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

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 for 55423 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<5x10-8). Additionally, a significant association of rs35704242 in NIBAN1 was associated with the combined response of nonchemotherapy drugs(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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement AKG received funding from the Finnish Cancer Institute Foundation, Blood Disease Research Foundation, K. Albin Johanssons stiftelse sr Foundation, and Maud Kuistila Memorial Foundation. JL received funding from the Academy of Finland (Grant no 325999). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: One seventy-five bone marrow aspirates (leukemic cells) or peripheral blood samples from adult patients were collected with signed informed consent with protocols in accordance with the Declaration of Helsinki [study acronym HRUHLAB2, Helsinki University Hospital Ethical Committee Statement 303/13/03/01/2011 (original), latest amendment 7 dated June 15, 2016. Latest Helsinki University Hospital study permit HUS/395/2018 dated February 13, 2018]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors