
==== Front
Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

39184069
10.21203/rs.3.rs-4858231/v1
10.21203/rs.3.rs-4858231
preprint
1
Article
Impact of Genetic Ancestry on T-cell Acute Lymphoblastic Leukemia Outcomes
Teachey David https://orcid.org/0000-0001-7373-8987

Newman Haley
Lee Shawn
Pölönen Petri https://orcid.org/0000-0001-6128-9985

Shraim Rawan
Li Yimei https://orcid.org/0000-0001-9067-6992

Liu Hongyan
Aplenc Richard
Bandyopadhyay Shovik
Chen Changya
Chen Zhiguo
Devidas Meenakshi
Diorio Caroline
Dunsmore Kimberly
Elghawy Omar
Elhachimi Amira
Fuller Tori
Gupta Sumit
Hall Junior
Hughes Andrew
Hunger Stephen
Loh Mignon https://orcid.org/0000-0003-4099-4700

Martinez Zachary
McCoy Michael https://orcid.org/0000-0001-5215-2725

Mullen Cassidy
Pounds Stanley https://orcid.org/0000-0002-9167-2114

Raetz Elizabeth
Ryan Theresa
Seffernick Anna
Shi Gongping
Sussman Jonathan https://orcid.org/0000-0002-3057-3550

Tan Kai
Uppuluri Lahari
Vincent Tiffaney L
Wang'ondu Ruth
Winestone Lena
Winter Stuart
Wood Brent
Wu Gang https://orcid.org/0000-0002-1678-5864

Xu Jason
Yang Wenjian https://orcid.org/0000-0002-7305-5649

Mullighan Charles https://orcid.org/0000-0002-1871-1850

Yang Jun https://orcid.org/0000-0002-0770-9659

Bona Kira
16 8 2024
rs.3.rs-4858231https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4858231/v1
nihpp-rs4858231v1.pdf
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.
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