Association of GATA3 Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Minimal residual disease (MRD) after induction therapy is one of the strongest prognostic factors in childhood acute lymphoblastic leukemia (ALL), and MRD-directed treatment intensification improves survival. Little is known about the effects of inherited genetic variants on interpatient variability in MRD. METHODS: A genome-wide association study was performed on 2597 children on the Children's Oncology Group AALL0232 trial for high-risk B-cell ALL. Association between genotype and end-of-induction MRD levels was evaluated for 863 370 single nucleotide polymorphisms (SNPs), adjusting for genetic ancestry and treatment strata. Top variants were further evaluated in a validation cohort of 491 patients from the Children's Oncology Group P9905 and 6 ALL trials. The independent prognostic value of single nucleotide polymorphisms was determined in multivariable analyses. All statistical tests were 2-sided. RESULTS: In the discovery genome-wide association study, we identified a genome-wide significant association at the GATA3 locus (rs3824662, odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.35 to 1.84; P = 1.15 × 10-8 as a dichotomous variable). This association was replicated in the validation cohort (P = .003, MRD as a dichotomous variable). The rs3824662 risk allele independently predicted ALL relapse after adjusting for age, white blood cell count, and leukemia DNA index (P = .04 and .007 in the discovery and validation cohort, respectively) and remained prognostic when the analyses were restricted to MRD-negative patients (P = .04 and .03 for the discovery and validation cohorts, respectively). CONCLUSION: Inherited GATA3 variant rs3824662 strongly influences ALL response to remission induction therapy and is associated with relapse. This work highlights the potential utility of germline variants in upfront risk stratification in ALL.

Epidemiology of childhood malignant mediastinal masses and clinical factors associated with intensive care unit admission: A Singapore experience.

AIM: Majority of mediastinal masses in children are malignant. These masses are complex to manage as they have a risk of compression to surrounding structures. Many of these children have to be managed in the intensive care unit (ICU). Hence we sought to evaluate the local epidemiology of malignant mediastinal masses in children and their clinical presentation, and identified factors associated with ICU admission so that at-risk patients may be identified early. METHODS: This study is a retrospective review of institutional case records of 56 children below 18 years of age from 2000 to 2015 with a malignant mediastinal mass. We collected data on their presenting symptoms, clinical signs, radiological investigations, treatment and correlated these factors with admission to our ICU. RESULTS: Lymphoma was most common diagnosis, comprising 37 children (66.0%). There were 6 patients with neuroblastoma (10.7%), 3 patients with germ-cell tumour (5.4%) and 10 patients with T-cell acute lymphoblastic leukaemia (17.9%). Overall, 21 patients (37.5%) had to be admitted to the ICU. Almost all patients (98.2%) were symptomatic on presentation, of which lymphadenopathy was the most common (69.6%). Factors that are significantly associated with ICU admission are stridor, pericardial effusion and need for pleural drainage. CONCLUSIONS: Malignant mediastinal masses in children in our institution range from leukaemias and lymphomas to germ cell tumours and neuroblastomas, of which almost all are symptomatic. These children have a risk of cardiorespiratory collapse and many of them require intensive care. We identified factors that are associated with ICU admission, with the aim of early intervention of at-risk cases.