Impact of Genetic Ancestry on T-cell Acute Lymphoblastic Leukemia Outcomes

TL;DR

This study shows that genetic ancestry affects T-cell leukemia outcomes and risk classification, highlighting the need to consider ancestry in genomic analyses.

Contribution

The study reveals ancestry-specific differences in T-ALL genomics and survival, and develops a risk model that works across ancestries.

Findings

Genetic ancestry influences T-ALL molecular subtypes and survival outcomes.

A new risk stratification model successfully classifies patients across different ancestries.

Commonly altered genes in T-ALL have varying prognostic significance by genetic ancestry.

Abstract

The influence of genetic ancestry on biology, survival outcomes, and risk stratification in T-cell Acute Lymphoblastic Leukemia (T-ALL) has not been explored. Genetic ancestry was genomically-derived from DNA-based single nucleotide polymorphisms in children and young adults with T-ALL treated on Children’s Oncology Group trial AALL0434. We determined associations of genetic ancestry, leukemia genomics and survival outcomes; co-primary outcomes were genomic subtype, pathway alteration, overall survival (OS), and event-free survival (EFS). Among 1309 patients, T-ALL molecular subtypes varied significantly by genetic ancestry, including increased frequency of genomically defined ETP-like, MLLT10, and BCL11B-activated subtypes in patients of African ancestry. In multivariable Cox models adjusting for high-risk subtype and pathways, patients of Admixed American ancestry had superior 5-year EFS/OS compared with European; EFS/OS for patients of African and European ancestry were similar. The prognostic value of five commonly altered T-ALL genes varied by ancestry – including
NOTCH1
, which was associated with superior OS for patients of European and Admixed American ancestry but non-prognostic among patients of African ancestry. Furthermore, a published five-gene risk classifier accurately risk stratified patients of European ancestry, but misclassified patients of African ancestry. We developed a penalized Cox model which successfully risk stratified patients across ancestries. Overall, 80% of patients had a genomic alteration in at least one gene with differential prognostic impact by genetic ancestry. T-ALL genomics and prognostic associations of genomic alterations vary by genetic ancestry. These data demonstrate the importance of incorporating genetic ancestry into analyses of tumor biology for risk classification algorithms.