Identification of Polymorphisms Associated with Susceptibility to Therapy-Related MDS and AML.
Authors: Walgren Richard , McLaughlin Edward , Peterson Elise , Crosswhite Michael , Province Michael , McLeod Howard , Ley Timothy , Graubert Timothy , Morgan Gareth 
Published: April 2020

Rationale: Therapy-related acute myeloid leukemia (tAML) is a serious and life-threatening iatrogenic disease that occurs after conventional or high-dose chemotherapy, most commonly after exposure to topoisomerase-II inhibitors or alkylating agents. While susceptibility is likely multi-factorial, familial forms of AML are associated with heritable variations in CEBPA and RUNX1. We hypothesize that common germline variants in these and other genes somatically mutated in AML predispose patients to develop tAML.

Methods: To test this hypothesis, 10 genes (BAALC, CBFB, CEBPA, CSF3R, FLT3, HOXA9, KIT, NRAS, PML, and RUNX1) were selected which have been previously shown to be mutated or functionally associated with AML. From these genes, 41 predicted functional or tagging single nucleotide polymorphisms (SNPs) were selected. Genotyping was performed by SNPlex assay. Case samples were obtained from the MRC AML15 trial, and a total of 71 tAML cases, 204 de novo AML cases, and 131 healthy Caucasian controls were genotyped. For rs2256164, rs707656, and rs17084677 another 190 normal Caucasian control subjects were genotyped, and results were concordant with the primary control population. Statistical analyses examined possible associations between allelic or genotype frequencies of control subjects and either tAML or AML subjects. Levels of significance were adjusted for multiple comparisons.

Results: Of the 41 candidate SNPs, 20 are significantly associated with tAML (e.g. Control vs tAML MAF rs2256164 0.076 vs 0.154, rs707656 0.092 vs 0.114, rs17084677 0.023 vs 0.043). Of these, 17 are significantly associated with de novo AML (see Table. We also identified 3 SNPs which discriminate between tAML and AML susceptibility (rs2144012, rs1055308, and rs6662501, p &lt; 0.001).

Conclusions: Our results identify 20 common germline polymorphisms in leukemogenic genes associated with an increased susceptibility to tAML and AML. Validation efforts are ongoing in independent tAML and AML cohorts and, where applicable, will also include SNPs in linkage disequilibrium with these associated SNPs. Subsequent analysis will be expanded to credential the biologic significance of validated SNPs. Ultimately, identification of true susceptibility alleles will facilitate our understanding of the biology of tAML and aid in risk assessment/prevention of this iatrogenic disease.

Control vs tAML Control vs AML Gene RsID Allele Genotype Allele Genotype Threshold of significance: p &lt; 0.001; significant with * overdominant or † dominant model BAALC rs2256164 3.1 E-9 7.4 E-12 6.6 E-14 8.2 E-14 CBF rs16957169 8.6 E-12 1.0 E-7 3.8 E-16 CSF3R rs707656 2.4 E-8 6.5 E-8 3.5 E-6 1.2 E-5 CSF3R rs3917973 8.7 E-4 CSF3R rs3917997 2.1 E-5 1.9 E-7 1.7 E-8 2.5 E-13 CSF3R rs3918019 2.2 E-7 3.0 E-7 FLT3 rs11616983 2.9 E-4 8.6 E-7 FLT3 rs12872889 2.0 E-5 1.4 E-5 1.1 E-9 HOXA9 rs11978680 7.7 E-8 7.9 E-6 1.3 E-5 9.7 E-4† KIT rs17084677 1.1 E-5 2.9 E-6 KIT rs2213181 3.0 E-6 7.3 E-7 KIT rs6554199 3.7 E-4* 1.4 E-6 NRAS rs1065634 2.0 E-8 2.6 E-4 NRAS rs6694035 5.0 E-4 7.0 E-11 3.7 E-9 NRAS rs9724611 6.7 E-7 7.0 E-4 1.4 E-8 NRAS rs9724626 4.9 E-4 0.001 6.8 E-4 NRAS rs9724642 1.5 E-4 PML rs5742915 5.3 E-4† 4.9 E-6 9.7 E-6 RUNX1 rs1055309 1.1 E-7 8.2 E-9