Prognostic Impact of Somatic Copy Number Alterations in Childhood B-Lineage Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: The high prevalence of relapse in pediatric B-lineage acute lymphoblastic leukemia (B-ALL) despite the improvements achieved using current risk stratification schemes, demands more accurate methods for outcome prediction. Here, we provide a concise overview about the key advances that have expanded our knowledge regarding the somatic defects across B-ALL genomes, particularly focusing on copy number alterations (CNAs) and their prognostic impact. RECENT FINDINGS: The identification of commonly altered genes in B-ALL has inspired the development of risk classifiers based on copy number states such as the IKZF1plus and the United Kingdom (UK) ALL-CNA classifiers to improve outcome prediction in B-ALL. CNA-risk classifiers have emerged as effective tools to predict disease relapse; though, their clinical applications are yet to be transferred to routine practice.

Copy Number Alterations are Associated with the Risk of Very Early Relapse in Pediatric B-lineage Acute Lymphoblastic Leukemia: A Nested Case-control MIGICCL Study.

BACKGROUND: Refining risk stratification to avoid very early relapses (VER) in Mexican patients with B-lineage acute lymphoblastic leukemia (B-ALL) could lead to better survival rates in our population. AIM OF THE STUDY: The purpose of this study was to investigate the association between the United Kingdom ALL (UKALL)-CNA classifier and VER risk in Mexican patients with childhood B-ALL. METHODS: A nested case-control study of 25 cases with VER and 38 frequency-matched controls without relapse was conducted within the MIGICCL study cohort. They were grouped into the categories of the UKALL-CNA risk classifier (good [reference], intermediate and poor), according to the results obtained by multiplex ligation dependent probe amplification. Overall and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards analyses were conducted. RESULTS: The CDKN2A/B genes were most frequently deleted in the group with relapse. According to UKALL-CNA classifier, 33 (52.4%) patients were classified as good, 21 (33.3%) intermediate and 9 (14.3%) poor-risk B-ALL. The intermediate and poor risk groups were associated with an increased risk of VER (HR = 4.94, 95% CI = 1.87-13.07 and HR = 7.42, 95% CI = 2.37-23.26, respectively) in comparison to the good-risk patients. After adjusting by NCI risk classification and chemotherapy scheme in a multivariate model, the risks remained significant. CONCLUSIONS: Our data support the clinical utility of profiling CNAs to potentially refine current risk stratification strategies of patients with B-ALL.

Association Between the Brain-derived Neurotrophic Factor Val66Met Polymorphism and Overweight/Obesity in Pediatric Population.

BACKGROUND: The brain-derived neurotrophic factor (BDNF) rs6265 (G196A; Val66Met) single nucleotide polymorphism has been associated with BMI and obesity in distinct populations, both adult and pediatric, with contradictory results involving either Val or Met as the risk variant. AIM OF THE STUDY: To determine the association between the BDNF Val66Met polymorphism and BMI in Mexican children and adolescents. METHODS: BDNF Val66Met genotyping by restriction fragment length polymorphism and nutritional status characterized by their BMI-for-age z-scores (BAZ) from pediatric volunteers (n = 498) were analyzed by Fisher's exact test association analysis. Standardized residuals (R) were used to determine which genotype/allele had the major influence on the significant Fisher's exact test statistic. Odds ratios were analyzed to measure the association between genotype and normal weight (≥-2 SD < + 1 SD) and overweight (≥ + 1 SD, including obesity, Ow + Ob) status with 95% confidence intervals to estimate the precision of the effect as well as 95% credible intervals to obtain the most probable estimate. RESULTS: Comparisons between GG (Val/Val), GA (Val/Met) and AA (Met/Met) genotypes or Met homozygotes vs. Val carriers (combination of GG and GA genotypes) showed significant differences (p = 0.034 and p = 0.037, respectively) between normal weight and the combined overweight and obese pediatric subjects. Our data showed that children/adolescents homozygous for the A allele have increased risk of overweight compared to the Val carriers (Bayes OR = 4.2, 95% CI**[1.09-33.1]). CONCLUSION: This is the first study showing the significant association between the BDNF rs6265 AA (Met/Met) genotype and overweight/obesity in Mexican pediatric population.

Copy Number Alterations Associated with Acute Lymphoblastic Leukemia in Mexican Children. A report from The Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia.

B-cell precursor acute lymphocytic leukemia (B-ALL) represents a worldwide public health issue. Particularly, Mexico is one of the countries with the highest incidence of ALL in children. Between the multiple factors involved in ALL etiology, genetic alterations are clearly one of the most relevant features. In this work, a group of 24 B-ALL patients, all negative for the four most frequent gene fusions (ETV6-RUNX1, BCR-ABL1, TCF3-PBX1 and MLL-AF4), were included in a high-resolution microarray analysis in order to evaluate genomic copy-number alterations (CNAs). The results of this preliminary report showed a broad genomic heterogeneity among the studied samples; 58% of the patients were hyperdiploid and 33% displayed a chromosome 9p deletion of variable length affecting genes CDKN2A/B, two patients displayed genomic instability with a high number of focal CNAs, three patients presented unique duplications affecting 2q, 12p and 1q, respectively, and one patient displayed no copy number imbalances. The copy-number profile of 44 genes previously related to B-ALL was heterogeneous as well. Overall results highlight the need for a detailed description of the genetic alterations in ALL cancer cells in order to understand the molecular pathogenesis of the disease and to identify any prognostic markers with clinical significance.