Childhood Cancer Etiology: Recent Reports

Stella M. Davies, MD, PhD, and Julie A. Ross, PhD

Parental Occupations and Childhood Brain Tumors

The etiology of childhood brain tumors has been ex-plored with respect to several factors including parentalsmoking, electromagnetic field exposure, nitrosamines indiet, and parental occupational exposures. In this case-control study by Cordier et al. [Cancer Causes & Control,8:688–697, 1997], further associations with parental oc-cupational exposures are presented. Three European cen-ters participated in this study including Milan, Italy;Paris, France; and Valencia, Spain. Participation andcontrol selection were slightly different among the threecenters. Children who resided in northern Italy and werediagnosed up to the age of 15 years with a brain tumorduring the period 1985–1988 were eligible; 90 cases of108 eligible participated (83%). Individually matched(4:1) controls (date of birth, gender, and area of resi-dence) were selected from computerized health insurancecoverage records. A total of 318 were interviewed of 399selected (80%). Children diagnosed with a brain tumorbetween 1985 and 1987 in Paris were eligible for thisstudy; 75 interviews were completed of 109 familiesidentified (69%). Frequency-matched controls (year ofbirth) were drawn from a random sample of telephonedirectories; of 158 families identified to be eligible forthis study, 113 were interviewed (71%). In Spain, twotumor registries ascertained 111 children with brain tu-mors diagnosed between 1983 and 1990; 86 familieswere interviewed (77%). Controls were identified fromcensus tracts; two controls were individually matched tocases on gender and year of birth (170 controls of 240eligible were interviewed (71%)).

Overall, there were 251 cases and 601 controls. Allcases and controls were interviewed in person in thehome. Parents were asked to describe the tasks per-formed, the type of industry, the weekly hours worked,and the products handled. Fathers were available forabout 38% of the case interviews and 27% of the controlinterviews. The authors report that maternal occupationalexposure during the 5-year period before birth to highlevels of solvents was associated with an increased riskof astroglial (OR4 2.3; 95% CI4 0.9–5.8) and periph-eral neuroectodermal tumors (OR4 3.2; 95% CI 41.0–10.3). Maternal occupation as a nurse was associatedwith an increased risk of astroglial tumors (OR4 2.2;95% CI4 1.0–4.9). An increased risk of childhood braintumors overall was associated with paternal work in ag-riculture (OR4 2.2; 95% CI4 1.0–4.7). For specific

histologic categories, the authors found an increased riskof PNET associated with paternal work in motor vehicle–related occupations (OR4 2.7; 95% CI4 1.1–6.6), andoccupations that involved exposure to polycyclic aro-matic hydrocarbons (OR4 1.5, 95% CI4 1.1–2.1). Theauthors suggest further research into these associations.

COMMENT

In this study, the positive (albeit non–statistically sig-nificant) association between maternal exposure to sol-vents and risk of astroglial tumors has been reported inother epidemiologic studies. Less convincing in thisstudy are the paternal data. Proxy paternal interviewswere completed in the majority of cases and controls, andthere was differential participation of the fathers withrespect to case status (i.e., more case fathers were inter-viewed in person compared with control fathers). Previ-ously, in a validation study that examined agreement be-tween the mother’s and father’s description of the fa-ther’s occupation [Schnitzer et al., Am J Epidemiol,141:872–877, 1995], marked discrepancies existed be-tween what the mother said the father did and what thefather said he did. In the study by Cordier et al, the dataconcerning the father’s occupational exposures as relatedby the mother (e.g., polycyclic aromatic hydrocarbon ex-posure) are suspect. It would have been interesting to seewhat differences existed between the proxy interviewsand the actual paternal interviews, although the numberswould be small. It is important to consider all methodo-logic aspects of a study before conclusions can be made.

Julie A. Ross

More on Congenital Abnormalities andChildhood Cancer

The association of childhood malignancy with majorgenetic anomalies (e.g., Down syndrome; Beckwith-Wiedemann syndrome) has been well-described. Addi-tionally, direct biological evidence has been presentedfor the prenatal origin of leukemia in children with noevident genetic anomaly [Schumacher et al., Eur J Pedi-atr, 151:432–434, 1992]. It is logical therefore to look formore subtle morphological evidence of in utero adverseevents, or of more subtle genetic predisposition in chil-dren with leukemia. Mehes et al. [Am J Med Genet75:22–27, 1998] looked for an increase in what they term

Medical and Pediatric Oncology 32:49–51 (1999)

© 1999 Wiley-Liss, Inc.

‘‘mild errors of morphogenesis’’ in children with ALLand their siblings compared with a control group of chil-dren with infections but no leukemia. All cases wereexamined directly by the authors using a checklist of 55potential anomalies, including minor malformations suchas birthmarks and phenogenetic variants of ear shape, eyeshape, and abnormalities of the digits such as syndactylyand clinodactyly. The ALL casesandtheir sibs showed asignificant excess of errors of morphogenesis (1.59 and1.51 errors per subject, respectively, compared with 0.74,0.67, and 0.69 in mothers, fathers, and controls).

COMMENT

Interpretation of the data presented by Mehes et al. iscomplicated by the presence of an excess of errors insiblings of cases, none of whom have developed leuke-mia. This argues against exposure to a teratogen as acause of the error and of leukemia, particularly as theexcess of errors was only seen when all errors were stud-ied; there was no excess of any single error. It also arguesagainst any strong genetic predisposition, although aweak predisposition requiring additional events for leu-kemogenesis could explain the findings. It is possiblethat leukemia and the errors represent abnormalities ofdevelopmental genes acquired in utero. Of note, similarfindings of minor anomalies have been reported in neu-roblastoma [Gale et al., Proc Natl Acad Sci USA,94:13950–13954, 1997].

Stella M. Davies

Neuroblastoma—Finding the Missing Gene at 1p?

Two recent articles have described the identificationand preliminary characterization of a putative tumor sup-pressor at 1p36, a region frequently deleted in neuroblas-toma and other tumors (e.g. melanoma, Wilms tumor,ductal breast cancer, colorectal carcinoma and endome-trial cancers) [Kaghad et al., Cell, 90:809–819, 1997;Jost et al., Nature, 389:191–194, 1997]. The gene (cur-rently called p73) bears remarkable sequence similarityto the DNA-binding, transactivation, and oligomerizationdomains of p53. Similar to p53, overexpression of p73inhibits the growth of neuroblastoma and osteosarcomacell lines and promotes apoptosis in osteosarcoma andbaby-hamster kidney cells. In contrast to p53, p73 isexpressed at low levels in all normal tissues, and expres-sion does not appear to be induced by DNA damage.Previous studies of neuroblastoma have shown that thechromosome that sustains the 1p36 deletion is almostexclusively of maternal origin, indicating that a tumorsuppressor gene in this region is likely to be imprinted.Kaghad et al. have shown that in cells without a 1p36deletion, expression of p73 is monoallelic (i.e., im-

printed), and in a single informative normal individual,expression is maternal as would be predicted.

COMMENT

While the data are early, all indications are that p73may be a new and important tumor suppressor gene.However, as pointed out in a lucid commentary [Clurmanand Groudine, Nature, 389:122–123, 1997] the case isnot yet proven. To be labeled a tumor suppressor genetypically one expects to see somatic mutations in primarytumors, a criterion which has not yet been met for p73.Because the gene is imprinted, loss of the single ex-pressed allele is of course sufficient for complete loss offunction without the necessity for mutation in the re-tained allele. However, a search for somatic mutation ofp73 in tumors without 1p36 deletion will be valuable insupporting the case for p73 as an important tumor sup-pressor. The other traditional strong supporting evidencefor tumor suppressor activity is an increased incidence ofcancer in ‘‘knock-out’’ mice, and such animals are likelyto be described in the near future, although it should beremembered that this is an imperfect model system (e.g.,Rb knock-outs do not get retinal tumors).

Stella M. Davies

Childhood Cancer in Canada—What’s HappeningWith Neuroblastoma?

There have been several recent reports describing theincidence and mortality of childhood cancers in specificcountries. These descriptive statistics help in formulatinghypotheses, especially when marked discrepancies inrates occur between countries. Gao et al. [Cancer Causes& Control, 8:745–754, 1997] examined the incidenceand mortality records of all childhood cancers diagnosedbetween 1982 and 1991 under the age of 15 in Canada.They used the Canadian National Cancer Incidence Re-porting System (NCIRS) (which ascertains over 95% ofall childhood cancers) and vital statistics mortality filesmaintained by the Health Statistics Division. The authorswere particularly interested in comparing the rates ofneuroblastoma with other childhood cancers in light ofthe recent Quebec Neuroblastoma Screening Project[Woods et al., Lancet 348:1682–1687, 1996], which sug-gested that although screening for neuroblastoma leads toincreased incidence in infants, it fails to decrease theincidence of advanced disease in older children and, thus,likely does not reduce mortality. Trends were examinedby comparing data from the periods 1982–1986 and1987–1991. Overall, the annual age standardized inci-dence rate of childhood cancer declined between thesetwo time periods (155 per million and 151 per million,respectively). However, rates for neuroblastoma wererelatively constant (11.8 and 11.4 per million, respec-

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tively). Consistent with other reports, acute lymphoblas-tic leukemia incidence peaked at around 3 years (ap-proximately 110 per million), astrocytoma incidencerates remained relatively constant throughout childhood,and Hodgkin disease rates increased after the age of 10years. Overall, mortality rates declined for all cancersover the two periods. For neuroblastoma, however, themortality rate remained constant.

COMMENT

Although these data cannot argue for or against theeffectiveness of screening for neuroblastoma on mortal-ity in Canada (particularly since Quebec data are notspecifically addressed), they do raise a broader issue.Specific urine metabolites are excreted in higher amountsin greater than 90% of infants with neuroblastoma; thus,screening could potentially lead to early detection of thedisease and a reduction in mortality. It is becoming in-creasingly apparent, however, that neuroblastoma ischaracterized by at least two distinct clinical-biologicmanifestations [Brodeur, Am J Pediatr Hematol, 14:111–116, 1992]. The first type is detected by screening in thefirst 6 months of life and is destined to have a goodprognosis regardless of screening. The second type(those with unfavorable biology) may be less likely to bepicked up by screening as it occurs usually after 1 year ofage. Studies elsewhere are examining the utility ofscreening at later time points.

Julie A. Ross

Why Retinoic Acid Cures AcutePromyelocytic Leukemia

Acute promyelocytic leukemia (APL) is associatedwith t(15;17), a translocation that fuses the gene for theretinoic acid receptor alpha (RARA) with the gene PML,thought to encode a transcription factor. A variant APLtranslocation t(11;17) fuses RARA with a different part-ner, PLZF. PML-RARA patients commonly achievecomplete (though not sustained) remissions with phar-macological doses oftrans-retinoic acid; in contrastPLZF-RARA cases respond poorly if at all [Licht et al.,Blood, 85:1083–1094, 1995]. Two recent studies [Lin etal., Nature 391, 811–814, 1998; Grignani et al., Nature391:815–818, 1998] describe the role of histone deacety-lase in APL leukemogenesis and in determining the re-

sponse to therapy. Transcriptionally active chromatin(i.e., parts of chromosomes in which genes are beingactively expressed) has a high level of histone acetyla-tion. Histone deacetylase therefore can act as a repressorof transcription (i.e., can switch off gene expression).When retinoic acid is absent, RARA recruits histonedeacetylase activity via an interaction with proteinscalled nuclear co-repressors (N-CoR or the relatedSMRT), and switches off expression of target genes. Inthe presence of retinoic acid this activity is reversed, andgene expression is switched on. The fusion proteins gen-erated by translocations in APL interact with the nuclearco-repressors, and the interaction cannot be released byphysiological levels of retinoic acid, leading to inappro-priate repression of gene activity. The PML-RARA com-plex is released by pharmacological doses of retinoicacid so the cells respond to therapy. In contrast, thePLZF-RARA protein has two nuclear co-repressor bind-ing sites, one of which is released by retinoic acid andone which is not, leading to failure of therapy. Impor-tantly, both studies describe the effect of pharmacologicinhibitors of histone deacetylase (Trichostatin A or so-dium butyrate), showing dramatic potentiation of reti-noid-induced differentiation of retinoid-sensitive cellsand restoration of retinoid responsiveness in retinoid-resistant cells.

COMMENT

While understanding biology should lead to rationaldesign of therapy, this has rarely occurred in practice.Identification of active therapeutic agents has commonlybeen the result of a process of trial and error. This worksuggests an exciting therapeutic strategy that might havebroader application than just APL as other studies indi-cate the importance of histone acetylation and alteredchromatin organization in carcinogenesis. The t(8;16)translocation found in AML fuses the MOZ gene withthe CBP histone acetyltransferase protein [Borrow et al.,Nature Genet, 14:33–41, 1997]. Additionally, Luo et al.[Cell, 92:463–473, 1998] have shown that the Rb proteinrepresses gene transcription by recruitment of histonedeacetylase. I believe we will be hearing a lot more onthis topic in the coming year.

Stella M. Davies

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