PERSPECTIVESEpidemiologic Studies of Childhood Leukemia: Where Do We Go From Here?

Julie A. Ross, PhD*

Key words: childhood cancer; epidemiology; Down syndrome; cancer etiology

INTRODUCTION

Over the past 3 decades, epidemiologic studies ofchildhood leukemia have revealed little consistent infor-mation with respect to etiology. This could largely beattributed to the heterogeneity of the disease and insuf-ficient study power to test hypotheses within more ho-mogenous subgroups. For example, in the 1970s and1980s, most epidemiologic studies of childhood leuke-mia included only two disease stratifications withinanalyses: acute myeloid leukemia (AML) and acute lym-phoblastic leukemia (ALL) [reviewed in 1]. Most studiescould not adequately evaluate risk within immunopheno-types or morphologic subgroups, much less age-specificgroups. In the last 10 years, however, several large epi-demiologic studies of childhood leukemia have been de-signed to enable hypothesis testing within smaller sub-sets; results from these studies suggest that focused, epi-demiologic investigations of rare groups might providenew answers. Moreover, in conjunction with data fromclinical and laboratory studies, not only are distinct sub-groups discerned but new hypotheses can be formulated.Discussed below are two such subgroups: infants withleukemia and children with Down syndrome and leuke-mia.

INFANT LEUKEMIA

Infants diagnosed with leukemia in the 1st year of lifeare distinguished from older children by their uniquemorphologic, immunologic, clinical, and genetic presen-tation. Overall, for leukemias diagnosed in children lessthan 15 years of age, the percentage of ALL cases isabout 4 times that of AML [2]. In contrast, the ratio ofALL to AML in infancy is approximately 1 [3]. InfantALL typically presents with a very early pre-B-cell phe-notype, sometimes with myeloid antigen markers as well.Infant AML (non-Down syndrome) typically presentswith an M4 or M5 morphology [3]. These immunophe-notypes and morphologic types are not often observed inolder children [reviewed in 1]. The clinical features ofinfant leukemia are quite notable: often there is high blastcount, organomegaly, and central nervous system (CNS)

involvement [4]. There is a striking female predominancein infant leukemias, whereas in the older age groups thereis a significant excess of males [5]. Overall, infants withleukemia fare quite poorly, with a 5-year survival ofabout 30% [4]. Moreover, distinct genetic abnormalitieshave been reported in infant leukemias.

Infant leukemia (both AML and ALL) is associatedmore often with abnormalities involving a gene,MLL, onchromosome 11 band q23 than any other region [re-viewed in 1]. Current estimates suggest that about 60%of infants with AML and about 80% of infants with ALLhave anMLL abnormality in their leukemia cells [6].Identical abnormalities of theMLL gene have also beenobserved in treatment-related AMLs that can develop inchildren and adults following therapy for a primary can-cer [7]. This form of treatment-related AML is associatedwith therapies involving DNA topoisomerase II inhibi-tors including the epipodophyllotoxins etoposide andteniposide [8]. The involvement of epipodophyllotoxinsin DNA topoisomerase II inhibition may be directly re-lated to theMLL abnormalities observed in secondaryAMLs [9].

Based on the finding from treatment-related leuke-mias, it is reasonable to hypothesize that maternal expo-sure to DNA topoisomerase II inhibitors during preg-nancy could be associated with an increase risk of infantleukemia [10]. Preliminary epidemiologic data suggestthat maternal exposure to topoisomerase II inhibitors(particularly in the diet) is positively associated with in-fant AML only, which supports the observations in treat-ment-related AMLs [11]. Thus, a focused molecular epi-demiologic study of infant leukemia which specificallyaddresses exposure to environmental inhibitors of DNAtopoisomerase II could provide further understanding of

Division of Pediatric Epidemiology and Clinical Research, Depart-ment of Pediatrics, University of Minnesota, Minneapolis, Minnesota

*Correspondence to: Julie A. Ross, Division of Pediatric Epidemiol-ogy and Clinical Research, Department of Pediatrics, University ofMinnesota, Box 422, 554 CCRB, 420 Delaware St. S.E., Minneapolis,MN 55455.

Received 10 June 1998; Accepted 13 July 1998

Medical and Pediatric Oncology 32:65–67 (1999)

© 1999 Wiley-Liss, Inc.

gene-environment interactions inMLL leukemia (bothinfant and treatment-related).

DOWN SYNDROME-LEUKEMIA

Some studies suggest a 10- to 20-fold increased risk ofleukemia in children with Down syndrome (DS) [12,13],with some reports suggesting as high as a 500-fold in-creased risk of a particular type of AML (AML-M7)[14]. Current estimates predict that 1 in 95 children withDS will eventually develop leukemia [15].

Molecular biologic investigations have been under-way to attempt to explain this increased risk of leukemiain DS, and studies have focused on the extra copy ofchromosome 21. Trisomy 21 also appears to be one ofthe more frequentacquiredabnormalities in childhoodleukemia [16], suggesting that genes on chromosome 21may be important in the genesis of leukemia [17]. TheAML-1 gene has been mapped to chromosome band21q22.2-22.3 (an area believed to be responsible for theDS phenotype) [18]. Perhaps the most significant bio-logic data reported to date which provides a potential linkbetween DS and childhood leukemia is the translocationthat has been observed between chromosome 8 and theAML-1 gene on chromosome 21. Approximately 46% ofchildhood AML cases with an M2 morphology demon-strate this translocation [19]. Finally, there have beenreports of significant differences in the clinical charac-teristics of the leukemias of children with DS comparedto those of children without this syndrome [20]. In par-ticular, children with DS and AML are significantlyyounger at diagnosis than non-Down children with AML.There are no substantial differences in age at diagnosisfor ALL.

However, it is extremely important to note that thevast majority of DS children will never develop leuke-mia. Thus, it is likely that there are other factors in ad-dition to an extra copy of chromosome 21 which play arole. Based on the case histories and characteristics ofsome DS children, and previous findings for childhoodleukemia [1], there are at least three potential areas forfurther research in the epidemiology of DS-leukemia(which are currently the focus of a national Children’sCancer Group epidemiologic study).

1. Investigation of medical treatments.DS childrenare subjected to more comprehensive medical testingthan children without the syndrome [21]. General pedi-atric guidelines for preventive health care recommendthat DS children routinely undergo several medicalscreening procedures in the first few years of life, includ-ing radiographs. Many of these screening procedures arerecommended at specified intervals throughout child-hood.

2. Investigation of infection susceptibility and dietary

deficiencies.Several studies have described and investi-gated the increased susceptibility of DS children to in-fections. In particular, defects in cell-to-cell communica-tion and decreased white cell counts have been observedin some of these children [22]. This impairment in im-mune function could put a DS child at increased risk ofdeveloping leukemia. They are also more prone to vita-min and mineral deficiencies than other children [23]. Inparticular, many with DS tend to be zinc deficient; zincdeficiency has been associated with impaired immunefunction.

3. Investigation of childhood leukemia risk factors.Several risk factors previously associated with childhoodacute leukemia could be important in the development ofleukemia in DS children. In utero exposure to diagnosticX-rays is one of the few known causes of childhoodleukemia; however, due to the extremely low number ofindividuals exposed, the population attributable risk isquite small. Other factors that have been associated withchildhood leukemia include maternal history of fetal loss,maternal alcohol consumption, infant birth weight (high),parental and child pesticide exposure, and certain paren-tal occupational exposures [reviewed in 1]. There arealso several less well-documented associations includingmaternal marijuana use, maternal age, and birth order. Byand large, the only potentially shared risk factor for bothDS and childhood leukemia is advanced maternal age. Itis unknown, however, if any of these risk factors play arole in leukemia development in DS. Investigation ofthese potential risk factors in the etiology of leukemia inDS might also lead to a better understanding of their rolein leukemia in non-Down children.

SUMMARY

Much of our knowledge of the mechanisms of carci-nogenesis has resulted from the study of rare cancers,including retinoblastoma, angiosarcoma, and vaginalclear cell carcinoma. Due to the heterogeneity of child-hood leukemia, epidemiologic studies that focus on chil-dren with unique clinical and genetic manifestations ofthe disease could potentially lead to further understand-ing of leukemogenesis.

ACKNOWLEDGMENTS

The author is supported by the Children’s Cancer Re-search Fund.

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