Abstract
Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair
Highlights
Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a major cause of non-relapse mortality in patients treated for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL).[1] therapy-related myelodysplasia. aAdjusted for gender (t-MDS)/AML is associated with exposure to alkylating agents and topoisomerase II inhibitors
Using both genotype and gene expression analyses, we investigated whether individual genetic variability in these pathways modify the risk of t-MDS/AML in patients with HL or NHL exposed to genotoxic agents (Figure 1)
Gene expression patterns were studied in hematopoietic stem/progenitor cells (HSC) from peripheral blood stem cell (PBSC) autografts from a subset of 12 NHL cases and 22 matched controls
Summary
Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair. Previous studies have been largely inconclusive, primarily because of the focus on single genes.[3,4] In the few studies where multiple genes were examined simultaneously, individuals with more than one risk variant were at higher risk.[5,6] We hypothesized that genetic variations encoded in key genes in the pathways of drug metabolism, apoptosis, DNA synthesis, methylation and repair, as well as genes involved in de novo AML,[7] could potentially contribute to the risk of t-MDS/AML Using both genotype and gene expression analyses, we investigated whether individual genetic variability in these pathways modify the risk of t-MDS/AML in patients with HL or NHL exposed to genotoxic agents (Figure 1). The homozygous A allele of A1298C increased the risk 33-fold (P 1⁄4 0.0005) when combined with the Pro carrier of P72R compared with its combination with homozygous Arg in the adjusted analysis
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