Gene copy number alterations in Indian children with B-acute Lymphoblastic Leukemia: Correlation with survival outcome

Background: Acute Lymphoblastic Leukemia (ALL) is the most common lymphoid malignancy occurring in children. Copy number alterations like CDKN2A/B, IKZF1, ETV6, RB1 and BTG1 gene deletions have been shown to be associated with differential survival outcome. The literature on survival outcome of children with each gene deletion is very limited. The targeted therapy for some of these gene deletions are under trial in adult ALL. Our study will provide insight in the role of such genes in disease biology. Methods: A total of 91 children with newly diagnosed ALL were enrolled and monitored for response to treatment and were followed up for 4.0 years and analyzed for copy number alterations by Multiplex ligation dependent probe amplification assay (MLPA) using SALSA MLPA probemix P335–B2 ALL-IKZF1 kit. Survival analysis was performed using event free survival (EFS) as the end point.Survival curves between two groups were calculated using Kaplan-Meier analysis and compared using log-rank tests. Other comparisons were performed using the Chi-squared or Fisher's exact test. All analyses were performed using Stata 14.0. Results: We observed gene copy number alterations in 51.6% of children with B-ALL subgroup. CDKN2A/B was the most commonly observed gene deletion followed by PAX5, ETV6, IKZF1, RB1, BTG1 and EBF1. Children with CDKN2A/B, IKZF1, RB1 and BTG1 gene deletion had significantly lesser event free survival as compared to those without gene deletions in short term follow up while ETV6 and EBF1 gene deletions and PAR1 gene alterations did not have any impact on survival outcome. Discussion: Event free survival in children with CDKN2A/B, IKZF1, RB1 and BTG1 gene deletions was significantly lower in short term possibly due to aggressive disease phenotype with faster progression. We found PAR1 gene alterations to be associated with better event free survival in long term follow up though it did not show significant association. Conclusions: CDKN2A/B, IKZF1 and RB1 gene deletions were independently associated with poor event free survival. We opine that individual gene deletions, and not integrated copy number alterations profile, may be used for risk stratification and the CDKN2A/B, IKZF1 and RB1 may serve as poor prognostic markers.