Germline ATP2B2 Variant Associates With Central Nervous System Involvement in Childhood Acute Lymphoblastic Leukemia

ABSTRACT Background Genome‐wide association studies (GWASs) can uncover inherited determinants of clinically relevant leukemia phenotypes, but their utility depends on precise phenotyping. Central nervous system (CNS) involvement in childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) is prognostically important, but its underlying biology remains poorly understood. We investigated inherited determinants using a sensitive, standardized definition of CNS involvement. Procedure We conducted a pooled observational cohort GWAS of CNS involvement at diagnosis among 674 patients with BCP‐ALL from the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 and ALLTogether1 cohorts. CNS involvement was defined as ≥10 leukemic blasts detected in diagnostic cerebrospinal fluid by flow cytometry (FCM). Association testing used logistic regression adjusted for white blood cell count and genetic ancestry. Cox regression assessed variant associations with time to relapse. Findings were evaluated in an independent Associazione Italiana di Ematologia e Oncologia Pediatrica–Berlin–Frankfurt–Münster ALL 2000 protocol (AIEOP‐BFM2000) cohort through targeted analysis. Results Among 10,242,929 variants passing quality control, rs13059398, an intronic ATP2B2 variant, was associated with CNS involvement at genome‐wide significance ( p = 3.28 × 10 −8 ; odds ratio [OR] = 6.07; 95% confidence interval, 3.2–11.5). The variant was carried by 21/113 (18.6%) CNS‐positive and 29/559 (5.2%) CNS‐negative patients. Although directionally consistent in the validation cohort, the association was not statistically significant. ATP2B2 , predominantly expressed in CNS tissues, encodes the plasma membrane Ca 2+ ATPase plasma membrane calcium ATPase 2 (PMCA2). There was no association with time to relapse. Conclusions Germline variation at ATP2B2 was associated with FCM‐defined CNS involvement in childhood BCP‐ALL. These findings identify ATP2B2 as a candidate locus for further investigation of the biological mechanisms underlying leukemic CNS involvement.