(CANCER RESEARCH 58. 448-452. February 1. I998|

A Lack of Neuroblastoma in Down Syndrome: A Study from11 European Countries1

Daniel Satgé,2Annie J. Sasco, Niels L. T. Carlsen, Charles A. Stiller, HervéRubie, Barbara Hero,

Bruno de Bernardi, Jan de Kraker, Carole Coze, Per Kogner, Froydis Langmark,Friederike G. A. J. Hakvoort-Cammel, Daniel Beck,3 Nicolas von der Weid, Sheila Parkes,

Olivier Hartmann, Robert J. J. Lippens, Willem A. Kamps, and Daniele Sommelet

Laboratory of Pathologv. Centre Hospitalier. 19000 Tulle. Frunce ¡D.S.]: Epideiniologv for Cancer Prevention, 1ARC, 69372 Lyon, France ¡A.J. S.j; Pediatrie HematologyOncolngy. Odense University Hospital, DK-5000 Odense C, Denmark ¡N.L T. C.¡; Childhood Cancer Research Group, Department of Pediatrics. Oxford OX6HJ. UnitedKingdom {C.A.S.f: Pediatrie Hemalologv Oneologv. MédecineInfantile G, Centre Hospitalier Universitaie Purpan, 31059 Toulouse, France ¡H.R.f: Pediatrie HematologvOncnlngy, Klinik fürKinderheilkunde, D-5IXM) Cologne. Germany ¡B.H.¡: Department of Hemalology Oncology. Giannina Gaslini Children's Hospital, 1614K Genova. Italy

IB. d. B.I: PédiatrieHetnatologv Oncologi: Emma Kinder Ziekenhuis. Academic Medical Center. 1I05AZ Amsterdam, the Netherlands [J. d. K.I: Pediatrie Oncology. UniversityHospital Lit Tiimme. 133N5 Marseille, France /C. C/; Childhood Cancer Research Unit. Department of Pediatrics. Karolinska Hospital. S-17176 Stockholm. Sweden ¡P.K.j: TheCancer Registry of Nonvav. Institute for Epidemiological Research Mtmtebello. 0310 Oslo. Nonvav IF. L.j: Pediatrie Hetnatologv Oneologv: Sophia Children's Hospital, 60 3015

(ij Rotterdam, rite Netherlands ¡F.G. A. J. H-C.j: Pediatrie Hemalology Onetilogy, Centre Hospitalier Universitaire. Vaudois, 1011 Lausanne, Switzerland ¡D.B.¡;PediatrieHeniaíoli>gvOncologi', Inselspital, 3010 Hern. Switzerland ¡N.v. d.W.¡; West Middlands Regional Children's Tumour Research Group, Birmingham Children's Hospital.

Birmingham B16 RET, United Kingdom ¡S.P.j: Pediatrie Hetnatology Oncology. Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif, France ¡O.H.]: PediatrieHemuiology Oncology, University Hospital Nijmegen. 6.500 HB Nijmegen. the Netherlands ¡R.J.J.Lj: Pediairic Hematology Oncology. Beatrix Children's Hospital. 9700 RB

Groningen, the Netherlands ¡W.A. K.J: and Pediatrie Hematology Oncology, University Hospital, 54511 Nancy, France ¡D.SJ

ABSTRACT

An epidemiológica! investigation in 11 European countries comprisingu total childhood population of 54.1 million children and using 8 separatedata sources was conducted to evaluate the occurrence of neurohlastomain Down syndrome IDS). No cases of US were detected among 6724 infantsand children with neurohlastoma, although more than five were expected.This highly significant result (P = 11.11045according to the Poisson test) is

consistent with data in the literature, which contains only two poorlydetailed cases in epidemiológica! studies and one ganglioneuroma in a DSmosaic patient. Like other tumors, such as leukemias, testicular germ celltumors and lymphomas are in excess in US patients; the lack of neuro-

blastomas does not reflect a general decreased incidence of cancer butrather a specific underrepresentation of this precise tumor. S-100 h pro

tein, the gene for which maps to the long arm of chromosome 21, (a) isoverproduced in DS patients, (/>) produces growth inhibition and differentiation of neural cells in vitro, (c) is abundant in good-prognosis neuro-

hlastomas, and u/> has been shown to induce growth inhibition anddifferentiation and cell death in several human and murine neuroblas-

toma cell lines and could be responsible for this variation. Additionalepidemiológica! and experimental studies are warranted to confirm ourinterpretation of these data.

INTRODUCTION

An association between congenital anomalies and childhood cancers is now clearly demonstrated: thus, a better knowledge of this linkmay help identify genes involved in cancer development ( 1). Amonggenetic diseases, there are several, such as DS,4 neurofibromatosis

type 1, Beckwith-Wiedemann syndrome, and tuberous sclerosis,

which are associated with an excess of various neoplasms (2). As faras we know, a decreased incidence of a specific neoplasm in aparticular genetic disease has never been reported. An updated reviewof the literature on solid tumors in DS patients (3) yielded only twocases of neuroblastoma (4, 5) and one ganglioneuroma (6). Because

Received 8/28/97; accepted 12/2/97.The costs of publication of (his article were defrayed in part by the payment of page

charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section 1734 solely to indicate this fact.

1This study was supported by u grant from Ligue pour la Lutte contre le Cancer.

Division Corrézienne. The Childhood Cancer Research Group was supported by theDepartment of Health, the Scottish Home and Health Department, and the CancerResearch Campaign.

- To whom requests for reprints should be addressed, at Laboratory of Pathology.

Centre Hospitalier. 19000 Tulle. Trance. Phone: (33) 555-29-79-13; Fax: (33) 555-29-79-31.

1Deceased.4 The abbreviation used is: DS. Down syndrome.

neuroblastoma is the most frequent solid cancer found in childrenbefore the age of 5 years, accounting for 6 to 10% of all childhoodcancers (7), we suspected that this finding could be the indication ofa lower incidence of this neoplasm in this constitutional chromosomalanomaly. We investigated this hypothesis by studying a series of morethan 6000 cases of neuroblastoma compiled in 11 European countries.

MATERIALS AND METHODS

Cases were identified in 11 European countries. 6 of them through pediatriecancer registries: the British National Registry on Childhood Tumors for GreatBritain; the German Childhood Tumor Registry for Germany; and the NordicChildhood Cancer Registry for Finland. Iceland. Norway, and Sweden. Thedata from Denmark came from the Danish Cancer Registry. In Germany, theNational Childhood Cancer Registry began in 1980, and coverage was lesscomplete in the early years (8). These German data include only the formerWest Germany and not East Germany before reunification. In the Netherlands,cases came from the four regional pediatrie oncology centers that cover thewhole geographic area. The Swiss data about incidence of pediatrie cancerwere provided through the network of the Swiss Pediatrie Oncology Group,which includes all (n = 8) Swiss institutions involved in the management of

childhood cancer in this country. In Switzerland, this coverage is considered tobe close to 100%. In France and Italy, cases were gathered from centralizedsources that hold data on children with neuroblastoma who are seen in Franceby the members of the SociétéFrançaised'Oncologie Pédiatriqueand in Italy

by the members of the Cooperative Group for Neuroblastoma. These two datasources are considered to cover 90c/c of the whole population. To gather as

many cases as possible, we included the longest period available for eachregistry or centralized data source varying from 5 to 48 years. Although theupper limit for age varied according to each registry, inclusion of the age rangebetween 14 and 18 years does not lead to any substantial problem, given thefact that neuroblastomas occur mainly before 10 years of age (7). Eligible caseswere those diagnosed as histologically proven peripheral neuroblastomas,including, tor some registries, in situ neuroblastomas and central nervoussystem neuroblastomas. In situ neuroblastomas are minute, incidentally encountered adrenal neuroblastomas usually found during autopsies of infants(9). In five national registries, systematic recording of the conditions associated with each case is provided, permitting the detection of DS cases. In theothers, systematic registration was not indicated, but major malformationswere mentioned, and it was possible to indicate the presence or absence of DSin children. Moreover, cancer treatment for a DS patient raises difficulttherapeutic problems due to enhanced drug toxicity (well documented forleukemias; Ref. 10). which would have attracted the attention of clinicians andalerted them to the condition. For comparison purposes, we checked thepresence of three other conditions clinically associated with neuroblastomas;neurofibromatosis type 1. Hirschsprung's disease, and Beckwith-Wiedemann

syndrome (11. 12).

448

Research. on September 14, 2018. © 1998 American Association for Cancercancerres.aacrjournals.org Downloaded from

DOWN SYNDROMK AND NEUROBLASTOMA

We evaluated the DS population based on the rate at birth as indicated bythe European Registration of Congenital Anomalies (13). which gives thecrude rates during the years 1990-1994 in the 25 registries at around 10.4 DS

per 10,000 live births (or one for 961.5 births). Because prenatal screening hasimproved during the last decade (14). we think that this value underestimatesthe DS population at birth for the first years of the study. Life expectancy islower in individuals with DS compared to the general population, with only76.6% of individuals still alive at age 15. This allowed us to calculate aminimum estimate of the proportion of the population ages 0-14 years with

DS in the study regions (15).We used the Poisson statistic test to compare the number of cases of

neuroblastoma observed in the DS population with the number expected based

on general population rates.

RESULTS

Table 1 shows that no case of DS was found among 6724 cases ofneuroblastoma. Taking the rate of occurrence of DS as 1 in 961.5 livebirths and the survival rate to age 15 as 76.6%, at least 5.40 cases ofDS would be expected among 6724 cases of neuroblastoma. ThePoisson probability of observing no case is 0.0045. This estimation isconservative, taking into account the fact that most neuroblastomacases occur before 10 years of age and that 78.4% of DS childrensurvive that age. By allowing in our population older subjects at a verylow risk of neuroblastoma. we may underestimate the expected figure,thereby diluting slightly the observed effect.

Because the incidence of neurofibromatosis type 1 is estimated at 1in 3,000 individuals (16), and because some cases are sometimes notdiagnosed before 15 years of age, the 19 cases observed in the studyshow an important excess of neuroblastomas in this condition, asexpected. Similarly, because the incidence of Beckwith-Wiedemann

syndrome, which is usually diagnosed in the first months of life, isestimated to be 1 in 13,700 (17) the four cases observed in this studyshow an important excess of neuroblastomas in this condition, asexpected. Because Hirschsprung's disease occurs in approximately 1

in every 5,000 infants born alive births and its diagnosis is mademostly during the 1st year of life (18). the only case observed in thisstudy does not support the idea of an excess of neuroblastoma in thiscondition. Taken together, these results indicate that in this populationof 0-18 years of age. infants and children with diseases known to be

at risk for this nervous system neoplasm were not missed.

DISCUSSION

This study failed to detect a single case of DS among 6724 infantsand children with neuroblastoma, whereas according to our estimationof the DS population, more than 5 cases were expected. This result ishighly significant but has to be discussed regarding possible biases,particularly the possibility of undeclared DS cases. The eventuality ofunrecognized DS among neuroblastoma patients is unlikely, becausethis syndrome is clearly visible and clinically identifiable (19) with aneasy cytogenetic verification. More subtle and rare mulformativeconditions and syndromes are recorded (12) in some registries. Asecond possibility is the underdiagnosis and undertreatment of amalignancy such as neuroblastoma in this genetic disorder. This isalso unlikely: the well-known excess of leukemia argues against a

general underdiagnosis of malignant conditions in DS patients. Furthermore, clinicians will be alerted because of the difficulties ofclinical and complementary examinations due to the mental impairment of these patients (20), as well as treatment problems due toenhanced drug toxicity in the case of leukemias ( 10) and solid tumors(21). For these reasons, it is unlikely that a DS case would beoverlooked by a team or a clinician. A third possibility is the lack ofregistration of recognized DS cases. This does not apply to the 5386cases included in the registries in which registration of associatedmalformations is systematic. This is also not likely for the other 1338cases (all cases from West Midlands. United Kingdom, before 1970;fewer than half of the French cases; and all cases from the Netherlands, Finland, Iceland, Norway, and Sweden), because major prob-

Table 1 Cases of DS compared to cases of neurofibromatosis type I. Beckwith-Widemann syndrome, and Hindupnuig'l disease in a European series of neun>blu.\lnmus

CountryDenmarkFinlandFranceGermanyGreat

BritainIcelandItalyNetherlandsNorwaySwedenSwitzerlandTotalPeriod

covered1943-19911985-19941990-1

995'1987-1992"1992-1994"1979-19951971-19941957-1970'1985-19941979-19941972-1994'1975-1995*1982-1995'1970-1995'"1985-19941985-19941971-1995Age

range for inclusionin theregistry0-140-140-150-150-150-140-140-140-140-150-180-180-140-140-140-140-16Number

ofneuroblastomas34194«Of171*781398I94y100310834or/724813486152214*6724Systematic

registration ofassociatedconditionsYesYe»Ye»NoNoYe»YeiNoYe»Ye«NoNoNoNoYe»YesYe»NF"10200161)05010200119/2.2"BW*00000010000(102(I014/0.5"HD'0(11)000100000000001/1.3"DSrf0000(10(100000000000/5.4

" Cases of neurofibromatosis type I.h Cases of Beckwith-Wiedemann syndrome.' Cases of Hirschsprung's disease.rfCases of DS.f Locali/ed disease and metastatic disease under 1 year of age.

in siiti neuroblastomas included.* Metastatic disease after 1 year of age.'' Central nervous system neuroblastomas included.' West Middlands.J Amsterdam area.* Nijmegen area.

Groningen area.'" Rotterdam area." Cases of neurofibromatosis type I. Beckwilh-Wiedemann syndrome, and Hirschsprung's disease expected (age not adjusted).

" Cases of DS expected (age adjusted).

449

Research. on September 14, 2018. © 1998 American Association for Cancercancerres.aacrjournals.org Downloaded from

DOWN SYNDROME AND NEUROBLASTOMA

lems with diagnosis and treatment were mentioned. In addition. Table1 includes 19 cases of neurofibromatosis type 1. 1 of Hirschsprung's

disease, and 4 of Beckwith-Wiedemann syndrome, indicating that

congenital abnormalities were not being missed. A fourth possibilitywould be missing a neuroblastoma in a DS child who died of someother cause. This is probably also unlikely to happen, but, given theincidence of in xiiu neuroblastomas in some autopsy series of infantswith congenital anomalies (9). it does need to be considered. Therefore, we believe that the results strongly suggest a decreased incidenceof neuroblastomas in the DS population.

These results are in agreement with a previous search of theliterature. There is only one ganglioneuroma published as a casereport in a mosaic DS patient (6) and two neuroblastomas included intwo series of childhood tumors associated with malformations (4, 5).These last cases are very poorly documented; one is found in anepidemiológica! series at a time when the various kinds of childhoodsmall round cell tumors were not well differentiated (4), and it is notpossible to completely exclude a nonneuroblastoma case registered asa neuroblastoma. Finally, after a careful manual and computer search,we could not find a single well-documented neuroblastoma in a

nonmosaic DS subject. Two series of 1632 neuroblastomas (22, 23)and a compilation of malformations associated with neuroblastomas(24) contained no trisomy 21 cases. Similarly, no case of neuroblastoma was found among 135 DS children with cancer in the BritishRegistry of Childhood Tumors (2), whereas this cancer accounts for6-10% of childhood neoplasms in the Caucasian population. Our data

are also interesting, because this is the first large study in a Europeanregion with populations as different as those of Italy and the Nordiccountries. In situ neuroblastoma, the incidence of which is estimatedto be 40-50 times higher than florid neuroblastoma (11), has been

observed with various malformations (9, 25) including trisomy 13(26) and trisomy 18 (27). To our knowledge, it has never beenreported with trisomy 21, which is. however, much more common.Finally, besides trisomy 13 and 18. neuroblastoma has been observedwith various exceptional constitutional chromosomal anomalies (28,29). On the other hand, it is well accepted that DS individuals have a20-30-fold excess risk of leukemias. particularly of the M7 type (30).

They may possibly also have more lymphomas (31. 32) and testiculargerm cell tumors (21. 33) than the general population. Thus, thesupposed decreased incidence of neuroblastoma does not reflect ageneral decrease of cancers in individuals with DS. but rather suggestsa possible specific phenomenon concerning this particular peripheralnervous tumor.

A modification of a neoplasm incidence rate may result froma genetic impairment, from environmental factors, or from a combination of the two (34). Several genetic disorders have been described in association with neuroblastomas: neurofibromatosis type 1,Beckwith-Wiedemann syndrome. Hirschsprung's disease. Turner syndrome. Duchenne's muscular dystrophy, and cystic fibrosis. Further

more, homozygous deletion of neurofibromatosis I gene has recentlybeen observed in a primary human neuroblastoma (35). The first twoconditions are most likely to represent risk factors, but at the presenttime, no definitive relationship between a higher risk of neuroblastoma and a genetic disease has been proven (11, 12). Genetic factorshave been evoked to explain some ethnic variations in the incidenceof neuroblastomas (36, 37). More recently, it has been proposed thatthe underlying risk could well be the same in all populations and thatvariations in recorded incidence simply reflect variations in the proportions of tumors that are diagnosed and registered (37). We are notaware of any work suggesting a lower risk of developing neuroblastoma in a particular genetic disease (38).

Several gestational factors have been considered either in isolatedcase reports or in analytical epidemiological studies (11, 12, 23, 34,

39). A risk has been suggested in the offspring of mothers at theextremes (young or old) of their childbearing age (34) and afterexposure to sex hormones (39). Because early or late childbearing ageis a well-known risk factor for trisomy 21 (19) and because exposure

to sex hormones is a suspected risk factor for trisomy 21 (40), wewould expect a higher incidence of neuroblastoma in individuals withDS compared to the general population. Given the lack of strongenvironmental or other types of external confounding factors andgiven the major repercussions of the supplementary chromosome onthe DS phenotype, we consider that a genetic mechanism is probablyalso involved in the rarity of neuroblastomas in individuals with DS.

The DS phenotype is the result of an imbalance due to an excess ofgenetic material on the supernumerary chromosome 21. A parentalimprinting mechanism is theoretically possible, but it has not beenobserved, at least postnatally. for chromosome 21 (41). The dysregu-

lation of one or more genes situated on other chromosomes has beenseen in an animal model of DS (42). This implies that it is not possibleto exclude, a priori, the role of a gene that is not situated onchromosome 21 in certain aspects of DS. However, the most probablemechanism is an overproduction through gene dosage effect of proteins, the genes for which map to chromosome 21 (43). We proposethat chromosome 21 may have a protective effect against neuroblastoma by inhibiting the onset and/or the growth of the tumor. Becausecentral issues in molecular cancer research include to find out whetherparticular genetic alterations can provide information that is of diagnosis and pronostic value (44), we think that this observation isimportant. It is interesting to note that three recent studies on neuroblastoma genomic imbalances using comparative genomic hybridization showed that gain of chromosomal material is much more oftenfound in neuroblastoma cells than are chromosome losses (45-47).

All of these investigations found that gain of chromosome 17 materialis the most common aberration detected in 63-75% of investigated

cases. Moreover, extra material from chromosome 21 was not foundin any investigated tumor in these independent studies, whereas thephenomenon of additional chromosomal material could be detectedfor all other chromosomes in several tumors.

On the distal part of the long arm of chromosome 21 maps theS-ÌOOßgene (48), which fills many conditions for being implicated,

at least in part, in the lack of neuroblastomas in individuals with DS.A previous work (49) discusses the following arguments more extensively: S-100 b protein, the dimeric product of the gene, is secreted

principally in glial cells and nonneural cells of the peripheral nervoussystem (50) and induces differentiation of neural cells in vitro (51).S-100 b protein is overproduced in blood plasma (52) and nervous

tissues (53) in patients with DS. A comparative study of 44 DSpatients and 28 controls showed a clear excess of serum S-100 b

protein (160 pg/ml) compared to controls (76 pg/ml; P < 0.001; Ref.52). An immunohistochemical study suggested that the amount ofS-100 protein in astrocytes of DS brains was even greater than the1.5-fold expected (53). This protein is abundant in the stroma ofwell-differentiated neuroblastomas with good prognosis and is rare or

absent in undifterentiated neuroblastomas of very poor outcome (54).Protein S-100 b induces inhibition of growth and death of severalhuman and murine neuroblastoma cell lines in vitro (49, 55-57).

Several observations indicate an underdevelopment of the peripheral nervous system in individuals with DS, with a reduced number ofneurons in esophageal plexus ganglions (58) and tooth agenesis,which is probably related to impaired mandibular innervation (59).Furthermore, autopsy studies of children with DS disclosed fairlyhypoplastic changes of the adrenal medulla, which is considered as asympathetic ganglion (60-62). It is tempting to speculate that this

inhibition of growth of the nervous tissue could also result from amoderate but chronic overproduction of S-100 b protein, which in-

450

Research. on September 14, 2018. © 1998 American Association for Cancercancerres.aacrjournals.org Downloaded from

DOWN SYNDROME AND NEUROBLASTOMA

hibits neural cell growth and enhances differentiation, in prenatal (53,63) and postnatal life (52). A unifying model would be that inindividuals with DS. the overproduction of S-100 b protein through agene dosage effect could produce both a deleterious effect on peripheral nervous tissue and a beneficial effect, inhibiting the onset and/orthe growth of neuroblastomas.

Because the level of differentiation in neuroblastoma is of greatimportance for the response to treatment (64), we think that aprotein inducing neuroblastoma cells and inhibition of growth,differentiation, and death in vitro is a good candidate to explain therarity of this tumor in a disease in which it is overproduced.However, because cancer is a multistep process, we do not excludethe possibility that other factors and possibly other genes onchromosome 21 act together to prevent the development of thisneuroectodermal tumor in people with DS. For instance, severalgenes of the IFN system map to the long arm of chromosome 21,whereas IFN has extensive and quite diverse effects on nervoustissues (65). If S-100 b protein is effective in decreasing theincidence of neuroblastomas in individuals with DS, it could bevery interesting to see, at least in some patients with sporadicneuroblastoma, whether there was a quantitative or qualitativeanomaly of this protein or its biochemical pathways. Also, wewonder whether S-100 b protein could not be used as a differentiation inducer to treat neuroblastomas and even to prevent theonset of neuroblastomas in conditions at risk, when they will beknown.

We conclude that this large study clearly demonstrates the lack ofneuroblastoma in people with DS. This is in full agreement with theliterature research we conducted. To our knowledge, this is the firsttime that a genetic disease has been linked with the lack of a precisetumor. This model may be the paradigm of a particular approach ofthe decreased incidence of some neoplasms in genetic diseases. It canbe applied to other tumors that are underrepresented in those with DSand to other genetic diseases. More specifically, our results are infavor of a protective effect of chromosome 21 against neuroblastomadevelopment, as supported by recent genetic studies using comparative genomic hybridization. However, at the present time, to confirmthese data and our interpretation, more epidemiological and experimental studies are needed, such as genetic transfer involving wholechromosome 21, chromosomal regions, or expression vectors forspecific genes, including the gene S-100 ß.

ACKNOWLEDGMENTS

We gratefully acknowledge Beatrice Bezamat. Nathalie Villeyras. and Su-

zan Haver for secretarial assistance. We thank every contributor not includedin the author list who kindly provided additional information concerning casesrecorded and members of the different registries for use of the data onneuroblastoma.

REFERENCES

1. Narod. S. A.. Hawkins. M. M. Robertson, C. M.. and Stiller. C. A. Congenitalanomalies and childhood cancer in Great Britain. Am. J. Hum. Genet.. 60: 474-485.

1997.2. Narod. S. A.. Stiller, C. A., and Lenoir. G. M. An estimate of the heritable fraction

of childhood cancer. Br. J. Cancer. 63: 993-999. 1991.

3. Satge. D., Sommelet. D-, Geneix. A.. Malet. P., and Vekemans. M. Tumoral Profilein Down syndrome: a step towards the understanding of the consequences of aneu-

ploidy and the development of cancer. Am. J. Hum. Genet.. 55 (Suppl.l: A303. 1994.4. Miller. R. W. Childhood cancer and congenital defects: a study of LI. S. death

certificates during the period 1960-1966. Pediatr. Res.. 3: 389-397. 1969.5. Foulkes, W. D.. Buu, P. N.. Filiatrault. D.. Ledere. J-M.. and Narod. S. A. Excess of

congenital abnormalities in French-Canadian children with neuroblastoma: A caseseries study from Montreal. Med. Pediat. Oncol.. 29: 272-279. 1997.

6. Hosoi. H., Sawada. T.. Nakajima. T.. Kuroda. H., Saida. T.. Sugimoto. T., Tokiwa.K., and Ogita, S. A case of mosaic Down's syndrome concomitant with ganglioneu-

roma. J. Pediatr. Surg., 24: 210-211, 1989.

7. Stiller. C. A., and Parkin. D. M. International variations in the incidence of neuroblastoma. Im. J. Cancer. 52: 538-543. 1992.

8. Kaatsch. P., Haap, G., and Michaelis. J. Childhood malignancies in Germany:methods and results in nationwide registry. Eur. J. Cancer. 3IA: 993-999. 1995.

9. Beckwith. J. B.. and Perrin. H. V. In situ neuroblustomas: a contribution to ine naturalhistory of neural crest tumors. Am. J. Pathol.. 4Õ: 1089-1104, 1963.

10. Ragab, A. H.. Abdel-Mageed. A., Shuster, J. J.. Frankel. L. S., Pullen. J.. Van Eys, J.,Sullivan. M. P.. Boyett. J.. Borowit/. M.. and Crist, W. M. Clinical characteristics andtreatment outcome of children with acute lymphoblastic leukemia and Down's

syndrome. Cancer (Phila.). 67: 1057-1063. 1991.11. McWilliams. N. B. Neuroblastoma in infancy, neonatal neuroblastoma and associated

conditions. In: C. Pocheldy (ed.), Neuroblastoma: Tumor Biology and Therapy, pp.230-232. Boca Raton: CRC Press, 1990.

12. Carlsen, N. L. T. Neuroblastomas in Denmark 1943-19X0. Acta Paediatr. Suppl.. 403:1-27, 1994.

13. EUROCAT (European Registration of Congenital Anomalies). Down syndrome. In:15 Years Surveillance of Congenital Anomalies in Europe: 1980-1994. pp. 120-149.Brussels: EUROCAT Working Group. 1997.

14. Mutton. D. E., Alberman, E., Ide. R.. and Bobrow. M. Results of first year ( 1989) ofa national register of Down's syndrome in England and Wales. Br. Med. J., 303:

1295-1297, 1991.

15. Baird. P. A., and Sadovnick. A. D. Life tables for Down syndrome. Hum. Genet., 82:291-292, 1989.

16. Jones, K. L. Neurofibromatosis syndrome. In: Smith's Recognizable Patterns of

Human Malformation, pp. 452-453. Philadelphia: W. B. Saunders. 1988.17. Schneid. H., Vazquez, M. P.. Vacher, C.. Gourmelen. M.. Cabro!. S., and Le Bouc.

Y. The Beckwith-Wiedemann syndrome phenolype and the risk of cancer. Med.Pediatr. Oncol.. 28: 411-415. 1997.

18. Rescorla, F. J.. Morrison, A. M.. Engles. D., West, K. W., and Grosfeld. J. !..Hirschsprung's disease: evaluation of mortality and long-term function in 260 cases.

Arch. Surg.. 127: 934-942. 1992.

19. A Report from the International Clearinghouse for Birth Defects Monitoring Systems:Down's Syndrome. In: Congenital Malformations Worldwide, pp. 157-162. Amster

dam: Elsevier, 1991.20. Satgé,D.. Le Toumeau. A.. Verger. J. P.. Lefort, S., Geneix, A., Malet. P., Diebold.

J.. and Vekemans, M. Down syndrome and cenlroblaslic lymphoma. Palhol. Res.Pracl., 192: 1266-1269, 1996.

21. Dexeus, F. H.. Logothetis. C. J.. Chong. C.. Sella. A., and Ogden. S. Geneticabnormalities in men with germ cell tumors. J. Urol., 140: 80-84. 1988.

22. Miller. R. W., Fraumeni, J. F.. and Hill. J. A. Neuroblastoma: epidemiologie approachto its origin. Am. J. Dis. Child.. 115: 253-261. 1968.

23. Negus, J. P., Smithson. W. A.. Gunderson. P.. King. F. L.. Singher. L. J., andRobison. L. L. Prenatal and perinatal risk factors for neuroblastoma. Cancer (Phila.),fil: 2202-2206, 1988.

24. Sy, W. M., and Edmonson, J. H. The developmental defects associated with neuroblastoma: enologie implications. Cancer (Phila.), 22: 234-238. 1968.

25. Shanklin. D. R.. and Sotelo-Avila. C. In \itu tumors in fetuses, newborns and younginfants. Biol. Neonal., 14: 286-316. 1969.

26. Feingold, M., Gheradi, G. J.. and Simons, C. Familial neuroblasioma and trisomy 13.Am. J. Dis. Child., 121: 451, 1971.

27. Robinson. M. G.. and McCorquodale. M. M. Trisomy 18 and neurogenic neoplasia.J. Pediatr. 99: 428-429. 1981.

28. Fryns. J. P.. Moerman. P.. Kleczkowska, A., and Van den Berghe. H. Neuroblasiomaand partial I5q duplication in the fetus. Ann. Genet.. 37: 42-43, 1994.

29. Qureshi. F.. Jacques. S. M.. Johnson. M. P.. Reichler. A., and Evans. M. I. Microscopic neuroblastoma in a fetus with a tie /irmi unbalanced translocalion 3:10. Am. J.Med. Genet., 53: 24-28, 1994.

30. Power, L. W.. and Register. M. K. Down syndrome and acute leukemia: epidemiological and genetic relationships. Lab. Med.. 22: 630-636, 1991.

31. Barber. R., and Spiers, P. Oxford survey of childhood cancers: progress report II.Mon. Bull. Minist. Health Lond.. 23: 46-52, 1964.

32. Scholl. T., Stein. Z., and Hansen. H. Leukemia and other cancers, anomalies andinfections as causes of death in Down's syndrome in the United Slates during 1976.

Dev. Med. Child. Neurol.. 24: 817-829, 1982.33. Satgé,D., Sasco, A. J., Curé,H.. Leduc. B.. Sommelet. D., and Vekemans. M. J. An

excess of teslicular germ cell tumors in Down's syndrome: three case reports and a

review of the literature. Cancer (Phila.), 80: 929-935, 1997.

34. Carlsen. N. L. T. Neuroblasiomas presenting in the first year of life: epidemiologicaldifferences from those presenting al older ages. Cancer Delecl. Prev., 20: 251-261,

1996.35. Martinsson. T., Sjöberg.R-M.. Hedborg. F.. and Rogner. P. Hormwygous deletion of

the neurofibromatosis-1 gene in the tumor of a patient with neuroblastoma. CancerGenet. Cytogenet., 95: 183-189, 1997.

36. Miller. R. W. Rarity of neuroblastoma in East Africa. Lancet. 335: 659-660. 1990.37. Stiller, C. A., and Parkin, D. M. Geographic and ethnic variations in the incidence of

childhood cancer. Br. Med. Bull.. 52: 682-703. 1996.38. Brodeur. G. M., and Fong, C. T. Molecular biology and genetics of human neuro

blastoma. Cancer Genet. Cytogenet.. 41: 153-174. 1989.39. Mandel. M., Toren. A.. Rechavi, G., Dor. J.. Ben-Bassat, I., and Neumann. Y.

Hormonal treatment in pregnancy: a possible risk factor for neuroblastoma. Med.Pediatr. Oncol.. 23: 133-135. 1994.

40. Janerich. D. T.. and Bracken. M. B. Epidemiology of trisomy 21: a review andtheoretical analysis. J. Chron. Dis., 39: 1079-1093, 1986.

41. Sloll. C., Alembik, Y.. Doit. B.. and Feingold, J. No evidence for genomic imprintingin liveborn Down syndrome patients. Ann. Genet.. 3K: 13-18, 1995.

42. Holtzman, D. M.. Bayney. R. M.. Li. Y.. Khosrovi. H.. Berger. C. N., Epstein, C. J.,

451

Research. on September 14, 2018. © 1998 American Association for Cancercancerres.aacrjournals.org Downloaded from

DOWN SYNDROME AND NKUROBLASTOMA

and Mobley. W. C. Dysregulation of gene expression in mouse trisomy 16. an animalmodel of Down syndrome. EMBO J.. //. 619-627, 1992.

43. Epstein. C. J. Specificity wr.v/i.v nonspecificity in the palhogenesis of aneuploidphenotypes. Am. J. Med. Genet.. 29: 161-165. 1988.

44. Schwab. M. Is there a neuroblastoma ami-oncogene? In: A. E. Evans. G. J. D'Angio.

A. G. Knudson. Jr., and R. Seeger (eds.). Advances in Neuroblastoma Research. Vol.3. pp. 1-9. New York: Wiley-Liss. 1991.

45. Planta?. D.. Mohapatra. G.. Maithay. K. K.. Pellarin. M.. Seeger. R. C., and Feuerstein. B. Ci. Gain of chromosome 17 is the most frequent abnormality detected inneuroblastoma by comparative genomic hybridisation. Am. J. Pathol.. 150: 81-89,

1997.46. Lastowska. M.. Nacheva, E., McGuckin. A.. Curtis. A.. Grace. C.. Pearson, A., and

Bown. N. Comparative genomic hybridi/ation study of primary neuroblastoma tumors. Genes Chromosomes Cancer, /#: 162-169. 1997.

47. Brinkschmidt. C.. Christiansen. H.. Terpe, H. J.. Simon. R.. Boecker. W.. Lampert. F..and Stoerkel. S. Comparative genomic hybridi/.alion (CGH) analysis of neuroblasto-

mas: an important methodological approach in paediatric tumour pathology.J. Pathol.. INI: 394-400, 1997.

48. Allore. R.. O'Hanlon, D.. Price, R.. Neilson. K.. Willard. H. F., Cox, D. R.. Marks.

A., and Dunn. R. J. Gene encoding the ßsubunit ufSIOO protein is on chromosome21: implications for Down syndrome. Science (Washington DC). 23V: 1311-1313,

1988.49. Salgé.D. A decreased incidence of neuroblastomas in Down syndrome and overpro

duction of S-KK) b protein: an hypothesis. Med. Hypotheses. 46: 393-399. 1996.50. Donato. R. Perspectives in S-HK) protein biology. Cell Calcium. 12: 713-726. 1991.51. Winningham-Major. F.. Slaecker. J. L.. Barger. S. W., Coats, S., and Van Eldik, L. J.

Neurile extension and neuronal survival activities of recombinant SI(K) fi proteins thatdiffer in the content and position of cysteine residues. J. Cell. Biol.. KM: 3063-3071,1989.

52. Kalo, K., Suzuki, F.. Kurobe, N.. Okajima. K.. Ogasawara, N.. Nagaya. M., andYamanaka. T. Enhancement of S-KX) ßprotein in blood of patients with Down's

syndrome. J. Mol. Neurosci.. 2: 109-113. 1990.

53. Griffin. W. S. T.. Stanley. L. C.. Ling. C.. White. L. MacLeod. V.. Perrot. L. J..

White. C. L.. and Araos. C. Brain interleukin I and S-IOO immunoreactivity are

elevated in Down syndrome and Alzheimer disease. Proc. Nati. Acad. Sci. USA, 86:7611-7615. 1989.

54. Nagoshi. M.. Tsuneyoshi. M.. and Enjoji. M. S-KK) positive undifferentiated neuro-

hlastomas with a special reference to the tumor stroma related to favorable prognosis.Pathol. Res. Pract.. Ititi: 273-283. 1992.

55. Kligman. D.. and Hsieh. L. S. Neunte extension factor induces rapid morphologicaldifferentiation of mouse neuroblastoma cells in defined medium. Dev. Brain Res.. .Õ.Õ:296-300. 1987.

56. Selinfreund. R. H.. Barger. S. W.. Pledger, W. J.. and Van Eldik. L. J. Neurotrophicprotein S100 ßstimulates glial cell proliferation. Proc. Nati. Acad. Sci. USA, 88:3554-3558. 1991.

57. Fano. G., Mariggio, M. A., Angelella, P., Nicoletti, !.. Amónica, A., Fülle,S., andCalissano. P. The S-KK) protein causes an increase of intracellular calcium and deathof PC 12 cells. Neuroscience. S3: 919-925, 1993.

58. Nakazato. Y.. and Landing. B. H. Reduced number of neurons in esophageal plexusganglia in Down syndrome: additional evidence for reduced cell number as a basicfeature of the disorder. Pedialr. Pathol.. 5. 55-63. 1986.

59. Rüssel.B. G.. Kjaer. I. Tooth agenesis in Down syndrome. Am. J. Med. Genet.. 55:466-471. 1995.

60. Lange. P. Beitrage zur pathologischen Anatomie des Mongolismus. Monatsschr.Kinderheilkde.. 5: 233-243. 1906.

61. Gordon. M. B. Morphological changes in the endocrine glands in mongolian idiocywith report of two cases. Endocrinology, 14: 1-6, 1930.

62. Benda. C. E. The adrenals in mongolism. In: The Child with Mongolism. pp.136-139. New York: Gruñe& Stratton, Inc.. I960.

63. Mito. T.. and Becker. L. E. Developmental changes of S-KM) protein and glialfibrillary acidic protein in the brain in Down syndrome. Exp. Neurol.. 120: 170-176,1993.

64. Israel. M. A. Disordered differentiation as a target for novel approaches to thetreatment of neuroblastoma. Cancer (Phila.). 71: 3310-3313, 1993.

65. Maroun. L. E. Interferon action and chromosome 21 trisomy (Down syndrome) 15years later. J. Theor. Biol.. 181: 41-46. 1996.

452

Research. on September 14, 2018. © 1998 American Association for Cancercancerres.aacrjournals.org Downloaded from

1998;58:448-452. Cancer Res   Daniel Satgé, Annie J. Sasco, Niels L. T. Carlsen, et al.   European CountriesA Lack of Neuroblastoma in Down Syndrome: A Study from 11

  Updated version

  http://cancerres.aacrjournals.org/content/58/3/448

Access the most recent version of this article at:

   

   

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/58/3/448To request permission to re-use all or part of this article, use this link

Research. on September 14, 2018. © 1998 American Association for Cancercancerres.aacrjournals.org Downloaded from