# Space–time clustering of childhood high hyperdiploid B-cell precursor acute lymphoblastic leukemia: a nationwide Swedish study

## TL;DR

This study found that a specific genetic subtype of childhood leukemia in Sweden shows space-time clustering, suggesting possible environmental or infectious causes.

## Contribution

The study is the first to examine space-time clustering in childhood ALL by genetic subtype, revealing clustering in high hyperdiploid cases.

## Key findings

- High hyperdiploid BCP-ALL cases showed significant space-time clustering at birth and diagnosis.
- No clustering was observed in other ALL subtypes like T-ALL or ETV6::RUNX1.
- Findings suggest etiologic differences in BCP-ALL subtypes, warranting further research on environmental factors.

## Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. While space–time clustering of ALL cases has been suggested, only one prior study has examined clustering by genetic subtype. We investigated space–time clustering of childhood ALL in Sweden, both overall and by genetic subtype. The cohort included 1,629 children age 0–18 years diagnosed with ALL between 1992 and 2017, comprising 1,446 B-cell precursor ALL (BCP-ALL) and 183 T-cell ALL (T-ALL) cases. Two BCP-ALL subgroups were analyzed: high hyperdiploidy (HeH, n = 466) and ETV6::RUNX1 (n = 225). The Unbiased Knox Test and Unbiased Combined Knox Test were used to assess space–time clustering at the municipality level, accounting for multiple testing and population shifts. The Density-Based Spatial Clustering of Applications with Noise (DBSCAN) algorithm was applied to identify significant clusters. Logistic regression was used to evaluate demographic differences between clusters, including age, sex, and birth order. Significant space–time clustering was observed in the HeH subgroup for both place and date of birth (p = 0.005) and place and date of diagnosis (p = 0.011), at space–time thresholds of 40 km/18 months and 30 km/24 months, respectively. No clustering was detected in the overall BCP-ALL group, T-ALL group, or the ETV6::RUNX1 subgroup. Space–time clustering at birth and diagnosis was observed in the HeH subgroup, suggesting potential etiologic heterogeneity in BCP-ALL. These findings support further investigation of environmental and infectious exposures across immunophenotypes and genetic subtypes in larger cohorts.

The online version contains supplementary material available at 10.1007/s10654-025-01323-9.