Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukaemia patients

Abstract

Acute myeloid leukemia (AML) is a rare aggressive blood cancer without any long-term cure. 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, economic 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 largest exome-wide association study (EWAS) of ex-vivo drug response performed to date with 175 AML cases and 47 drugs. We used information from 55423 exonic SNPs to perform the analysis. We identified exome-wide significant (p<9.02 x10-7) 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<5x10-8). Additionally, a significant association of rs35704242 in NIBAN1 was associated with the combined response for nonchemotherapy medicines (p=2.51x10-8), and BI.2536, gefitinib, and belinostat were identified as the central traits. Our study represents the largest EWAS study 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.