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wit.i-:. ~ - a ELSEVIER Biochimica et Biophysica Acta 1288 (1996) F141-F150 BB. Biochi~ic~a et Biophysica A~ta Review Genetic epidemiology of childhood cancer Steven A. Narod * Department of Medicine, UniversiO' of Toronto, Women's College Hospital, 7th floor, Room 750A, 790 Bay Street, Toronto, Ont., Canada M5G 1N8 Received 27 August 1996 Contents Introduction .................................................... F141 1.1. Proportion of childhood cancers ...................................... F141 1.2. Types of mutations ............................................. F142 1.3. Patterns of inheritance ............................................ F142 2. Types of studies .................................................. Fl43 2.1. Associations with known syndromes .................................... F143 2.2. Family studies ................................................ F143 2.3. Ethnic studies ................................................ F144 2.4. Multiple primary cancers .......................................... F144 2.5. Linkage analysis/mutation analysis .................................... F144 2.6. Parental occupational and environmental exposures ............................ F144 3. Specific cancer syndromes ............................................ F145 3.1. Retinoblastoma ............................................... F145 3.2. Wilms turnout ................................................ F146 3.3. The Li-Fraumeni syndrome ......................................... F147 3.4. Neurofibromatosis and tuberous sclerosis .................................. F148 References ...................................................... F148 1. Introduction 1.1. Proportion of childhood cancers The central questions of the genetic epidemiology of cancer change once the genes responsible for the various syndromes have been identified. Several genes which cause hereditary cancer syndromes in adults have been cloned, but only a small number of genes underlying inherited forms of childhood cancer are now known. This may be because cancer in children is much less frequent than in adults, or because the hereditary fraction of cancer is less * Corresponding author. Fax: + 1 416 3513767; e-mail: [email protected] 0304-419X/96/$15.00 Copyright © 1996 Published by Elsevier Science B.V. PH S0304-419X(96)00031-5 for children than for adults. The term hereditary cancer is used to refer to those cancers that are due to mutations that are either inherited from a parent, or which have arisen de novo in a parental germ cell. By examining the cases of cancer in the National Registry of Childhood Tumours in Great Britain, the proportion of cancers in childhood that are due to inherited mutations has been estimated to be less than 5% [1]. An underlying genetic condition was listed for 509 (3.07%) of the 16564 cases of childhood cancer. The most common genetic syndromes were bilat- eral retinoblastoma (162 cases), Down syndrome (135 cases), neurofibromatosis (90 cases) and tuberous sclerosis (20 cases). Undoubtedly, this estimate will increase as new syndromes and new cancer susceptibility genes are identi- fied. Olsen et al. did not find an increased incidence of All rights reserved.

Genetic epidemiology of childhood cancer

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Page 1: Genetic epidemiology of childhood cancer

w i t . i - : . • ~ - a

ELSEVIER Bioch imica et B iophys ica Ac ta 1288 (1996) F 1 4 1 - F 1 5 0

BB. Biochi~ic~a et Biophysica A~ta

R e v i e w

Genetic epidemiology of childhood cancer

Steven A. Narod *

Department of Medicine, Universi O' of Toronto, Women's College Hospital, 7th floor, Room 750A, 790 Bay Street, Toronto, Ont., Canada M5G 1N8

Received 27 Augus t 1996

Contents

Int roduct ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F141

1.1. Propor t ion o f chi ldhood cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F141

1.2. Types o f mutat ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F142

1.3. Pat terns o f inheri tance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F142

2. Types o f studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F l 4 3

2.1. Associa t ions with k n o w n syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F143

2.2. Fami ly studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F143

2.3. Ethnic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F144

2.4. Mult iple p r imary cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F144

2.5. L inkage a n a l y s i s / m u t a t i o n analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F144

2.6. Parental occupat ional and envi ronmenta l exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . F144

3. Specif ic cancer syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F145

3.1. Re t inoblas toma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F145

3.2. Wi lms turnout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F146

3.3. The Li -Fraumeni syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F147

3.4. Neurof ibromatos is and tuberous sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F148

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F148

1. Introduction

1.1. Proportion of childhood cancers

The central questions of the genetic epidemiology of cancer change once the genes responsible for the various syndromes have been identified. Several genes which cause hereditary cancer syndromes in adults have been cloned, but only a small number of genes underlying inherited forms of childhood cancer are now known. This may be because cancer in children is much less frequent than in adults, or because the hereditary fraction of cancer is less

* Cor respond ing author. Fax: + 1 416 3513767; e-mail: narod@ftn .ne t

0 3 0 4 - 4 1 9 X / 9 6 / $ 1 5 . 0 0 Copyr igh t © 1996 Publ ished by Elsevier Science B.V. PH S 0 3 0 4 - 4 1 9 X ( 9 6 ) 0 0 0 3 1 - 5

for children than for adults. The term hereditary cancer is used to refer to those cancers that are due to mutations that are either inherited from a parent, or which have arisen de novo in a parental germ cell. By examining the cases of cancer in the National Registry of Childhood Tumours in Great Britain, the proportion of cancers in childhood that are due to inherited mutations has been estimated to be less than 5% [1]. An underlying genetic condition was listed for 509 (3.07%) of the 16564 cases of childhood cancer. The most common genetic syndromes were bilat- eral retinoblastoma (162 cases), Down syndrome (135 cases), neurofibromatosis (90 cases) and tuberous sclerosis (20 cases). Undoubtedly, this estimate will increase as new syndromes and new cancer susceptibility genes are identi- fied. Olsen et al. did not find an increased incidence of

All r ights reserved.

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F142 S.A. Narod / Biochimica et Biophysica Acta 1288 (1996) F141-F150

cancer among 11 380 parents of 5863 children with cancer in Denmark [2]. Their results confirm the belief that only a small minority of childhood cancers are due to hereditary factors. The observed exception was a significant excess of breast cancer in the mothers of children diagnosed with osteogenic, or soft tissue sarcoma before the age of three, in keeping with previous reports [3].

1.2. Types o f mutations

Constitutional mutations which predispose to cancer may be either point mutations, which disrupt a single gene, or chromosomal rearrangements, which may affect several genes. Point mutations of the Rb gene cause retinoblas- toma, and are the single most common cause of inherited childhood cancer. A small proportion of retinoblastomas (5%) are due to cytogenetic deletions of chromosome 13q14 [4]. Children with Down syndrome (trisomy 21) have a 20-fold increased risk of acute leukemia; in particu- lar, the relative risk of acute non-lymphocytic leukemia is very high before age four in these children [1]. Other relevant cytogenetic anomalies include chromosome 1 lp13 deletions in the WAGR syndrome and 1 lp15 duplications in the Beckwith-Weidemann syndrome (discussed below). However, with few exceptions, chromosomal mutations are rare causes of childhood cancer. In the National Reg- istry of Childhood Tumours (UK) chromosomal abnormal- ities were reported for only 1.2% of the children with cancer (C. Stiller, personal communication).

Several recessive syndromes are associated with an increase in the frequency of chromosomal fragility and with elevated rates of cancer. Chromosomal instability may be revealed by increased rates of sister chromatid exchanges or chromosome breaks, or by mutagen sensitiv- ity; these rare conditions will be mentioned only briefly here. Bloom syndrome (BS) is characterized by growth deficiency, a characteristic facial appearance, and child- hood cancer [5]. High rates of sister chromosome ex- change, chromosome gaps and breaks are observed in BS [5]. The gene for BS maps to chromosome 15q26.1 and codes for a DNA helicase [6]. Mutations are more common among Ashkenazi Jews [7], due to a founder effect for a deletion/insertion mutation at nucleotide 2281 [6]. All mutations appear to lead to loss of function of the gene, but it is not yet clear if the cancer excess is due to the impaired function of the helicase system, or is an indirect result of high rates of chromosome breakage. BS is atypi- cal among the chromosome breakage syndromes because, in addition to leukemias and lymphomas, there is a very high incidence of epithelial solid tumours; in particular colon cancer and head and neck cancer occurs at an early age. In contrast, the cancers associated with ataxia- telangiectasia (AT) and with Fanconi anemia (FA) are mostly lymphomas and leukemias [8]. Genetic rearrange- ments at the loci for T-cell receptors and immunoglobins leads to lymphoid malignancies [9]. Both BS and AT are

associated with immunodeficiency. Other inherited condi- tions with a congenitally impaired immune response and a predisposition to lymphoma and leukemia include severe combined and common variable immunodeficiency, the X-linked immunoproliferative syndrome and the Wiskott- Aldrich syndrome [8]. Not all instability syndromes are associated with elevated rates of cancer, e.g. genetic insta- bility in the fragile X syndrome is restricted to the region of the fragile site and the syndrome has not been associ- ated with increased rates of cancer.

Tumour suppressor genes are believed to be responsible for the majority of dominant hereditary cancer syndromes. Under the tumour suppressor model, any of a range of genetic mutations which lead to an absent or inactive protein are expected to lead to a similar phenotypic effect. This appears to be true for the Li-Fraumeni syndrome and for retinoblastoma. However, regulatory mutations with reduced penetrance have also been described for familial retinoblastoma [ 10]. One dominant cancer syndrome that is not due to a tumour suppressor gene is multiple endocrine neoplasia type 2 (MEN2A and MEN2B). A small number of missense mutations in the ret proto-oncogene lead to C-cell hyperplasia, medullary thyroid cancer and pheochromocytoma [11]. However, nonsense mutations of the ret proto-oncogene are also found in familial Hirsch- prung disease [12]. In rare cases a single segregating ret mutation may lead to MEN2A and Hirschprung disease in the same family. One possible mechanism for this unusual phenotype is that the ret mutation leads to an RNA that is stably expressed in C-cells but is unstable in the develop- ing colon - - such a mutation would act dominantly in the thyroid but would mimic an inactivating mutation in the colon.

1.3. Patterns o f inheritance

Not all hereditary cases of cancer are familial. If the mutation is de novo, then both parents and all sibs of the patient will be non-carriers, but the mutation may be transmissible to future children. Retinoblastoma, neurofi- bromatosis and familial polyposis are associated with high de novo mutation rates. However, if a mutation is highly penetrant and is lethal prior to reproductive age, or if it causes impaired reproduction, then there will be no oppor- tunity for transmission to children and all cases will be sporadic. This is typically the case for the chromosomal abnormalities associated with childhood cancer, although extended cancer pedigrees due to chromosome transloca- tions in adults have been described. In certain cases of dominant diseases, the familial pattern may go unrecog- nized. Because the penetrance of familial Wilms' tumours is typically low, several unaffected relatives may be posi- tioned in the pedigree between two affected children, and the family cluster may go unnoticed.

Genetic counselling for dominant conditions is also complicated by the possibility of gonadal mosaicism [13].

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This is the result of somatic mutation early in embryogene- sis, resulting in a population of cells that contain a cancer predisposing mutation and a population of normal cells. If both populations are present in the germ cells there will be a significant risk for disease in the sibling of an affected child, proportionate to the number of mutant cells in the parental germline. Tests to detect mutations in the parents may be negative, if based solely on DNA from circulating lymphocytes, and may falsely lead the geneticist to the conclusion that the recurrence risk for future siblings is negligible.

If a disease is recessive it will be rare to have multiple cases in a family, especially if the average family size is small. It is possible that familial clustering of a childhood cancer (e.g. Hodgkin's disease) could be due to a recessive susceptibility gene; this could be proven by linkage stud- ies. However, because of the high frequency of sporadic cases, and the rarity of familial childhood cancers, it has not yet been possible to establish the existence of a recessive childhood cancer syndrome in the absence of an extended phenotype. This is in contrast to several domi- nant childhood cancer syndromes (e.g. Li-Fraumeni syn- drome, familial Wilms' tumour and retinoblastoma) for which many extended pedigrees have been observed. An increased frequency of parental consanguinity is a signal of a recessive disease. In one study from Japan a high rate of parental consanguinity was reported more frequently in parents of siblings with leukemia [14] than in population controls, but this observation has not been replicated.

X-linked conditions associated with cancer include the X-linked immunodeficiencies mentioned above [8], the Simpson-Golabi-Bemel syndrome [15] and incontinentia pigmenti (IP) [16]. IP is a rare X-linked dominant syn- drome associated with an increased rate of cancer in girls [16]. It is believed that the IP mutation is lethal in males.

If only a single copy of a gene is normally active, then the gene is said to be imprinted; usually it is only the maternally derived or paternally derived allele that is active. Paragangliomas, or carotid body tumours, are slow growing tumours of the head and neck derived from the neural crest [17]. Familial paragangliomas appear as domi- nant traits with reduced penetrance. However, only chil- dren of cartier males express this trait - - i.e. it is only the paternally derived allele that is believed to be active and the children of female carriers are therefore not at risk [18]. This is the best example of an inherited imprinted cancer gene. Susceptibility to paragangliomas maps to chromo- some l l q [18].

Uniparental disomy (UPD) is the phenomenon whereby both copies of a chromosome, or a portion of a chromo- some, are inherited from the same parent. If the disomic genes are imprinted, then typically two inactive or active copies will be present. A proportion of children with the Beckwith-Weidemann syndrome have been found to have uniparental disomy for part of the short arm of chromo- some 11 [19]. It has been proposed that UPD of chromo-

some 1 lp leads to a doubling in the activity of insulin like growth factor 2 (IGF2), a gene which maps to this region. Children with Beckwith-Weidemann syndrome are at in- creased risk of Wilms' tumour, but UPD is rare in children with Wilms' tumour in the absence of this syndrome [20]. UPD is not a classical genetic mechanism of disease, because the DNA sequence is believed to be intact, and because the abnormality is expected to revert to normal in subsequent generations.

2. Types of studies

2.1. Associations with known syndromes

Some types of cancer have been identified as hereditary because they are seen in excess in patients with a known genetic disease or congenital malformation. Several early observations of childhood cancers and specific malforma- tions accelerated the discovery of cancer susceptibility genes. Associations may be due to multiple effects of a single gene, or to contiguous gene syndromes. Congenital malformations are seen approximately twice as frequently as expected in children with cancer [21]. Specific associa- tions between cancers and malformations are rare - - more commonly a particular malformation is seen in a wide range of childhood cancer types; e.g. spine and rib abnor- malites, pyloric stenosis and ventricular septal defects have been reported to be in excess for cancers at many sites [21-23]. The genetic basis for the majority of these syn- dromes is not known, but it is likely that somatic mutations are involved. It is surprising that the sites of childhood cancer associated with the highest rates of malformations (Wilms' tumours, germ cell neoplasms, Ewing sarcomas) are not associated with the highest recurrence risks in siblings and offspring. Some sites (e.g. Hodgkins disease) are associated with high sibling recurrence risks [24], but with low rates of malformations [21]. Excluding children with Down syndrome, the excess of malformations appears to be restricted to children with solid tumours [21].

2.2. Family studies

A particular cancer may be seen in striking excess in a single family - - barfing chance occurrence this observa- tion is evidence for a genetic basis for the type of cancer observed. In order to quantify the excess risk it is neces- sary to compare the incidence of cancer in relatives of cases with that of an appropriate control group. This can be done historically (case-control study) or prospectively (cohort study). In a case-control study the frequency of cancer in relatives of patients with cancer is compared to the frequency of cancer in relatives of healthy controls. In a cohort study, the risk of cancer is measured by following a group of patients who are defined at the time of study entry as having a positive family history of cancer, and

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comparing the incidence rate of cancers in this group to the rate in the general population, Segregation analysis is a statistical technique which is used to extend these simple study designs in order to define the underlying genetic model for a set of cancer families. Typically, one tries to fit the pedigree set to a known pattern of transmission; e.g. dominant, recessive or X-linked. If the data set does not fit well to any of these single gene models then more compli- cated genetic models are considered. These include multi- factorial models (genes and environmental effects com- bined) and polygenic models (more than one gene in- volved in a single family).

2.3. Ethnic studies

Studies of cancer rates in different ethnic groups may provide clues to etiology, especially when combined with information about rates of cancers in migrants [25]. Retinoblastoma was found to be bilateral more frequently in Caucasians (48%) than in Asian children (23%), sug- gesting a higher proportion of hereditary cases in Cau- casians [26]. Both Wilms' tumour and rhabdomyosarcoma are less frequent among Asian children than among Cau- casians [26].

Ewing sarcoma is reported to be rare in black children [27]. These bone tumours are the consequence of a somatic translocation between chromosomes 11 and 22, leading to the production of a mutant chimeric protein [28,29]. It is not clear if this translocation is rare in blacks - - perhaps it occurs but is less likely to lead to cancer. It is possible that the bony matrix in black children is less suitable to tumour growth. Conversely, children with osteogenesis imperfecta appear to be more susceptible to Ewing sarcoma [21].

2.4. Multiple primary cancers

A second primary cancer in a child may be due to the effect of treatment of the first malignancy, to chance, to carcinogenic exposure, or to genetic predisposition. Child- hood adrencortical cancer carries a very high risk of second primary cancer [30]. This risk is probably due to p53 mutations, which are seen in up to 50% of these children [31]. Children with soft tissue sarcomas and a second malignancy may also be from families with the Li-Fraumeni syndrome [32]. An elevated rate of papillary thryoid cancers is reported among childhood cancer sur- vivors, especially those with neuroblastomas [33,34]. It has been proposed that this is due to the treatment effect of the neuroblastoma, but a common genetic predisposition to the two cancer types is an alternate explanation. Children with Wilms' tumour are also at increased risk of thyroid cancer. Children with retinoblastoma are at increased risk for a second primary bone cancer and later in life they are at risk for bladder cancer, melanoma, brain tumours and small cell lung cancer of the lungs [35,36]. The risk

appears to be restricted to the 50% of children with the inherited form of retinoblastoma.

2.5. Linkage analysis / mutation analysis

The objective of linkage analysis is to identify the chromosomal location of a cancer susceptibility gene. Finding linkage to a specific region may also confirm the genetic basis of a cancer syndrome, and lead to refined estimates of gene penetrance and the degree of genetic heterogeneity. In linkage analysis, a polymorphic genetic marker is sought which segregates in one or several large cancer families with the predisposition to cancer. Typi- cally, linkage is established when a single allele of marker from a known chromosomal position is found to be carried by all of the affected patients in a family. The finding is then confirmed by examining additional markers and fami- lies. Linkage analysis is complicated by the fact that different genes may be cause the cancer susceptibility in different families, and by the presence of both hereditary and non-hereditary (i.e sporadic, or chance) cases of can- cer in the same family. However, because of the rarity of childhood cancer (as compared to adult carcinomas) the possibility of misclassification due to sporadic cases of childhood cancer is remote. In the cases of familial retinoblastoma and the Beckwith-Weidemann syndrome, cytogenetic abnormalities in cancer patients led investig- tors to search for linkage on chromosomes 13q and l lp respectively [37,38]. In contrast, the p53 gene on chromo- some 17q was implicated in the Li-Fraumeni syndrome by the candidate gene approach, rather than by formal linkage analysis [39]. Recently, Rahman and colleagues performed a comprehensive search using 180 markers distributed throughout the genome to map a gene for hereditary Wilms' tumour to chromosome 17q [40].

Once the susceptibility gene is identified, it is then possible to estimate the proportion of cases of cancer attributable to inherited mutation directly, by sequencing the constitutional DNA in an unselected series of cancer cases. This has now been done for adrenocortical cancer and p53 mutations [31] and for Wilms' tumours and WT1 [411.

2.6. Parental occupational and environmental exposures

For several decades there has been concern that parental preconceptual exposure to ionizing radiation or to muta- genic chemicals may induce germinal mutations and thereby increase the frequency of childhood disease, in- cluding cancer. It might be expected that these increases would be limited to dominant genetic conditions (i.e. sentinel phenotypes) much attention has been focussed on childhood cancer and congenital malformations, although the heritable component of these is small. Past studies have focused on bilateral retinoblatoma and Wilms tumours, considering these to be due to constitutional genetic muta-

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S.A. Narod/ Biochimica et Biophysica Acta 1288 (1996) F141-FI50 Fl45

tions; while this is certainly true for retinoblastoma there is little support for this hypothesis for Wilms' tumour [42]. The only two childhood tumours for which substantial fractions currently are known to be due to genetic causes are retinoblastoma and adrencortical cancer.

Two groups who have been studied closely are children of parents exposed to the atomic bomb blast at Hiroshima and Nagasaki and children of men working at the Sell- afield nuclear plant. There was no excess of childhood cancers in a cohort of 31 150 children of parents exposed to the atom bomb [43]. The proportion of retinoblastoma among all cancers in the exposed cohort (6.6%) was not significantly greater than for Japan as a whole (4.4%).

The strongest evidence to date that environmental fac- tors induce cancers through parental exposure comes from the study of Sellafield workers [44]. A significantly in- creased rate of leukemia was observed among the children of male employees of this nuclear plant. The average radiation exposures of the fathers of the leukemia cases were higher than those of unaffected children. This has been an area of controversy and the basis for the excess has not yet been resolved, although several alternate hy- potheses have been put forward. The genetic issues are reviewed in reference [45]. Much of the skepticism sur- rounding the interpretation of this finding was that the mutation rate implied was very high, and leukemia is not considered to be a genetic disease (in the absence of Down syndrome and a few rare recessive conditions). McLaugh- lin et al. were unable to confirm this association in Ontario children who lived in the vicinity of a nuclear installation [46].

More than 30 studies have been published in which an association has been sought between childhood cancer and parental occupation. These are reviewed in Refs. [47] and [48] and will be discussed only briefly here. Several occu- pational risk factors for childhood cancer have been pro- posed, but with the possible exception of welding and Wilms' tumour, there have been no consistent associations. In four combined studies, there were 14 fathers of Wilms tumour cases who were employed as welders (3.2%), versus 0.7% of control fathers (reviewed in Ref. [48]) One of the most studied relationships is that of motor vehicle exhaust fumes and infant leukemia. There have been sev- eral suggestive studies, but there have been negative re- ports as well.

3. Specific cancer syndromes

3.1. Ret inoblas toma

Approximately 50% of retinoblastomas are hereditary, including all familial and bilateral cases, and cases associ- ated with chromosome 13q deletions [1]. Because the treatment for bilateral retinoblastoma has improved in recent decades, patients with bilateral disease are having

greater numbers of children, and it has been predicted that the hereditary proportion of retinoblastomas should there- fore increase [49].

The involvement of chromosome 13 in retinoblastoma was reported in 1963 [50]. It is currently estimated that 13q deletions are present in 5% of cases [4]. The mapping of familial retinoblastoma to 13q markers and the observation of high rates of LOH of chromosome 13q in retinoblas- tomas led to the cloning of the Rb gene [51]. Retinoblas- toma is the classic model system for inherited childhood cancers. In 1971, Knudson quantified the two-hit model based on his observations of the frequencies and age distributions of unilateral and bilateral sporadic and famil- ial retinoblastomas [52]. The basic model states that retinoblastomas are due to the inactivation of both alleles of a single gene. Some individuals in the population carry an inherited mutant copy of the Rb gene. In these carriers, a second somatic Rb mutation in a retinal cell will lead to the inactivation of both alleles and to the creation a cell with malignant potential. Consistent with this hypothesis, cases of retinoblastoma may be familial (appearing as a dominant trait with incomplete penetrance) or may be sporadic. The model also predicts (assuming a Poisson distribution) that there should be two to three retinoblas- tomas per carrier, and that 5-10% of carriers should be unaffected. The mean age of diagnosis of bilateral cases is approximately 7 months, versus 20 months for unilateral cases [53].

In the case of non-inherited retinoblastoma both inacti- vating mutations would be somatic, occurring in a single cell or cell lineage. Molecular evidence supporting this hypothesis came from studies of loss of heterozygosity (LOH) of chromosome 13q markers in retinoblastomas [54]. For familial retinoblastomas the normal chromosome 13q allele is typically lost in the tumour cells. In bilateral sporadic cases of retinoblastoma which show LOH, the maternal allele is preferentially lost. This observation is believed to reflect the unequal mutation rates in the two sexes, and that the paternal chromosome is more suscepti- ble to mutation [55]. In keeping with this hypothesis, the paternal age of new cases of hereditary retinoblastoma is elevated [49].

Knudson recognized that the actual situation was likely to be more complex, commenting: 'prior to the appearance of cases in a branch of a family, penetrance is very low, after its occurrence, penetrance is very high', i.e. the penetrance is dependent on the clinical status of the carrier parent. For example, if the parent was unaffected, then 57% of the offspring had bilateral turnouts, if unilaterally affected, 77% of children were bilateral, and if the parents had bilateral tumours, 88% of the children had bilateral tumours [49]. This phenomenon of 'delayed mutation' or 'premutation' is not predicted by the two-hit model. A similar phenomenon (genetic anticipation) is observed in mytonic dystrophy and in several other dominant neuro- logic diseases, where it is due to instability in the inherited

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mutation [56]. The mechanism for anticipation in retinoblastoma is not known.

Knudson also assumed that the two mutations were independent of each other. This assumption was ques- tioned by others [57] who noted that data from a larger series of cases did not fit a Poisson distribution. It is now known from molecular studies that the two hits often are not independent [58]. A significant proportion of tumours involve somatic recombination (i.e., the second allele does not undergo mutation but is replaced with the mutant allele during mitosis and cell division).

There have been other modifications to the original model as well. Additional chromosomal events may be involved and the total number of required hits remains to be determined; for example, a large proportion of retinoblastomas (25-40%) show amplification of a region of chromosome 6p [59]. A further departure from the original model is transmission ratio distortion. The propor- tion of affected offspring was noted to be in excess of 50% by Munier et al. [60]. In eight retinoblastoma families 25 of 34 children of Rb mutation carriers were found to be carriers [60], and an excess of affected males was also found. This excess was restricted to the offspring of male carriers. In reviewing the literature on this subject, Nan- mova and Sapienza [61] note an excess of male cases of retinoblastoma with sporadic bilateral disease (the majority of these cases are thought to be due to new mutations of the Rb gene). In the families reviewed, more than 50% of the children of male carriers with bilateral sporadic disease were males, and of these, more than 50% were affected. Slightly fewer than 50% of girls of affected males were affected. Despite these observations, it should be noted that there is no male excess of retinoblastomas in the general population, even though sporadic bilateral cases represent about 30% of all cases.

3.2. W i l m s t u m o u r

Although familial Wilms' turnouts are rare (1-2% of the total) [62], there are compelling reasons to attribute a significant proportion of Wilms' tumours to genetic fac- tors, including ethnic variation in rates. Wilms' tumour is infrequent in Asians and is more frequent than expected in Africans [63] but the factors underlying these differences have not yet been identified. Wilms' tumour is also associ- ated with specific abnormalities of chromosome 1 lp and is a feature of several hereditary cancer syndromes.

The two-hit model of carcinogenesis was initially based on the inspection of incidence data for retinoblastoma and was later applied to Wilms' tumour [64]. Under this model, it was expected that all bilateral cancers, and a significant proportion of unilateral cancers, would be inherited. Based on the assumption that bilateral tumours were hereditary, Knudson and Strong estimated that 38% of all Wilms' tumours would be hereditary, including a significant pro- portion of unilateral, non-familial cases. If this were true, then children of unilateral cases would be at significantly

elevated risk for the same type of cancer. However, fol- low-up studies of offspring of cases of Wilms' tumour have not supported this hypothesis. In two studies, none of 224 children of cases of Wilms' tumour were affected [65,66]. A more likely hypothesis is that bilateral tumours are due to genetic mosaicism resulting from a mutation or somatic recombination arising early in embryogenesis [42]. In support of this, Chao et al. [67] have shown that partial LOH can be found in the normal kidneys and in the blood lymphocytes of some children with Wilms tumours. The associated tumour tissue in these four cases showed com- plete LOH, implying that the tumours arose in predisposed tissues, possibly from additional mutations.

Several genes are known to be associated with an increased susceptibility to Wilms' tumour, including WT1, the genes for the Beckwith-Weidemann syndrome (BWS)[68], the Simpson-Golabi-Bemel (SGB) syndrome [69] and Bloom syndrome [70]. Wilms tumours have also been reported in families with neurofibromatosis [71] with the breast-ovarian cancer syndrome [72] and with the hyperparathyroidism jaw tumour syndrome [73]. Hartley et al. [74] reported a family history of the Li-Fraumeni syndrome in two children with WT; an additional four children had histories suggestive of the syndrome. Families with multiple cases of Wilms tumours are rare. In these families incomplete penetrance is the rule, and the proba- bility of expression appears to increase with succeeding generations (anticipation). The gene for hereditary Wilms' tumour has not been found, although cancer susceptibility in one large French-Canadian family maps to chromosome 17q [40]. It will be of particular interest to see if this gene will be mutated in a large proportion of sporadic Wilms' tumours.

The region of chromosome 1 lp13 was implicated in Wilms' tumour because 1-5% of cases of WT have a cytogenetically detectable abnormality at this locus [75]. Depending on the size of the deletion, multiple genes will be involved and multiple organs affected, including the eye (aniridia) and the genitourinary and the cardiovascular systems. Children with chromosome 1 lp l3 deletions com- monly experience growth and developmental delays (WAGR syndrome) [76]. Genitourinary and cardiovascular malformations are also more common than expected in children with Wilms' tumors without obvious deletions [21,77,78].

By defining the critical region of deletion in sporadic and familial Wilms tumours, the WT1 gene was identified [78]. WT1 codes for a transcription factor with four zinc finger domains that is critical to urogenital development [79]. Surprisingly, somatic and constitutional point muta- tions of WT1 are infrequent events in Wilms' tumour ( < 10% of cases) [80]. Children with WAGR or the Denys-Drash syndrome are exceptions. Patients with the Denys-Drash syndrome (genitourinary abnormalities, pseudohermaphroditism and developmental delay) fre- quently have a mutation in a zinc finger of WT1 - - in 19

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of 36 cases the mutation involved the same amino acid [81]. Familial Wilms' tumours are not attributable to WTI mutations [40,82-84] with the notable exception of a father and son with Wilms' tumour, cryptorchidism and hypospadias [85].

Approximately one-third of Wilms' tumours show LOH for chromosome l i p markers, often including the WT1 region at l lp13, but more frequently involving l lp15 (Ref. [86]). In about one-third of tumours showing LOH, the LOH is restricted to l lp15. LOH may be due to chromosome loss, to deletion, to nondisjunction or to somatic recombination. Nondisjunction with reduplication or somatic recombination may lead to the presence of two normal copies of a single parental allele (i.e. mosaic uniparental disomy). In almost all cases, the matemally derived alleles are lost [87]. The majority of new deletions in the WAGR syndrome originate on the paternal copy of chromosome 11 (Ref. [88]). The observation of preferential paternal WT1 mutation and maternal WT1 allele loss in tumours is consistent with the classical tumour suppressor model, whereby a mutant paternal allele is inherited and is later 'unmasked' by the loss of the maternal counterpart. This is the case for retinoblastoma. However, if this were also true for Wilms' tumour, we would expect LOH to be more frequent among cases with a clear genetic predisposi- tion (e.g. familial cases) than among sporadic unilateral cases - - this has not been shown. Furthermore, the LOH may precede the other mutations. Chao et al. found [67] four cases of bilateral LOH in patients with unilateral Wilms tumour, due to somatic recombination. In each case the maternal allele was lost. Their finding implies that the presence of two presumably normal (paternal) copies of chromosome 1 lp region may predispose to Wilms' tumour by creating a selective growth advantage. Because the frequency of l i p LOH is much greater (40%) than the frequency of WT1 mutations ( < 10%) [80] it is unlikely that WT1 acts as a classic tumour suppressor gene. It is possible that the maternal WT1 allele is pre-eminent in suppressing tumour growth - - however, both WT1 alleles are expressed [89] and in some tumours both WTl alleles are lost by different mechanisms [90].

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome which is characterized by abdominal wall defects, macroglossia and gigantism. The syndrome is usually sporadic, but a small proportion of cases are familial [91]. Because obligate carriers in BWS families may be only mildly affected (e.g., childhood macroglossia, umbilical hernias) or may be unaffected, the penetrance of the condition has not been established. Beckwith-Weide- mann syndrome is more common in identical twins, but, surprisingly, these cases are usually discordant [92]. Ab- normalities of chromosome 1 lp15.5 are seen in a minority of cases, and include paternally-derived duplications, translocations, and uniparental patemal disomy [19,93]. A gene for familial BWS has been mapped by linkage analy- sis to the same region [38].

An excess of embryonal tumours is seen in children with BWS, but the reported frequencies of cancer varies widely. Only two cancers were reported in a series of 76 BWS cases (2.6%) in the UK [94]. Wiedemann reported cancer in 7.5% of 388 BWS cases [95], and recently, Weksberg et al. observed 7 cancers in a historical cohort of 57 children with BWS (unpublished data). The cumulative incidence to age 15 for any cancer was estimated to be 27%. The excess risk in this cohort was restricted to Wilms' tumour (5 cases) and rhabdomyosarcoma (2 cases). Adrenocortical cancers, hepatoblastomas [94] and neurob- tastomas [96] have also been reported. It has been sug- gested that the risk of embryonal tumours may be particu- larly high in BWS children with hemihypertropy [95] or with uniparental disomy [19].

The most compelling candidate gene for BWS is in- sulin-like growth factor 2 (IGF2), which maps to within the region of uniparental disomy and duplication on chro- mosome 1 lp15.5. (Ref. [97]). The maternally derived copy of this gene is normally suppressed through imprinting [98]. Loss of imprinting of IGF2 has been seen somatically in Wilms tumour [99] and constitutionally in BWS [100]. The phenomenon has also been seen in children with Wilms tumour and overgrowth, but without the more obvious signs of BWS [20]. It has been suggested that mosaic uniparental disomy may explain the hemihypertro- phy, but bialleleic expression of IGF2 has been observed on both the normal and hypertrophic sides. Currently, the simplest model is that constitutional overexpression of IGF2, either through duplication, uniparental disomy, or loss of imprinting, predisposes to BWS. Point mutations in the coding region of IGF2 have not been seen in sporadic or in familial BWS, suggesting that overexpression is not due to activating mutations within gene. The WT1 gene may suppress IGF2 expression [101,102].

The X-linked Simpson-Golabi-Behmel syndrome (SGB) shares several features with BWS, including pre- and postnatal overgrowth, and an increased cancer risk, in particular for Wilms tumour [69]. SGB is caused by muta- tions in the glypican 3 gene [103]. This gene is believed to moderate IGF2 activity and thereby regulate the growth of embryonic mesodermal tissues.

3.3. The Li -Fraumeni syndrome

The Li-Fraumeni syndrome (LFS) is the familial asso- ciation of childhood cancer with early-onset breast cancer, brain tumours and leukemia. The characteristic childhood tumours include bone and soft tissue sarcomas and adreno- cortical cancer. LFS is inherited as a dominant trait. Most of the excess risk is for cancers occurring below the age of 50 (Ref. [104]). In its classic form, LFS is defined by a proband with childhood sarcoma and two first-degree rela- tives with cancer below age 45.

Mutations of the p53 tumour suppressor gene are found somatically in a wide range of human cancers [105].

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Germline mutations in the coding region of p53 have been found in approximately one-half of LFS families [39,106,107] but there are several reports of 'classical' LFS families with no mutation in the gene [107]. Similarly, p53 mutations may be present in other families that do not meet these criteria. Frebourg et al. [107] identified p53 mutations in 8 of 15 families that met the classical LFS criteria and Birch et al. [108] found p53 mutations in 6 of 12 classical LFS families. In the latter study, five families had young children with rhabdomyosarcomas and three had adrenocortical cancers. Codon 248 appeared to be a frequent site of mutation in both studies. Families with a similar cancer spectrum, but with fewer total cases, have been called Li-Fraumeni-like families. Birch et al. found p53 mutations in only one of nine families of this type. It is not yet clear if LFS families without identified p53 mutations are due to p53 mutations outside of the coding region or are due to other susceptibility genes. It is possi- ble that mutations in other genes which help regulate the cell cycle may be mutated in these families, or that muta- tions in other genes may lead to functional inactivation of the p53 protein.

Several studies have tried to estimate the burden of childhood cancers attributable to inherited p53 mutations. It is expected that the cancer sites for which the relative risk in LFS are the highest, will be the sites with the highest frequency of p53 mutations. Adrenocortical cancer is a rare childhood cancer (3 per million), but the risk is magnified approximately 100-fold in families with LFS. The majority of LFS families with adrenocortical cancer carry mutations in p53 [109] and p53 mutations have been found in approx. 50% of unselected children with adreno- cortical cancer [31]. Adrenocortical cancer and retinoblas- toma are probably the two sites of childhood cancer associ- ated with the highest hereditary fractions.

Germline mutations of p53 have also been found in seven of 235 children, and in two of 13 children with osteosarcoma [110,111]. A mutation was found in one of 25 children with ALL [112]. Because multiple primary cancer is a signal for genetic susceptibility, it was pre- dicted that a significant proportion of patients with more than one cancer would carry p53 mutations. Mutations were found in four of 59 patients with multiple primary cancers [32], in one of four with multifocal osteosarcoma [113] and in nine of 51 glioma patients with either a second primary tumour, with a family history of cancer or with multifocal disease [113].

Soft tissue sarcomas make up about 5% of childhood cancers. After adrenocortical cancer, rhabdomyosarcoma is the site most characteristic of LFS. Diller et al, found p53 mutations in three of 33 children with rhabdomysarcoma [114]. Mutations were associated with sarcomas of very early onset, in keeping with other studies that report that the risk of breast cancer is elevated in mothers, when a child is diagnosed with rhabdomyosarcoma below the age of three [2].

Soft tissue sarcomas are also seen in excess in children with neurofibromatosis, the Beckwith-Weidemann syn- drome and tuberous sclerosis [1,115]. An increased fre- quencies of stillbirths in the mothers of children with soft tissue sarcoma has also been reported [115,116].

In summary, the LFS is a genetically heterogeneous disease with a very wide range of tumour sites. A clear clinical definition of the syndrome is not yet possible. One of the responsible genes is p53, and families with cases of adrencortical cancer or early onset rhabdomyosarcoma are those most likely to harbour p53 mutations.

3.4. N e u r o f i b r o m a t o s i s a n d tuberous sc leros i s

Children with neurofibromatosis type 1 (von Reckling- hausen disease) are at 16-fold risk of developing cancer before age 15 [1]. The majority of the excess is accounted for by central and peripheral nervous system tumours (RR = 47) acute leukemias (RR = 3.8) and by soft tissues sarcomas (RR = 54) [1]. Rhabdomyosarcoma of the uro- genital system is characteristic of NF1 [117]. Also, 70% of leukemias in NF1 are non-lymphocytic, as compared to only 20% in the general pediatric population. A high proportion of children with Triton tumour (malignant schwannoma with rhabdomyosarcoma component) have NF1 mutations [118].

The NF1 gene on chromosome 17q has several proper- ties of a tumour suppressor gene. However attempts to identify somatic NF1 mutations in sporadic cancers of the type associated with NFI have been mostly unsuccessful. Following the initial report of Li et al. [119], where NFI mutations were found in patients with myelodysplastic syndrome without NF1, there have been few examples of somatic mutation reported.

There is suggestive evidence that particular NFI fami- lies show clustering of specific tumour types [120]. To date no particular NF1 mutations have been identified which are associated with a greater tendency to malignancy.

Tuberous sclerosis is estimated to affect one in 15 000 children in the UK and to be responsible for one in 800 cancers in that country [121]. Children with tuberous scle- rosis are at 70-fold increased risk of brain and spinal neoplasms and 50-fold risk of rhabdomyosarcoma [1]. There are two loci for tuberous sclerosis, on chromosomes 9q and 16p [122,123] but it has not been established if the Cancer risks differ in the two syndromes. The chromosome 16p gene for tuberous sclerosis (TSC2) has now been cloned [124]. The function of this protein (tuberin) is uncertain, although it appears to act as a tumour suppressor gene.

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