Genetic Susceptibility to Therapy-Related Leukemia (t-MDS/AML) After Hodgkin Lymphoma (HL) or Non-Hodgkin Lymphoma (NHL).
Authors: Ding Yan , Sun Can-Lan , Francisco Liton , Sabado Melanie , Li Liang , Hahn Brian , Larson Garrett , Forman Stephen J. , Bhatia Ravi , Bhatia Smita 
Published: October 2019

Abstract
Abstract 199

Therapy-induced t-MDS/AML is the leading cause of non-relapse mortality after HL or NHL. However, there exists a wide variation in t-MDS/AML susceptibility – potentially explained by individual variability in drug metabolism, DNA repair and apoptosis, or in genetic profiles shared with de novo AML. Using a matched case-control study design, we examined the association between t-MDS/AML and candidate genes (n=29) in relevant biological pathways, including hematopoietic regulation (RUNX1, HLX1); apoptosis (TP53, MDM2); drug metabolism (CYP3A4, CYP1A1, GSTM1, GSTP1, GSTT1, NQO1); DNA repair (MGMT, MUTYH, MLH1, MSH2, MTHFR, RAD51, RAD51C, RAD52, XRCC1, XRCC2, XRCC3, XRCC4, XPD); and genes associated withde novoAML (LAMC2/NMNAT2, SGCE/PEG10, FRAP1, and PTPRT). The study cohort consisted of 46 cases with t-MDS/AML after HL/NHL and 46 controls with HL/NHL, but without t-MDS/AML (matching criteria: primary diagnosis, age and year of primary diagnosis, length of follow-up and genetic ancestry [see Table]). Sequenom MassArray and PCR were used to analyze 55 SNPs and 2 deletions in these genes. After correction for multiple testing, we could not identify significant association between any single SNP and t-MDS/AML. However, we did confirm enrichment of risk genotypes in t-MDS/AML for 2 of 4 loci previously implicated in de novo AML by a genome wide association study in Caucasians: LAMC2/NMNAT2 (minor allele carrier [MAC] odds ratio [OR]=4.0, p=0.1) and PTPRT (MAC OR=4.5, p=0.06). Next, we tested the hypothesis that TP53 plays a role in mediating apoptotic response to DNA damage following genotoxic exposures. We modeled interactions between a common coding SNP of TP53 causing a Pro 72 to Arg variant (P72R: Pro allele is associated with ∼15-fold decreased apoptotic capacity compared to Arg) and other candidate SNPs. We identified significant interaction between TP53 and several SNPs in MTHFR (Min. likelihood ratio pinteraction=0.0003 and 0.04 adjusted after 10000 permutations). Although the homozygous T allele of rs7538516 (associated with lower MTHFR expression) was not associated with t-MDS/AML by itself, it increased the risk 11-fold (OR=11.4, p=0.005) when combined with a Pro/Arg or Pro/Pro genotype of P72R compared to its combination with Arg/Arg. This observation suggests that reduced MTHFR activity (associated with increased risk of chromosomal aberrations during DNA repair), in combination with reduced apoptotic capacity (Pro/Arg or Pro/Pro variant of TP53), increases the risk of t-MDS/AML. Next, we examined expression levels of these 29 genes (79 probe sets in Affymetrix U133 Plus 2.0 microarrays) in a subset of 13 cases matched with 28 controls. Using a general linear model adjusted for age, gender, race, and exposure to alkylating agents, topoisomerase inhibitors and radiation, we detected 11 of the 29 (38%) genes to be differentially expressed between cases and controls (p<0.05). Strong signals (p<0.05 after Holm-Bonferroni adjustment) were observed for TP53 (apoptosis), genes involved in drug metabolism (CYP3A4 [activation], GSTM1, GSTP1, and GSTT1 [detoxification]), in DNA repair (MSH2), and genes associated with de novo MDS/AML (NMNAT2, PEG10). Taken together, these observations provide evidence supporting the following: i) a significant association between individual capacity of apoptosis, drug metabolism, DNA repair, and t-MDS/AML; and ii) shared genetic susceptibility between t-MDS/AML and de novo AML. These observations not only further our understanding of the pathogenesis of t-MDS/AML, but also help identify those at the highest risk, setting the stage for targeted surveillance or pharmacological interventions.

Disclosures:
No relevant conflicts of interest to declare.