Genetic Susceptibility to Therapy-Related Leukemia (t-MDS/AML) After Hodgkin Lymphoma (HL) or Non-Hodgkin Lymphoma (NHL)

• Published in: Blood 2009-11, Vol.114 (22), p.199-199
• Main Authors: Ding, Yan, Sun, Can-Lan, Francisco, Liton, Sabado, Melanie, Li, Liang, Hahn, Brian, Larson, Garrett, Forman, Stephen J., Bhatia, Ravi, Bhatia, Smita
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V114.22.199.199

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