The study of rare cancers has led to major findings in cancer etiology. Infants with leukemia may represent another such rare group. Infants with leukemia are clinically, epidemiologically, and biologically distinct from older children with leukemia. Approximately 60% of infants with acute myeloid leukemia (AML) and 75% of infants with acute lymphoblastic leukemia (ALL) present with an MLL gene rearrangement in their leukemia cells. Molecular studies demonstrate that infant leukemia's arise in utero. Our preliminary data indicate that maternal exposure to environmental agents, including DNA topoisomerase II inhibitors, are important in the etiology of infant leukemia. Further, others and we have evidence to suggest that the etiology of MLL positive infant leukemia is distinctly different from MLL negative infant leukemia. We are uniquely positioned to expand our current study to increase the statistical power to evaluate associations between MLL positive and MLL negative infant leukemia. Further, we can collect DNA retrospectively and prospectively from both mothers and infants to investigate the role of specific genetic polymorphisms in the etiology of infant leukemia.
Our specific aims are to: a) interview an additional 240 mothers of infant cases (bringing the case total to 484) to increase the statistical power and make this the largest study to ask whether specific chemicals are associated with MLL infant leukemia; b) obtain DNA from infant cases to investigate genetic polymorphisms (including NQ01, MTHFR, GSTM1, GSTT1, GSTPi, MPO, COMT, IGF1) associated with infant leukemia; c) obtain DNA from case mothers and investigate the genetic polymorphisms described above in association with infant leukemia; and d) explore gene-environment interactions in the etiology of MLL infant leukemia. We hypothesize that specific exposure, including those associated with DNA Topoisomerase II inhibition, are more often associated with MLL-positive infant leukemia. Further, we hypothesize that genetic differences in the ability to detoxify environmental toxins contributes to genetic susceptibility to MLL-positive leukemia. Finally, we hypothesize that unfavorable genotypes, in combination with exposure to specific agents, increases the risk of MLL infant leukemia. This study will utilize the unique resources available through the Children's Oncology Group, and include ascertainment of cases over a four-year period (Jan 1, 2003-Dec 31, 2006).
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