Role of common host genome variants in Childhood Acute Lymphoblastic Leukemia

Childhood acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease, and while somatic alterations inform diagnosis and treatment stratification, germline variants - particularly common host genome variants - rarely influence clinical care. Over the past decade, various host genome variant studies have uncovered numerous common variants associated with ALL susceptibility, treatment efficacy, and toxicity risk. Yet, less than a handful have reached clinical implementation, with TPMT and NUDT15 variants being the only ones widely used clinically. Whether a variant can be readily translated into the clinical setting primarily depends on four features: (1) Phenotype severity, (2) phenotype rarity and the proportion of cases (overall or in subsets of patients) accounted for by genetic variants, (3) the application of the variant as an add-on clinical decision support tool, and (4) the availability, cost, and potential side effects of interventions and/or prophylaxis. Key barriers for such clinical translation include insufficient effect sizes, lack of replication across diverse populations, and lack of well-established treatment modification strategies. However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.

Authors

Institutions

Publication Details

Journal
Leukemia
Published
2025-12-08
DOI
https://doi.org/10.1038/s41375-025-02804-2
Primary Topic
Acute Lymphoblastic Leukemia research
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Role of common host genome variants in Childhood Acute Lymphoblastic Leukemia

Ulrik Kristoffer Stoltze, Stefanie V. Junk, Gabriele Escherich, Arndt Borkhardt et al.
Leukemia
Acute Lymphoblastic Leukemia research
article

Role of common host genome variants in Childhood Acute Lymphoblastic Leukemia

Ulrik Kristoffer Stoltze, Stefanie V. Junk, Gabriele Escherich, Arndt Borkhardt, Liv Andrés‐Jensen, Melanie M. Hagleitner, Louise Lundgren, Linea Natalie Toksvang, Marianne Helenius, Nuria Conde Cuevas, Christina Halsey, Μirella Αmpatzidou, Jonathan Josephs‐Spaulding, Kjeld Schmiegelow, Sophia Polychronopoulou, Ayo Wahlberg, Andishe Attarbaschi, Theis Bech Mikkelsen, Simone Pehn
article en

Abstract

Childhood acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease, and while somatic alterations inform diagnosis and treatment stratification, germline variants - particularly common host genome variants - rarely influence clinical care. Over the past decade, various host genome variant studies have uncovered numerous common variants associated with ALL susceptibility, treatment efficacy, and toxicity risk. Yet, less than a handful have reached clinical implementation, with TPMT and NUDT15 variants being the only ones widely used clinically. Whether a variant can be readily translated into the clinical setting primarily depends on four features: (1) Phenotype severity, (2) phenotype rarity and the proportion of cases (overall or in subsets of patients) accounted for by genetic variants, (3) the application of the variant as an add-on clinical decision support tool, and (4) the availability, cost, and potential side effects of interventions and/or prophylaxis. Key barriers for such clinical translation include insufficient effect sizes, lack of replication across diverse populations, and lack of well-established treatment modification strategies. However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.

LeukemiaVol. 40(1)
University of Copenhagen (DK), Hospital Sant Joan de Déu Barcelona (ES), Goethe-Institute United Kingdom (GB), Universität Hamburg (DE), Royal Hospital for Children (GB), Rigshospitalet (DK), University Medical Center Hamburg-Eppendorf (DE), Children's Hospital Agia Sophia (GR), St Anna Children's Hospital (AT), Princess Máxima Center (NL), St. Anna Children's Cancer Research Institute, Heinrich Heine University Düsseldorf (DE), Medical University of Vienna (AT), University of Glasgow (GB)
Børnecancerfonden, Novo Nordisk, Novo Nordisk Fonden, Interreg
Openalex Percentile: Top 50%
Acute Lymphoblastic Leukemia research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.