Looking for leukemia clues in of all places.meconium!

  • Published on

  • View

  • Download


  • Pediatr Blood Cancer 2007;49:607608

    HIGHLIGHTby Julie A. Ross, PhD1,2*

    Looking for Leukemia Clues in of all Places. . . :Meconium!(Commentary on LaFiura et al., pp. 624628)

    B ecause of the rarity of childhood cancer, epidemiologistsnecessarily rely on the case-control approach. In thesestudies, parents of cases and of healthy children are typically

    interviewed via questionnaire regarding exposures and experiences

    prior to the development of cancer in the case child and some

    predetermined date in the control child. It is difficult to interpret

    these studies, since we are relying on sometimes faulty recall.

    Moreover, potential hot-button questionnaire items can trigger

    additional angst and perhaps additional recall among case

    parents. For example, for pesticides, a case mom might recall a

    one-time episode in the first trimester of pregnancy when a

    pesticide was used in the kitchen to spray for ants where a

    control mom might not report such an event since she would not

    believe it to be noteworthy. Importantly, several epidemiologic

    studies have shown positive associations between pesticide

    exposure and certain childhood cancers [1,2], thus one of our major

    challenges is to devise ways to improve exposure and/or validate

    study results using other disciplines. Animal studies can provide

    certain clues, since exposure to high levels of certain pesticides can

    be experimentally carcinogenic. Another avenue is the creative use

    of biological specimens available at birth.

    For example, studies of chromosomal rearrangements present at

    birth are helping to inform the natural history of childhood

    leukemia. Many chromosomal rearrangements occur in childhood

    acute lymphoblastic leukemia (ALL) and acute myeloid leukemia

    (AML), but a few predominate. About 80% of ALL and 60%

    of AML among infants diagnosed less than 1 year of age show

    rearrangements of the MLL gene at chromosome band 11q23 and

    one of several partner chromosomes including most commonly,

    chromosomes 4, 9, or 19 [3,4]. Among children aged 115 years,

    rearrangements involving theETV6 gene on chromosome12 and the

    RUNX1 gene on chromosome 21 (known as TEL-AML1) are found

    in approximately 25% of childhood ALL [5]. RUNX1 is also

    involved in AML, with chromosomal translocations with a gene,

    ETO, on chromosome8 present in about 15%of cases.Of note, these

    samegene rearrangements (MLL-various partner genes,TEL-AML1

    and AML1-ETO) have been identified in neonatal blood spots

    collected at birth [6,7]. Twins with leukemia also share the same

    non-constitutive rearrangements [810]. These molecular observa-

    tions provide strong evidence that many childhood acute leukemias

    are initiated in utero. However, with the exception of MLL gene

    rearrangements, where it is still unclear what additional mutation(s)

    may be needed [11,12], TEL-AML1 and AML1-ETO are insufficient

    for frank leukemia development. About 1 in 100 cord blood samples

    from healthy children have the TEL-AML1 gene rearrangement, and

    about 1 in 500 have the AML1-ETO rearrangement [13]. These

    observations provide strong evidence that additionalmutationsmust

    occur before leukemia develops in most children.

    In this issue, Ge Yet al. [14] report on an elegant pilot study that

    examines correlations between specific pesticides present in

    meconium (i.e., an infants first bowel movement) and the AML1-

    ETO translocation in cord blood samples of healthy children.

    Meconium is an appropriate sample for these types of studies since it

    can provide a cumulative picture of pesticide exposure throughout

    the pregnancy. The investigators used a population of newborn

    infants from the Philippines where agricultural and home pesticide

    use is common. From a total of 49 infants,meconium analysis by gas

    chromatography/mass spectrometry revealed that 39 infants were

    exposed to the pesticide, proxopur, sometime during the in

    utero period, while 10 were unexposed. Total RNAs were also

    isolated from the 49 cord blood samples and nested RT-PCR

    was used to identify AML1-ETO fusion transcripts; if positive,

    the fusion transcript form was also identified. A total of 8/39

    proxopur-exposed infants and 1/10 proxopur-unexposed infants had

    theAML1-ETO transcript present in cord blood. Intriguingly, for the

    exposed infants, the AML1-ETO transcript levels were positively

    correlated with proxopur concentrations in the meconium. Further,

    the one infantwith the highest level ofAML1-ETO fusion transcripts

    was exposed to two pesticides, proxopur and cypermethrin. Of note,

    the level of AML1-ETO transcript in this infants cord blood was

    only about eightfold lower than levels reported from diagnostic

    AML blast samples. Fortuitously, the investigators were able to

    examine a peripheral blood sample from this infant 1 year later and

    found that the AML1-ETO transcripts were 300-fold lower than the

    childs cord blood sample. These results reinforce the necessity

    for additional genetic mutations (and perhaps environmental

    exposure(s)) prior to the development of overt leukemia in children

    with these translocations at birth.

    This study is important on many fronts. While it is recognized

    that it is a pilot, it shows how useful a maternalfetal cohort study

    can be in helping to inform childhood cancer epidemiology studies.

    Because of the rarity of childhood cancer overall, however, it will be

    2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21308

    Division of Epidemiology & Clinical Research, University of

    Minnesota, Minneapolis, Minnesota; 2Division of Population

    Sciences, University of Minnesota Cancer Center, Minneapolis,


    Julie A. Ross is Professor and Director of the Division of

    Epidemiology & Clinical Research and also Associate Director for

    Population Sciences in the University of Minnesota Cancer Center.

    *Correspondence to: Julie A. Ross, Division of Population Sciences,

    University of Minnesota Cancer Center, MMC 422, 420 Delaware St.

    S.E., Minneapolis, MN 55455. E-mail: ross@epi.umn.edu

    Received 18 June 2007; Accepted 18 June 2007

  • a challenge to have samples (e.g., cord blood, meconium) collected

    prospectively for studies of childhood leukemia. Some large

    international birth cohorts, including the National Childrens Study

    in the United States, have considered whether combining forces

    might help to address childhood cancer questions such as this [15].

    Secondly, the observation of a depletion in the number of affected

    AML1-ETO cells supports the contention that other events, whether

    environmental and/or endogenous, need to occur in order for

    leukemia to develop. It would also be of interest for the investigators

    to explore potential associations with TEL-AML1 using similar

    methods. Overall, the investigators are to be commended on a well-

    done and thoughtful study that reinforces the need to investigate

    observed associations from questionnaire data in other settings

    whenever possible.


    1. Nasterlack M. Pesticides and childhood cancer: An update. Int J

    Hyg Environ Health 2007.

    2. MaX,Buffler PA,Gunier RB, et al. Critical windows of exposure to

    household pesticides and risk of childhood leukemia. Environ

    Health Perspect 2002;110:955960.

    3. Rowley JD. Seminars from the University of Minnesota Chromo-

    some translocations: Dangerous liaisons. J Lab Clin Med 1998;


    4. Cimino G, Lo Coco F, Biondi A, et al. ALL-1 gene at chromosome

    11q23 is consistently altered in acute leukemia of early infancy.

    Blood 1993;82:544546.

    5. Fischer M, Schwieger M, Horn S, et al. Defining the oncogenic

    function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a

    mouse model. Oncogene 2005;24:75797591.

    6. Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin of

    acute lymphoblastic leukaemia in children [comment]. Lancet


    7. Wiemels JL, Xiao Z, Buffler PA, et al. In utero origin of t(8;21)

    AML1-ETO translocations in childhood acute myeloid leukemia.

    Blood 2002;99:38013805.

    8. Ford AM, Bennett CA, Price CM, et al. Fetal origins of the TEL-

    AML1 fusion gene in identical twins with leukemia. Proc Natl

    Acad Sci USA 1998;95:45844588.

    9. Ford AM, Pombo-de-Oliveira MS, McCarthy KP, et al. Mono-

    clonal origin of concordant T-cell malignancy in identical twins.

    Blood 1997;89:281285.

    10. Ford AM, Ridge SA, Cabrera ME, et al. In utero rearrangements in

    the trithorax-related oncogene in infant leukaemias. Nature 1993;


    11. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of

    genetic alterations in acute lymphoblastic leukaemia. Nature 2007;


    12. EguchiM, Eguchi-IshimaeM,GreavesM.Molecular pathogenesis

    of MLL-associated leukemias. Int J Hematol 2005;82:920.

    13. Mori H, Colman SM, Xiao Z, et al. Chromosome translocations

    and covert leukemic clones are generated during normal fetal

    development. Proc Natl Acad Sci USA 2002;99:82428247.

    14. Ge Y. Association between prenatal pesticide exposures and the

    generation of leukemia-associated t(8;21).

    15. Brown RC, Dwyer T, Kasten C, et al. Cohort profile: The

    International Childhood Cancer Cohort Consortium (I4C). Int

    J Epidemiol 2007.

    Pediatr Blood Cancer DOI 10.1002/pbc

    608 Ross