FLT3 mutation incidence and timing of origin in a population case series of pediatric leukemia

Patrick Chang, Michelle Kang, Anny Xiao, Jeffrey Chang, James Feusner, Patricia Buffler, Joseph Wiemels, Patrick Chang, Michelle Kang, Anny Xiao, Jeffrey Chang, James Feusner, Patricia Buffler, Joseph Wiemels

Abstract

Background: Mutations in FLT3 result in activated tyrosine kinase activity, cell growth stimulation, and a poor prognosis among various subtypes of leukemia. The causes and timing of the mutations are not currently known. We evaluated the prevalence and timing of origin of FLT3 mutations in a population series of childhood leukemia patients from Northern California.

Methods: We screened and sequenced FLT3 mutations (point mutations and internal tandem duplications, ITDs) among 517 childhood leukemia patients, and assessed whether these mutations occurred before or after birth using sensitive "backtracking" methods.

Results: We determined a mutation prevalence of 9 of 73 acute myeloid leukemias (AMLs, 12%) and 9 of 441 acute lymphocytic leukemias (ALLs, 2%). Among AMLs, FLT3 mutations were more common in older patients, and among ALLs, FLT3 mutations were more common in patients with high hyperdiploidy (3.7%) than those without this cytogenetic feature (1.4%). Five FLT3 ITDs, one deletion mutation, and 3 point mutations were assessed for their presence in neonatal Guthrie spots using sensitive real-time PCR techniques, and no patients were found to harbor FLT3 mutations at birth.

Conclusions: FLT3 mutations were not common in our population-based patient series in California, and patients who harbor FLT3 mutations most likely acquire them after they are born.

Figures

Figure 1
Figure 1
Relative location and sizes of FLT3 ITD mutations and deletion in 9 patients from the Northern California Childhood Leukemia Study. Black boxes - regions of duplication; white box - deletion of FLT3 sequence in one patient. * - positions where multiple breaks occurred.

References

    1. Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural history. Blood. 2003;102(7):2321–2333. doi: 10.1182/blood-2002-12-3817.
    1. Wiemels J. Chromosomal translocations in childhood leukemia: natural history, mechanisms, and epidemiology. J Natl Cancer Inst Monogr. 2008. pp. 87–90.
    1. Gale KB, Ford AM, Repp R, Borkhardt A, Keller C, Eden OB, Greaves MF. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(25):13950–13954. doi: 10.1073/pnas.94.25.13950.
    1. McHale CM, Wiemels JL, Zhang L, Ma X, Buffler PA, Guo W, Loh ML, Smith MT. Prenatal origin of TEL-AML1-positive acute lymphoblastic leukemia in children born in California. Genes Chromosomes Cancer. 2003;37(1):36–43. doi: 10.1002/gcc.10199.
    1. Wiemels JL, Cazzaniga G, Daniotti M, Eden OB, Addison GM, Masera G, Saha V, Biondi A, Greaves MF. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet. 1999;354(9189):1499–1503. doi: 10.1016/S0140-6736(99)09403-9.
    1. Wiemels JL, Leonard BC, Wang Y, Segal MR, Hunger SP, Smith MT, Crouse V, Ma X, Buffler PA, Pine SR. Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2002;99(23):15101–15106. doi: 10.1073/pnas.222481199.
    1. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650–665. doi: 10.1038/nrc1169.
    1. Armstrong SA, Mabon ME, Silverman LB, Li A, Gribben JG, Fox EA, Sallan SE, Korsmeyer SJ. FLT3 mutations in childhood acute lymphoblastic leukemia. Blood. 2004;103(9):3544–3546. doi: 10.1182/blood-2003-07-2441.
    1. Andersson A, Paulsson K, Lilljebjorn H, Lassen C, Strombeck B, Heldrup J, Behrendtz M, Johansson B, Fioretos T. FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns. Genes Chromosomes Cancer. 2008;47(1):64–70. doi: 10.1002/gcc.20508.
    1. Case M, Matheson E, Minto L, Hassan R, Harrison CJ, Bown N, Bailey S, Vormoor J, Hall AG, Irving JA. Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia. Cancer Res. 2008;68(16):6803–6809. doi: 10.1158/0008-5472.CAN-08-0101.
    1. Paulsson K, Horvat A, Strombeck B, Nilsson F, Heldrup J, Behrendtz M, Forestier E, Andersson A, Fioretos T, Johansson B. Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2008;47(1):26–33. doi: 10.1002/gcc.20502.
    1. Yamamoto T, Isomura M, Xu Y, Liang J, Yagasaki H, Kamachi Y, Kudo K, Kiyoi H, Naoe T, Kojma S. PTPN11, RAS and FLT3 mutations in childhood acute lymphoblastic leukemia. Leuk Res. 2006;30(9):1085–1089. doi: 10.1016/j.leukres.2006.02.004.
    1. Braoudaki M, Karpusas M, Katsibardi K, Papathanassiou C, Karamolegou K, Tzortzatou-Stathopoulou F. Frequency of FLT3 mutations in childhood acute lymphoblastic leukemia. Med Oncol. 2009;26(4):460–462. doi: 10.1007/s12032-008-9146-z.
    1. Weisberg E, Barrett R, Liu Q, Stone R, Gray N, Griffin JD. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist Updat. 2009;12(3):81–89. doi: 10.1016/j.drup.2009.04.001.
    1. Bachas C, Schuurhuis GJ, Hollink IH, Kwidama ZJ, Goemans BF, Zwaan CM, van den Heuvel-Eibrink MM, de Bont ES, Reinhardt D, Creutzig U, de Haas V, Assaraf YG, Kaspers GJ, Cloos J. High frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: implications for personalized medicine. Blood. 2010. in press .
    1. Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100(7):2393–2398. doi: 10.1182/blood-2002-02-0420.
    1. Cloos J, Goemans BF, Hess CJ, van Oostveen JW, Waisfisz Q, Corthals S, de Lange D, Boeckx N, Hahlen K, Reinhardt D, Creutzig U, Schuurhuis GJ, Zwaan Ch M, Kaspers GJ. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20(7):1217–1220. doi: 10.1038/sj.leu.2404246.
    1. Davidsson J, Paulsson K, Lindgren D, Lilljebjorn H, Chaplin T, Forestier E, Andersen MK, Nordgren A, Rosenquist R, Fioretos T, Young BD, Johansson B. Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations. Leukemia. 2010;24(5):924–931. doi: 10.1038/leu.2010.39.
    1. Aldrich MC, Zhang L, Wiemels JL, Ma X, Loh ML, Metayer C, Selvin S, Feusner J, Smith MT, Buffler PA. Cytogenetics of Hispanic and White children with acute lymphoblastic leukemia in California. Cancer Epidemiol Biomarkers Prev. 2006;15(3):578–581. doi: 10.1158/1055-9965.EPI-05-0833.
    1. Ma X, Buffler PA, Selvin S, Matthay KK, Wiencke JK, Wiemels JL, Reynolds P. Daycare attendance and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2002;86(9):1419–1424. doi: 10.1038/sj.bjc.6600274.
    1. Chang JS, Selvin S, Metayer C, Crouse V, Golembesky A, Buffler PA. Parental smoking and the risk of childhood leukemia. Am J Epidemiol. 2006;163(12):1091–1100. doi: 10.1093/aje/kwj143.
    1. Metayer C, Buffler PA. Residential Exposures to Pesticides and Childhood Leukaemia. Radiat Prot Dosimetry. 2009;132:212–219. doi: 10.1093/rpd/ncn266.
    1. Wiemels JL, Kang M, Chang JS, Zheng L, Kouyoumji C, Zhang L, Smith MT, Scelo G, Metayer C, Buffler P, Wiencke JK. Backtracking RAS mutations in high hyperdiploid childhood acute lymphoblastic leukemia. Blood Cells Mol Dis. 2010;45(3):186–91. doi: 10.1016/j.bcmd.2010.07.007.
    1. Ma X, Buffler PA, Gunier RB, Dahl G, Smith MT, Reinier K, Reynolds P. Critical windows of exposure to household pesticides and risk of childhood leukemia. Environ Health Perspect. 2002;110(9):955–960. doi: 10.1289/ehp.02110955.
    1. Moorman AV, Clark R, Farrell DM, Hawkins JM, Martineau M, Secker-Walker LM. Probes for hidden hyperdiploidy in acute lymphoblastic leukaemia. Genes Chromosomes Cancer. 1996;16(1):40–45. doi: 10.1002/(SICI)1098-2264(199605)16:1<40::AID-GCC6>;2-3.
    1. Raimondi SC, Pui CH, Hancock ML, Behm FG, Filatov L, Rivera GK. Heterogeneity of hyperdiploid (51-67) childhood acute lymphoblastic leukemia. Leukemia. 1996;10(2):213–224.
    1. Wiemels J, Kang M, Greaves M. Backtracking of leukemic clones to birth. Methods Mol Biol. 2009;538:7–27. full_text.
    1. Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R, Tsuchida M, Ida K, Hayashi Y. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004;103(3):1085–1088. doi: 10.1182/blood-2003-02-0418.
    1. Wiemels JL, Zhang Y, Chang J, Zheng S, Metayer C, Zhang L, Smith MT, Ma X, Selvin S, Buffler PA, Wiencke JK. RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia. Leukemia. 2005;19:415–419. doi: 10.1038/sj.leu.2403641.
    1. Burjanivova T, Madzo J, Muzikova K, Meyer C, Schneider B, Votava F, Marschalek R, Stary J, Trka J, Zuna J. Prenatal origin of childhood AML occurs less frequently than in childhood ALL. BMC Cancer. 2006;6:100. doi: 10.1186/1471-2407-6-100.
    1. Gilliland DG. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol. 2002;39(4 Suppl 3):6–11. doi: 10.1053/shem.2002.36921.
    1. Fasching K, Panzer S, Haas OA, Marschalek R, Gadner H, Panzer-Grumayer ER. Presence of clone-specific antigen receptor gene rearrangements at birth indicates an in utero origin of diverse types of early childhood acute lymphoblastic leukemia. Blood. 2000;95(8):2722–2724.
    1. Gruhn B, Taub JW, Ge Y, Beck JF, Zell R, Hafer R, Hermann FH, Debatin KM, Steinbach D. Prenatal origin of childhood acute lymphoblastic leukemia, association with birth weight and hyperdiploidy. Leukemia. 2008;22(9):1692–1697. doi: 10.1038/leu.2008.152.
    1. Taub JW, Konrad MA, Ge Y, Naber JM, Scott JS, Matherly LH, Ravindranath Y. High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood. 2002;99(8):2992–2996. doi: 10.1182/blood.V99.8.2992.
    1. Yagi T, Hibi S, Tabata Y, Kuriyama K, Teramura T, Hashida T, Shimizu Y, Takimoto T, Todo S, Sawada T, Imashuku S. Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia. Blood. 2000;96(1):264–268.

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