs1045642) AA/AA/AA combined genotypes had a strong association with death after HSTC OR 13.73 (CI 95% 1.94-97.17, p = .009). Combined genotypes GG/CC/GG with CDA (79A > C, rs2072671) CA genotype or CDA (-451G > A, rs532545) CT genotype, had a 4.11 OR (CI 95% 2.32-725, p = .007) and 3.8 OR (CI 95% 2.23-6.47, p = .027) with MRD >0.1% after first chemotherapy cycle, respectively. CONCLUSION: Our results highlight the importance of pharmacogenetic analysis in pediatric AML, particularly in populations with a high degree of admixture, and might be useful as a future tool for patient stratification for treatment.

Genomic alterations in a cohort of pediatric acute myeloid leukemia patients at two cancer centers in Colombia.

Few studies identifying genomic aspects in pediatric acute myeloid leukemia patients in Latin American countries have been reported. The aim of this study was to identify genomic alterations, clinical characteristics and outcomes in a cohort of pediatric AML patients. This descriptive observational cohort study included patients with confirmed de novo acute myeloid leukemia up to 18 years of age. Cytogenetics and conventional FISH analysis, next-generation sequencing and PCR testing were performed. The correlation of genomic data with treatment response and outcomes were analyzed. Of the 51 patients analyzed, 67.4% had a cytogenetic abnormality and 74.5% had a genetic variant. FLT3 variants (ITD or TKD D835) were found in 27.4%, followed by NRAS (21.6%), KRAS (13.7%) and WT1 and KIT (11.8%). Patients were stratified by risk (66.6% high-risk) after the end of induction. FLT3-ITD was associated with relapse (OR 11.25; CI 1.89-66.72, p 0.006) and NRAS with death during induction (OR 16.71; CI 1.51-184.59, p 0.022). Our study highlights the importance of rapid incorporation of genetic testing in pediatric AML in Colombia, as it directly affects treatment decisions and outcomes. Incorporation of targeted therapies with conventional chemotherapy is an increasingly urgent need in pediatric patients.

Genomic imbalances defining novel intellectual disability associated loci.

BACKGROUND: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). RESULTS: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. CONCLUSIONS: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

Malignant bone tumors in Pediatrics. Five year experience in a pediatric referral center / Tumores óseos malignos en pediatría. Experiencia de cinco años en un centro de referencia pediátrico

Abstract Background: Osteosarcoma (OS) and Ewing's Sarcoma (ES) are the two most common malignant bone tumors in children. A retrospective review of the records of children diagnosed in a pediatric hospital over a five year period (2008-2013) was performed. Objective: To present the experiences acquired during the treatment of these types of tumors and to compare the results obtained with those reported in the literature. Methodology: The database of the Oncology and Pathology Service of Fundación Hospital de la Misericordia (HOMI) was reviewed to identify patients with primary bone tumors referred for histopathology analysis. Results: 22 patients were diagnosed with OS, with a mean age of 11.9 years. 96% of cases were located in the lower extremities. All patients received neoadjuvant chemotherapy and 86% underwent surgical treatment; 13% survived. 15 patients were diagnosed with ES, with a mean age of 12.4 years. 67% of cases were located in flat bones, 53% of patients had metastasis when diagnosed, and all received neoadjuvant chemotherapy. 40% of patients received surgical intervention and 20% received radiotherapy. Survival at the completion of the reseearch was 33%. Conclusions: Cure and survival rates are lower than those reported in the literature despite efforts to improve treatments.

Resumen Introducción. El osteosarcoma (OS) y el sarcoma de Ewing (SE) son los tumores óseos malignos más frecuentes en edad pediátrica. En el presente estudio se realiza la revisión de los tumores malignos primarios de hueso diagnosticados en un hospital pediátrico de referencia en un período de cinco años (2008-2013). Objetivos. Mostrar la experiencia en el tratamiento de osteosarcomas y sarcomas de Ewing y comparar los resultados con lo reportado en la literatura. Materiales y métodos. Se revisó la base de datos del Servicio de Oncología y Patología de la Fundación Hospital de la Misericordia (HOMI) para identificar los pacientes con tumores primarios de hueso remitidos para estudio histopatológico. Resultados. 22 pacientes con edad promedio de 11.9 años tuvieron diagnóstico de OS; 96% de los casos se localizaron en la extremidad inferior, 100% de los pacientes recibieron quimioterapia neoadyuvante, 86% recibieron manejo quirúrgico y 13% sobrevivieron. 15 pacientes con edad promedio de 12.4 años tuvieron diagnóstico de SE; 67% de los casos se localizaron en huesos planos, 53% de los pacientes presentaron metástasis al diagnóstico, 100% recibieron quimioterapia neoadyuvante, 40% fueron llevados a cirugía y 20% recibieron radioterapia. La sobrevida fue de 33% al finalizar esta investigación. Conclusiones. Las tasas de curación y sobrevida son menores a las reportadas en la literatura a pesar de esfuerzos en mejorar los tratamientos.