Rare Drivers at Low Prevalence with High Cancer Effects in T-Cell and B-Cell Pediatric Acute Lymphoblastic Leukemia

TL;DR

This study identifies rare mutations with strong cancer effects in T-cell and B-cell pediatric leukemia, suggesting new therapeutic targets.

Contribution

The paper introduces a method to estimate cancer effects of mutations, highlighting rare drivers with high impact in pediatric ALL.

Findings

Mutations in IL7R, XBP1, and TOX showed high cancer effects despite low prevalence in B-cell ALL.

PIK3R1 and RPL10 mutations in T-cell ALL had high cancer effects even though they are rare.

CDKN2A mutations may influence other mutations epistatically, despite low prevalence and moderate cancer effects.

Abstract

The genomic analyses of pediatric acute lymphoblastic leukemia (ALL) subtypes, particularly T-cell and B-cell lineages, have been pivotal in identifying potential therapeutic targets. Typical genomic analyses have directed attention toward the most commonly mutated genes. However, assessing the contribution of mutations to cancer phenotypes is crucial. Therefore, we estimated the cancer effects (scaled selection coefficients) for somatic substitutions in T-cell and B-cell cohorts, revealing key insights into mutation contributions. Cancer effects for well-known, frequently mutated genes like NRAS and KRAS in B-ALL were high, which underscores their importance as therapeutic targets. However, less frequently mutated genes IL7R, XBP1, and TOX also demonstrated high cancer effects, suggesting pivotal roles in the development of leukemia when present. In T-ALL, KRAS and NRAS are less frequently mutated than in B-ALL. However, their cancer effects when present are high in both subtypes. Mutations in PIK3R1 and RPL10 were not at high prevalence, yet exhibited some of the highest cancer effects in individual T-cell ALL patients. Even CDKN2A, with a low prevalence and relatively modest cancer effect, is potentially highly relevant for the epistatic effects that its mutated form exerts on other mutations. Prioritizing investigation into these moderately frequent but potentially high-impact targets not only presents novel personalized therapeutic opportunities but also enhances the understanding of disease mechanisms and advances precision therapeutics for pediatric ALL.

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