Cyclin dependent kinase inhibitor 2A/B gene deletions are markers of poor prognosis in Indian children with acute lymphoblastic leukemia.

Abstract

Cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) genes are implicated in many malignancies including acute lymphoblastic leukemia (ALL). These tumor suppressor genes, with a key regulatory role in cell cycle are located on chromosome 9p21.3. Previous studies involving CDKN2A/B gene deletions have shown mixed associations with survival outcome in childhood ALL. Hundred and four newly diagnosed children with ALL (1-14 years) were enrolled in this study. Genomic DNA from pretreatment bone marrow/peripheral blood samples of these children was investigated for copy number alterations in CDKN2A/B genes using multiplex ligation dependent probe amplification assay. Immunophenotype subtyping and cytogenetic and molecular analysis of ALL was performed at start of induction chemotherapy in all children. Children were monitored for response to prednisolone (Day 8), complete morphological remission, and minimal residual disease at the end of induction. The minimum postinduction follow-up period was 6 months. CDKN2A/B deletions were seen in 19.8% (18/91) of B lineage acute lymphoblastic leukemia (B-ALL) and 38.5% (5/13) of T lineage acute lymphoblastic leukemia (T-ALL). Monoallelic CDKN2A/B deletions were found in 61.1% of total deletions in B-ALL while all the children with T-ALL harbored biallelic deletions. The prevalence of CDKN2A/B gene deletions was found to be significantly higher in older children (P=0.002), in those with higher leukocyte count (P=0.037), and in National Cancer Institute high risk group patients (P=0.001) in the B-ALL subgroup. Hazard ratio was significantly high for children with CDKN2A/B deletions in total cohort (P=0.004). Children with CDKN2A/B deletion had significantly lesser event free survival (P=0.03). CDKN2A/B deletions were significantly more prevalent in T-ALL subgroup and were found to have higher hazard ratio and lesser event free survival in total cohort in our study.