# Loss of Heterozygosity in Pediatric Acute Lymphoblastic Leukemia and Its Prognostic Impact: A Retrospective Study

## TL;DR

This study examines how loss of heterozygosity (LOH) in pediatric ALL is linked to prognosis and treatment response, identifying high-risk subgroups through genetic profiling.

## Contribution

The study introduces a novel approach to stratify pediatric ALL patients using LOH patterns and their association with clinical outcomes.

## Key findings

- B-ALL patients with extensive LOH, especially on chromosome 9, had poor prognosis and treatment response.
- T-ALL patients with biallelic CDKN2A deletion showed aggressive disease features.
- LOH profiling can help identify high-risk subgroups and predict treatment outcomes in ALL.

## Abstract

In acute lymphoblastic leukemia (ALL), loss of heterozygosity (LOH), including copy-neutral LOH, occurs alongside classic chromosomal aberrations. The aim of this study is to identify and analyze patterns of LOH, assess their frequency, and evaluate their association with clinical characteristics and early treatment response during the induction phase of the ALL protocol. The study included 853 children with ALL: 120 patients with B-ALL LOH+ and 58 patients with T-ALL LOH+. LOH was analyzed using CytoScan HD SNP microarrays. Multiple correspondence analysis and hierarchical clustering identified three clusters based on genetic and clinical profiles. In B-ALL, two clusters showed poor prognosis and treatment response, while Cluster 2—with CDKN2A duplication and rare LOH—had favorable outcomes. In T-ALL, Cluster 1 had a good prognosis despite CDKN2A LOH; Cluster 2 showed aggressive features with biallelic deletions; Cluster 3 lacked LOH of the CDKN2A gene and was characterized by a genetically stable profile. In B-ALL, whole-chromosome LOH, especially of chromosome 9, was frequent, unlike in T-ALL. LOH was less common in chromosomes affected by trisomy.

Background: In childhood acute lymphoblastic leukemia (ALL), in addition to classical chromosomal abnormalities, loss of heterozygosity (LOH), including copy-neutral LOH, is also observed. While LOH has been described in the literature, its clinical relevance in pediatric ALL remains unclear. The aim of this study is to identify and analyze patterns of LOH, assess their frequency, and evaluate their association with clinical characteristics and early treatment response during the induction phase of the ALL protocol. Methods: The study included 853 pediatric ALL patients, of whom 120 had B-ALL LOH+ and 58 had T-ALL LOH+. LOH was analyzed using CytoScan HD SNP microarrays. Patients were stratified using multiple correspondence analysis (MCA) and hierarchical clustering on principal components (HCPC), which identified three genetically and clinically distinct clusters. Results: In B-ALL, two clusters with extensive LOH—particularly involving chromosome 9—were associated with poor prognosis and suboptimal response to therapy. In contrast, Cluster 2, characterized by CDKN2A duplication and rare LOH, showed a favorable clinical course. In T-ALL, Cluster 1 had LOH in CDKN2A but favorable outcomes; Cluster 2 exhibited biallelic CDKN2A deletion and aggressive disease; Cluster 3 lacked CDKN2A alterations and showed a genetically stable profile. LOH was common on chromosomes not typically affected by trisomy and rare on those gained. Conclusions: Our study indicates that LOH profiling can positively influence patient stratification by identifying high-risk subgroups, inform prognosis by highlighting unfavorable genetic alterations, and help predict poor treatment response in specific clinical profiles.