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Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukemia patients
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Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukemia patients
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Journal Article
Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukemia patients
2025
Overview
Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by poor survival outcomes. Further, due to the extreme molecular heterogeneity of the disease, drug treatment response varies from patient to patient. The variability of drug response can cause unnecessary treatment in more than half of the patients with no or partial therapy responses leading to severe side effects, monetary as well as time loss. Understanding the genetic risk factors underlying the drug response in AML can help with improved prediction of treatment responses and identification of biomarkers in addition to mechanistic insights to monitor treatment response. Here, we report the results of the first Exome-Wide Association Study (EWAS) of ex-vivo drug response performed to date with 175 AML cases and 47 drugs. We used information from 55,423 germline exonic SNPs to perform the analysis. We identified exome-wide significant (
p
< 9.02 × 10
− 7
) associations for rs113985677 in
CCIN
with tamoxifen response, rs115400838 in
TRMT5
with idelalisib response, rs11878277 in
HDGFL2
with entinostat, and rs2229092 in
LTA
associated with vorinostat response. Further, using multivariate genome-wide association analysis, we identified the association of rs11556165 in
ATRAID
, and rs11236938 in
TSKU
with the combined response of all 47 drugs and 29 nonchemotherapy drugs at the genome-wide significance level (
p
< 5 × 10
− 8
). Additionally, a significant association of rs35704242 in
NIBAN1
was associated with the combined response for nonchemotherapy medicines (
p
= 2.51 × 10
− 8
), and BI.2536, gefitinib, and belinostat were identified as the central traits. Our study represents the first EWAS to date on ex-vivo drug response in AML and reports 7 new associated loci that help to understand the anticancer drug response in AML patients.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Adult
/ Aged
/ AML
/ Antineoplastic Agents - therapeutic use
/ Biomedical and Life Sciences
/ Biopsy
/ CCIN
/ Female
/ Genome-Wide Association Study
/ Humans
/ Leukemia
/ Leukemia, Myeloid, Acute - drug therapy
/ Leukemia, Myeloid, Acute - genetics
/ Male
/ NIBAN1
/ Patients
