Genetics of Beckwith-Wiedemann Syndrome-Associated Tumors: Common Genetic Pathways
Marja Steenman, 1,2 Andries Westerveld,’ and Marcel Mannens2*
“Department of Human Genetics, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
2Department of Clinical Genetics, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
A specific subset of solid childhood tumors-Wilms’ tumor, adrenocortical carcinoma, rhabdomyosarcoma, and hepatoblas- toma-is characterized by its association with Beckwith-Wiedemann syndrome. Genetic abnormalities found in these tumors affect the same chromosome region (11p15), which has been implicated in the etiology of Beckwith-Wiedemann syndrome. This suggests that the development of these tumors occurs along a common genetic pathway involving chromosome 11. To search for additional common genetic pathways, this article reviews the genetic data published for these tumors. It was found that, up until now, the only genetic abnormalities detected in all four tumors affect chromosome band 11p15 and the TP53 gene. In addition, there are several aberrations that occur in two or three of the neoplasms. It is concluded that, of the four tumors, the genetic relationship is most evident between Wilms’ tumor and rhabdomyosarcoma. Genes Chromosomes Cancer 28:1-13, 2000. @ 2000 Wiley-Liss, Inc.
BECKWITH-WIEDEMANN SYNDROME
The Beckwith-Wiedemann syndrome (BWS) is a disorder first described by Beckwith (1963), who presented the phenotype at the 11th annual meet- ing of the Western Society for Pediatric Research. Later, the syndrome was described in more detail in the literature by Wiedemann et al. (1964) and Beckwith (1969). It is characterized by several fea- tures, among which are abdominal wall defects, macroglossia, pre- and postnatal gigantism, earlobe pits or creases, facial nevus flammeus, hypoglyce- mia, renal abnormalities, and hemihypertrophy (Pettenati et al., 1986; Elliott et al., 1994). The syndrome occurs with an estimated incidence of 1:13,700 (Thorburn et al., 1970). BWS patients have a risk of 7.5% for the development of (mostly intra-abdominal) childhood tumors (Wiedemann, 1983). Tumors most frequently found are Wilms’ tumor (WT), adrenocortical carcinoma (ACC), rhabdomyosarcoma (RMS), and hepatoblastoma (HB). The fact that this specific subset of tumors is found with an increased frequency in BWS patients suggests that the etiology of these tumors follows a common genetic pathway, involving factors that play a role in the development of BWS. Further- more, there are indications that additional common genetic pathways exist, encompassing chromosome regions not affected in BWS patients. Clues for the existence of several common genetic pathways in the etiology of BWS-associated tumors are re- viewed in this article.
Genetics of Beckwith-Wiedemann Syndrome
Although most cases are sporadic (85%) (Pette- nati et al., 1986), families in which more than one sibling is affected have been noted. Linkage anal- ysis has shown that the disease cosegregates with chromosome band 11p15 (Koufos et al., 1989; Ping et al., 1989). Additional data, which indicate that this chromosome region may play a causative role in BWS, came from studies of chromosome abnor- malities involving the short arm of chromosome 11. Balanced translocations have been found in cells of nine BWS patients (Mannens et al., 1994; News- ham et al., 1995). The translocation breakpoints on chromosome 11 map to three distinct regions within 11p15.3-pter (Hoovers et al., 1995): Beck- with-Wiedemann syndrome chromosome region 1 (BWSCR1) near INS|IGF2, BWSCR2 5 Mb proxi- mal to BWSCR1, and BWSCR3 2 Mb more prox- imal (Fig. 1).
BWSCR1 consists of five translocation break- points. All of these breakpoints disrupt the KCNQ1 gene (Lee et al., 1997b). This gene encodes a voltage-gated potassium channel (Wang et al.,
Supported by: Dutch Cancer Society (KWF); Grant number: UVA 94-470; Stichting Kindergeneeskundig Kankeronderzoek; Grant number: SKK 98.07.
*Correspondence to: Marcel Mannens, Department of Clinical Genetics, University of Amsterdam, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
E-mail: m.a.mannens@amc.uva.nl
LOH
TSR
11pter
H19
IGF2
HASH2
BWSCRI
KVLQTI
CDKNIC
WT
5 Mb
DIIS12
RMS
BWSCR2
ZNF215
ZNF214
2 Mb
11
BWSCR3
11p15.3
1996), which plays a role in cardiac arrhythmias such as long-QT-1 (LQT1) or the Romano-Ward syndrome (Yang et al., 1997) and the Jervell- Lange-Nielsen syndrome (Neyroud et al., 1997). It is not known whether BWS patients are affected by cardiac arrhythmias, and therefore it is not clear how the KCNQ1 gene can be involved in the dis- ease. A second interesting gene in the BWSCR1 region is CDKN1C (or p57KIP2), proximal to KCNQ1. It is an inhibitor of cyclin-dependent kinases and is located at 11p15.5 (Matsuoka et al., 1995). Het- erozygous mutations have been identified in about 20% of BWS patients in two studies (Hatada et al., 1996a, 1996b; O’Keefe et al., 1997). Others, how- ever, have not been able to confirm this mutation frequency (Lee et al., 1997a, 1997b; Okamoto et al., 1998; J. Bliek, personal communication). Taken together, these studies show that CDKN1C muta- tion is not a major cause of BWS. A study of mice lacking expression of CDKN1C did reveal some of the BWS phenotypic features, such as the presence
of omphalocele and renal and adrenal cortex anom- alies (Zhang et al., 1997). These mice were lacking some of the other features found in the BWS pa- tients with CDKN1C mutations like macroglossia and gigantism. The authors suggested that this might be related to the fact that the imprinting of CDKN1C differs between mice and men. The hu- man CDKN1C gene shows 5% residual expression from the paternal allele, whereas in the mouse the imprinting is complete (Matsuoka et al., 1996). A gene located just distal to KCNQ1 is HASH2. This gene is expressed only in the extravillus tropho- blasts (Alders et al., 1997). The mouse homologue (Mash2) codes for a transcription factor, which is expressed during early mouse development and is essential for the development of the placenta (Guillemot et al., 1994). There have been no re- ports of an involvement of HASH2 in the etiology of BWS. A strong candidate for involvement in the etiology of BWS is the insulin-like growth factor 2 gene (IGF2), also located in the BWSCR1 region. Using mouse models, it was shown that the birth weight is dependent on the level of expression of Igf2 (DeChiara et al., 1990; Leighton et al., 1995a). Because overgrowth or gigantism is one of the main features seen in BWS patients, IGF2 is very likely to be involved. Another study showed that mutant mice overexpressing Igf2 displayed a phenotype overlapping with the BWS phenotype (Eggen- schwiler et al., 1997). An argument that this gene is not always involved comes from a study showing that a familial form of BWS was not linked to IGF2 (Nystrom et al., 1994). Downstream from IGF2 lies the H19 gene. This gene does not code for a pro- tein and may function through its RNA (Brannan et al., 1990). The expression of IGF2 and H19 appears to be linked, and the relevance of H19 to the BWS phenotype will be discussed in the next section.
The second BWS chromosome region (BWSCR2) is defined by two patients with translocation break- points in chromosome band 11p15.4. These pa- tients have only a minor BWS phenotype, both with hemihypertrophy. One of these patients de- veloped a Wilms’ tumor. Two genes were identi- fied in this region: ZNF214 and ZNF215 (Mannens et al., 1996; M. Alders, personal communication). Mutation analysis of these genes in BWS patients identified a putative mutation in the ZNF214 gene, found in a considerably higher proportion of the patients vs. the normal population (6/44 vs. 2/205). Analysis of the ZNF215 gene resulted in the iden- tification of a putative mutation in one BWS pa- tient (and the unaffected mother of the patient). This mutation was not found in the control popu-
lation. In addition, two of the five alternatively spliced transcripts of ZNF215 are disrupted by the two translocations defining BWSCR2 (M. Alders, personal communication). Finally, the third region BWSCR3 is characterized by one translocation breakpoint. So far no candidate genes have been identified.
Besides chromosomal translocation, there is an- other cytogenetic abnormality associated with BWS. Some patients were shown to have a dupli- cation of chromosome arm 11p (Slavotinek et al., 1997). However, most patients appear to be cyto- genetically normal. On the molecular level, there is a genetic aberration that is found in a substantial portion of the patients: paternal uniparental disomy (UPD) of 11p markers (Henry et al., 1991, 1993; Slatter et al., 1994; Steenman et al., 1994). This is found in around 16%-28% of the cases.
Epigenetics of Beckwith-Wiedemann Syndrome
The pattern of inheritance of the Beckwith- Wiedemann syndrome reveals clear parent-of-ori- gin effects. First, maternal transmission has been observed in pedigrees. In addition, in cases in which balanced translocations have been found (in- volving chromosome arm 11p), the der(11) was always of maternal origin (Mannens et al., 1994). Furthermore, as mentioned above, paternal UPD is found in a substantial portion of the patients. Like- wise, the duplications of 11p material are always of paternal origin (Slavotinek et al., 1997). These data all indicate a role for genomic imprinting in the etiology of BWS.
The discovery of imprinted genes on 11p15.5 in the BWSCR1 region further substantiated the hy- pothesis that BWS may be caused by imprinting errors. The first gene in this region found to be imprinted was IGF2 (Giannoukakis et al., 1993). The fact that this gene encodes a growth factor and is maternally imprinted makes it a good candidate for the BWS gene. In the paternal UPD and dupli- cation cases, a double dose of IGF2 may be present, explaining the overgrowth features and the devel- opment of tumors. In the (maternal) translocation cases and the cases in which no genetic abnormal- ity has been found, there may be an error in the imprinting of the maternal IGF2 allele, resulting in two active copies of the gene. This is underlined by the biallelic expression of IGF2 found in the majority of BWS patients without paternal UPD (Weksberg et al., 1993). Another imprinted gene just distal to IGF2 is H19. In contrast to IGF2, H19 is only expressed from the maternal allele (Rach- milewitz et al., 1992; Zhang et al., 1992; Rainier et
al., 1993). H19 is important for the maintenance of the imprinting status of IGF2. Deletion of the ma- ternal murine H19 gene and 10 kb of upstream sequence resulted in relaxation of Igf2 imprinting (Leighton et al., 1995a). Mice inheriting this dele- tion from their mother had a 27% increased body weight compared to those inheriting it from their father. In addition, deletion of enhancers that are located 3’ of H19 and are used by both Igf2 and H19 resulted in loss of Igf2 expression when inher- ited paternally (Leighton et al., 1995b). This loss of expression of Igf2 was reflected in the size of the animals; they were 80% of normal size. Hyper- methylation of the H19 promoter region has been observed in non-UPD BWS patients (Catchpoole et al., 1997) and has been shown to correlate with expression of the maternal IGF2 allele in BWS (Reik et al., 1995). This phenomenon has also been observed in three patients with somatic overgrowth without diagnostic features of BWS (Morison et al., 1996). Two of these patients developed a Wilms’ tumor. Two additional paternally imprinted genes in the region are CDKN1C (Chung et al., 1996; Hatada et al., 1996a, 1996b) and HASH2 (Alders et al., 1997). So far, there have been no reports on the detection of epigenetic aberrations of these genes in BWS patients. Paternal imprinting of the HASH2 gene might be the reason for the fact that paternal UPD of chromosome 11 is found as a mosaicism (Henry et al., 1993; Alders et al., 1997), since it has been shown in mice that deficiency of the mouse homologue Mash2 leads to nonviable mice (Guillemot et al., 1994). Other paternally im- printed genes on human chromosome 11 are IPL (Qian et al., 1997) and KCNQ1 (Lee et al., 1997a, 1997b; Gould et al., 1998).
Both genes identified in the BWSCR2 region, ZNF214 and ZNF215, are paternally imprinted (M. Alders, personal communication). Thus far there have been no reports on aberrant imprinting of these genes in association with BWS.
WILMS’ TUMOR
Genetics of Wilms’ Tumors
The tumor most often found to be associated with BWS is Wilms’ tumor or nephroblastoma (59% of the tumors found in BWS patients) (Wiede- mann, 1983). Overall, it occurs with a frequency of 1 in 10,000 children, mostly in children under the age of 5 years (Breslow, 1997). In patients suffering from BWS, the incidence is 800-1,000 X increased (McBride, 1997).
The genetics of Wilms’ tumors have been exten- sively studied. A high percentage (38%) (Steenman et al., 1997) shows loss of heterozygosity (LOH) at chromosome arm 11p. This region can be subdi- vided roughly into two parts: LOH of markers on 11p13 (van Heyningen et al., 1985) and on 11p15 (Mannens et al., 1988, 1990; Reeve et al., 1989). The region on 11p13 has been shown to be deleted in patients affected by the WAGR syndrome (Ric- cardi et al., 1978). WAGR stands for the combined occurrence of sporadic aniridia, WT, genitourinary abnormalities, and mental retardation. A gene in the candidate region (WT1) has been cloned (Call et al., 1990; Gessler et al., 1990). Mutations of this gene occur in only 10%-15% of sporadic Wilms’ tumors (Brown et al., 1993; Radice et al., 1993; Waber et al., 1993; Gessler et al., 1994; Varanasi et al., 1994), suggesting the existence of additional genes involved in Wilms’ tumorigenesis. The De- nys-Drash syndrome, another syndrome associated with Wilms’ tumor (Denys et al., 1967; Drash et al., 1970), shows constitutional mutations of the WT1 gene (Mueller, 1994). The region on 11p15 show- ing LOH in WTs can be subdivided into two re- gions: An 800-kb region containing the WT2 locus and an additional locus of 336 kb, proximal to WT2 (Karnik et al., 1998). WT can also be found in association with other syndromes, such as the tri- somy 18 syndrome (Geiser et al., 1969; Karayalcin et al., 1981; Faucette et al., 1991), the Perlman syndrome, and the Simpson-Golabi-Behmel syn- drome (Weksberg et al., 1996), the Sotos syndrome (Cohen, 1989), and the Klippel-Trenaunay syn- drome. The Li-Fraumeni syndrome is a rare famil- ial tumor syndrome (Li et al., 1969b). Patients suffering from this disease have been shown to contain germline mutations in the TP53 tumor sup- pressor gene (Malkin et al., 1990; Srivastava et al., 1990). The tumors that develop in these patients show a deletion of the wild-type TP53 allele (Holl- stein et al., 1991). Although WT is not considered to be part of the Li-Fraumeni syndrome (Moutou et al., 1994), there have been few reports of the occurrence of WT in families affected by this dis- ease (Hartley et al., 1993). Mutations in TP53 have been found in sporadic WTs and seem to be asso- ciated with a histological subtype. In a series of 140 WTs, mutations were restricted to tumors of the anaplastic subtype, showing aberrations in 8/11 samples (Bardeesy et al., 1994). This subtype is linked to a poor prognosis.
In 10% to 25% of WT, LOH of 16q markers is found (Coppes et al., 1992; Maw et al., 1992; Grundy et al., 1994; Austruy et al., 1995; Steenman
et al., 1997). It has been suggested that LOH at 16q is associated with an adverse prognosis (Grundy et al., 1994, 1998a). This does not seem to be the case for the presence of the der(16)t(1; 16)(q21;q13) (Grundy et al., 1998a). Another ge- netic abnormality that seems to confer an adverse outcome is LOH at 1p (Grundy et al., 1994; Steen- man et al., 1997). This abnormality was found in 12% and 18% of the cases, respectively. Chromo- some 7 also seems to be involved in WT. According to the literature, chromosome 7 is rearranged in 23% of the cases (Austruy et al., 1995). Several reports have noted the presence of an isochromo- some 7q as the sole genetic abnormality (Wang- Wuu et al., 1990; Sawyer et al., 1993; Wilmore et al., 1994; Peier et al., 1995; Sandoval et al., 1998). There have also been descriptions of WT patients with constitutional balanced translocations involv- ing chromosome arm 7p (Bernard et al., 1984; Rivera et al., 1985; Hewitt et al., 1991; Reynolds et al., 1996). In these cases, the normal chromosome 7 is often lost in the tumor by formation of an isoch- romosome 7q. LOH studies revealed a region on the proximal part of the short arm of chromosome 7 that is lost in around 10% of the tumors (Miozzo et al., 1996; Grundy et al., 1998b). Another region found to be frequently involved in LOH (14%) is 22q (Klamt et al., 1998). In a study that quantified chromosome 12 allelic imbalance in a series of 28 WTs, duplications were detected in 18% (Austruy et al., 1995).
An inventory of all quantitative chromosome ab- errations occurring in a series of 46 WTs was made using comparative genomic hybridization analysis (CGH) (Steenman et al., 1997). Chromosome re- gions showing loss of DNA in three or more sam- ples included 1p (11%), 11p (9%), 16q (13%), and 17p (7%). Regions showing gain of DNA in three or more samples included 1q (20%), 7q (9%), 8 (7%), 12q (17%), 17q (7%), and 18 (7%).
Epigenetics of Wilms’ Tumors
Because BWS seems to be an imprinting disor- der, it is expected that abnormal imprinting is in- volved in the development of the associated tu- mors. Indeed, there are clues pointing in that direction from molecular studies looking at LOH at chromosome 11 in Wilms’ tumors. It was noted that the alleles that were retained in the tumors were always of paternal origin (Reeve et al., 1984; Schroe- der et al., 1987; Mannens et al., 1988; Williams et al., 1989). This resulted in the hypothesis that a paternally imprinted tumor suppressor gene is in- volved in Wilms’ tumorigenesis. Alternatively, a
maternally imprinted gene involved in stimulation of cell growth could be involved in the cases show- ing paternal UPD of (part of) chromosome 11. At present, there are three candidate genes on 11p15 that show parent-of-origin-dependent monoallelic expression and belong to one of these two catego- ries: the tumor suppressor genes H19 and CDKN1C, which are maternally expressed (Rachmilewitz et al., 1992; Zhang et al., 1992; Rainier et al., 1993; Hatada et al., 1996a), and the paternally expressed growth-promoting gene IGF2 (Giannoukakis et al., 1993; Ogawa et al., 1993; Rainier et al., 1993). In two independent studies, it was shown that in around 70% of Wilms’ tumors that retain heterozy- gosity of markers on 11p15, the IGF2 gene is no longer imprinted (Ogawa et al., 1993; Rainier et al., 1993). Instead, the gene is expressed from both alleles. In 29% of the tumors without LOH of 11p15, the H19 gene was found to be biallelically expressed and one tumor was shown to have lost the imprint of both genes (Rainier et al., 1993). Interestingly, when looking at the expression lev- els of both genes, it became evident that the loss of imprinting (LOI) of IGF2 was associated with an abrogation of H19 expression (Moulton et al., 1994; Steenman et al., 1994). This finding correlates well with the supposed tumor-suppressive function of H19. Because the majority of BWS patients show constitutive relaxation of IGF2 imprinting (Weks- berg et al., 1993; Joyce et al., 1997) but not all of them develop tumors, relaxation of imprinting by itself cannot be sufficient to initiate tumorigenesis. Furthermore, hypermethylation of the H19 pro- moter region, which was found to be associated with LOI of IGF2 (Moulton et al., 1994; Steenman et al., 1994), was also found in the normal kidney tissue of two WT patients (Moulton et al., 1994). The second paternally imprinted tumor suppressor gene-CDKN1C-also shows reduced expression in WTs (Chung et al., 1996; Hatada et al., 1996a, 1996b). This occurred in concert with inactivation of H19 in 8/8 tumors with LOH at 11p15.5 and in 5/7 tumors with retention of heterozygosity but hypermethylation of H19 (Chung et al., 1996).
ADRENOCORTICAL CARCINOMA
Genetics of Adrenocortical Carcinomas
The second most common tumor found in BWS patients is adrenocortical carcinoma (ACC). It is found in 15% of patients that develop a tumor (Wiedemann, 1983). In the general population, ACC is an extremely rare tumor with an incidence of 1.7 new cases per 1,000,000 per year (Lipsett et
al., 1963). ACC occurs in both adults and children. However, a considerable number of the publica- tions about ACC do not reveal the age of the patients they describe. Therefore, in this section, we will not make a distinction between the genetic data available for ACC in either age group.
As in BWS, IGF2 seems to be involved in spo- radic ACC tumorigenesis. A considerable propor- tion of the malignant tumors (around 60%) display LOH at the 11p15.5 region (Yano et al., 1989; Gicquel et al., 1994), presumably all representing uniparental disomies (Gicquel et al., 1994). This is seen in both adult and childhood ACCs. In these cases, a good correlation was found with overex- pression of the IGF2 gene. These phenomena were found in a much smaller percentage in the benign adenomas. It has been hypothesized that adreno- cortical tumorigenesis is a multistep process with sequential progression from the normal to the ad- enomatous and then to the malignant cell (Gicquel et al., 1995). If this is the case, then IGF2 could be involved in the transition from adenoma to carci- noma (Reincke, 1998).
ACC is also found in association with other syn- dromes (Reincke, 1998). One of these is the Li- Fraumeni syndrome. In a study by Yano et al. (1989), in which sporadic ACCs were analyzed for the presence of LOH at three different chromo- some regions, indeed chromosome arm 17p (con- taining the TP53 gene) had become homozygous in all informative samples. LOH at 17p was not found in adrenocortical adenoma, the benign counterpart of ACC. Again, if the hypothesis is correct that adrenocortical tumors develop from normal tissue to adenomas to carcinomas, this would mean that LOH at 17p could be a late event in ACC tumor- igenesis. Two other groups identified mutations in the TP53 gene in around 30% of sporadic ACCs (Ohgaki et al., 1993; Reincke et al., 1994). In ad- dition, CGH analysis showed loss of 17p in 50% of the (sporadic) cases (Kjellman et al., 1996). Another hereditary tumor syndrome associated with adreno- cortical tumors is multiple endocrine neoplasia type 1 (MEN1) (Pang et al., 1994). In most cases associated with MEN1, adrenocortical adenomas are found. The disease is caused by mutation of the menin tumor suppressor gene (MEN1), located at 11q13 (Chandrasekharrapa et al., 1997). CGH anal- ysis of sporadic ACC indeed showed loss of 11q in 50% of the cases (Kjellman et al., 1996).
Other regions found to be lost in ACCs include chromosome arm 13q, which was shown to have lost heterozygosity in 50% of informative patients (Yano et al., 1989), and chromosome 2, as detected
by CGH in 50% of the patients (Kjellman et al., 1996). The CGH study showed gains of chromo- some arms 4q, 5p, and 5q in 50% of the ACCs. Genetic aberrations that were found in 38% of the tumors in this study were gains of 12, 15q, 16q, and 19p, and losses of 3p, 6q, 8p, 9p, 11p, 17q, 18q, and 22q. In both the LOH and the CGH studies, the (small) benign adenomas did not show the genetic changes detected in the carcinomas. Taken to- gether, these data clearly demonstrate that there are numerous differences between the genetic ab- errations found in adrenocortical adenomas and ad- renocortical carcinomas. These differences may re- flect various stages along the carcinogenic pathway.
Epigenetics of Adrenocortical Carcinomas
Up until now, there have been few studies de- termining the parental origin of the alleles, which are affected in the ACCs showing LOH at 11p15. One report describes five ACCs with UPD of 11p15 (Gicquel et al., 1994). Of these five cases, the researchers were able to identify the parental origin of the UPD as being paternal in one case. In another report, the allele-specific methylation of IGF2 was analyzed in ACCs exhibiting LOH at 11p15 (Gicquel et al., 1997). This showed that the lost allele was of maternal origin in 14/15 cases. The imprinting status of IGF2 was also investi- gated. It was found that LOI of IGF2 is associated with the malignant phenotype, since it was not detected in the adenomas but only in the carcino- mas. Similar to the situation in WT, the expression of H19 was decreased in ACCs that were affected by LOH and/or LOI of IGF2.
RHABDOMYOSARCOMA
Genetics of Rhabdomyosarcomas
Although rare, rhabdomyosarcoma (RMS) repre- sents the most common soft-tissue sarcoma in chil- dren under the age of 15 years (Raney et al., 1993). It occurs with a frequency of 1.3-4.5 cases per million children per year (Enzinger et al., 1983). Based on their histology, rhabdomyosarcomas can be subdivided into three major subtypes (Horn et al., 1958): embryonal (E-RMS), alveolar (A-RMS), and pleomorphic (P-RMS) rhabdomyosarcoma, of which E-RMS is the subtype associated with BWS. Of all newly diagnosed cases, 60% are E-RMS and 20% are A-RMS (Newton et al., 1988). Patients with E-RMS have a better prognosis than patients with A-RMS.
LOH at 11p is an abnormality frequently found in RMS (Koufos et al., 1985; Visser et al., 1997). In
one study, it was found in 72% of primary E-RMS and 20% of primary A-RMS (Visser et al., 1997). A gene located in this region, GOK (gene on chromo- some 11) or STIM1 (stromal interaction molecule 1), was postulated to be a candidate tumor suppres- sor gene in RMS (Sabbioni et al., 1997). No expres- sion was found in seven RMS cell lines, and trans- fection of the gene into the RMS cell line RD was followed by growth arrest of the cells. LOH at 16q was also found in both types (in 55% of E-RMS and 40% of A-RMS) (Visser et al., 1997). In total, LOH at 6p was found in 28% and LOH of 18p in 32% of the cases.
Studies of A-RMS have shown that they often (around 90%) contain a specific translocation. In most of these cases (68%) (Sreekantaiah et al., 1994), a t(2;13)(q35;q14) is found (Douglass et al., 1987). In a smaller subset of A-RMS (14%) (Sree- kantaiah et al., 1994), a variant translocation has been detected: t(1;13)(p36;q14) (Biegel et al., 1991; Douglass et al., 1991). Both of these translocations cause the formation of a chimeric protein. In the case of the t(2;13), a PAX3-FKHR fusion product is expressed (Barr et al., 1993; Galili et al., 1993; Shapiro et al., 1993), and in tumors with the t(1;13), a PAX7-FKHR product is detected (Davis et al., 1994). PAX3 and PAX7 are both transcription fac- tors involved in embryonal myogenesis. In the chi- meric proteins, the DNA binding domains of the PAX genes are retained and fused to the C-terminal region of the FKHR gene containing a strong trans- activation domain. It has therefore been proposed that both fusion proteins function as transcription factors, which aberrantly regulate transcription of genes controlled by PAX3 or PAX7 binding sites (Davis et al., 1994). The PAX3-FKHR fusion pro- tein has been shown to be a strong transcriptional activator (Sublett et al., 1995). In addition, both PAX3-FKHR and PAX7-FKHR are overexpressed in A-RMS, either by increased transcription (PAX3- FKHR) or by gene amplification (PAX7-FKHR) (Barr et al., 1996; Davis et al., 1997). Although the presence of either translocation is considered to be a characteristic of A-RMS, some cases with the t(1;13) show mixed histology of both the embryo- nal and the alveolar type (Biegel et al., 1991; Doug- lass et al., 1991), and a case of E-RMS containing the t(2;13) has been described (Mrozek et al., 1995). In addition, the age at diagnosis in patients with the t(1;13) is more consistent with E-RMS.
Cytogenetic analysis of RMS showed a high in- cidence of trisomy 2 (in 9/9 E-RMS samples) (Wang-Wuu et al., 1988) and a high incidence of structural rearrangements of chromosomes 1 and 3
(both in 4/5 RMS samples) (Trent et al., 1985). The alterations on chromosome 3 seem to cluster within 3p14-21. The presence of a der(16)t(1; 16)(q21;q13) is also noted in both RMS types and has been categorized as a secondary structural ab- normality (Mrozek et al., 1995).
RMS was one of the first tumors found to be associated with the Li-Fraumeni syndrome (Li et al., 1969a). Analysis of the frequency of TP53 mu- tations in sporadic RMS showed an incidence of 4/6 E-RMS and 1/4 A-RMS (Felix et al., 1992). Obvi- ously, these series are too small to draw any con- clusion regarding a difference between E-RMS and A-RMS.
DNA amplifications have been identified for re- gions at 2p (Driman et al., 1994) and 12q (Forus et al., 1993). Both A-RMS and E-RMS have been studied by CGH (Weber-Hall et al., 1996). The results showed clear differences between the two RMS subtypes. Aberrations found in E-RMS con- cerned gains and losses of whole chromosomes or large parts of chromosomes. Gains were most fre- quently found for chromosomes 2, 8, 12, and 13 (in 6/10 cases), chromosome 7 (in 5/10 cases), and chromosomes 17, 18, and 19 (in 4/10 cases). Losses were identified most often for chromosome 16 (in 4/10 cases), chromosome 10 (in 3/10 cases), and chromosomes 14 and 15 (in 2/10 cases). One tumor showed an amplification of 12q13-15. In the A- RMS samples, whole (or part of) chromosome gains and losses were found to a much smaller extent. In 10 tumors and 4 cell lines, gain of chromosome arm 17q was found in 4 cases. However, amplifications were present in a high percentage. Chromosome regions most often involved were 12q13-15 (in seven cases) and 2p25 (in five cases). The latter region contains the MYCN gene, which is known to be amplified in A-RMS (Dias et al., 1990; Driman et al., 1994). The regions containing the PAX7 and FKHR genes on 1p36 and 13q14 were found to be amplified in two cases.
Epigenetics of Rhabdomyosarcomas
As was found for WT, abnormal genomic im- printing of 11p15 appears to play a role in the development of RMS. When analyzing the paren- tal origin of markers on chromosome 11 retained in E-RMS showing LOH at that region, it became evident that these were always of paternal origin (Scrable et al., 1989). This is identical to the situ- ation found in WTs. Later studies looking directly at the imprinting status of the IGF2 gene showed LOI of this gene in both E-RMS and A-RMS in a high percentage of the cases: 6/7 (Zhan et al., 1994)
and 5/7 (Pedone et al., 1994). The latter study also found increased expression of IGF2 in tumors with monoallelic expression of the gene, hereby con- firming the important role postulated for IGF2 in the development of this tumor (Scott et al., 1985; El-Badry et al., 1990; Yun, 1992). The imprinting status of H19 has also been examined in RMS (Casola et al., 1997) and was found to be normal in both subtypes. However, the expression was re- duced significantly in 13/15 E-RMS and 2/11 A- RMS. This phenomenon was associated with ei- ther loss of the maternal (expressed) allele or LOI of IGF2. In contrast to the situation for WT, re- duced expression of H19 was not seen in all cases with LOI of IGF2.
HEPATOBLASTOMA
Genetics of Hepatoblastomas
Hepatoblastoma (HB) is a rare malignant epithe- lial tumor of the liver with an incidence of one case per million children (Mann et al., 1990). However, it is the most common malignant hepatic neoplasm of childhood. It occurs with a predominance in males (Ishak et al., 1967).
Although most cases are sporadic, some HBs are associated with either BWS or familial adenoma- tous polyposis coli (FAP) (Kingston et al., 1983; Li et al., 1987; Garber et al., 1988; Giardiello et al., 1991; Hughes et al., 1992). Because FAP patients carry mutations in the adenomatous polyposis coli (APC) gene (Groden et al., 1991; Kurahashi et al., 1995), sporadic HBs have also been analyzed for the presence of mutations in this gene. A study by Oda et al. (1996) indeed showed alterations of the APC gene in 69% of the sporadic cases. When FAP occurs in combination with extracolonic symptoms, it is commonly referred to as Gardner syndrome (Gardner, 1972). Patients suffering from this dis- ease also have an increased risk for the develop- ment of HB (Krush et al., 1988). The trisomy 18 syndrome can also be associated with HB, as has been found in four patients (Bove et al., 1996). One of the phenotypic features of trisomy 18 syndrome is the presence of an omphalocele (also found in BWS patients). It has been suggested that this feature may be one of the factors important in the development of HB in cases in which part of the liver has herniated into the omphalocele (Bove et al., 1996).
As was found for the other BWS-associated tu- mors, LOH at 11p15 has also been found indepen- dently by several researchers (Koufos et al., 1985; Kiechle-Schwarz et al., 1989; Byrne et al., 1993;
Albrecht et al., 1994) for HB. The series analyzed by Albrecht et al. (1994) was the largest and showed a percentage of LOH of 33%. An LOH study of chromosome 1 showed frequent loss of alleles in HBs (Kraus et al., 1996). Of 32 cases, 34% had lost heterozygosity for (a part of) chromosome 1, of which 22% were homozygous for markers on the (distal) short arm.
There has been one report of the occurrence of HB in the Li-Fraumeni syndrome (Tsunematsu et al., 1991); in addition, one study showed mutations of the TP53 gene in 1/3 of sporadic HB samples (Kar et al., 1993).
Cytogenetic analysis of HB revealed certain con- sistent chromosome anomalies. Most frequent are extra copies of chromosome arm 2q and chromo- some 20 (Swarts et al., 1996). There has also been one report describing a recurring translocation: der(4)t(1;4)(q12;q34), which results in partial tri- somy of most of chromosome arm 1q and partial monosomy of distal 4q (Schneider et al., 1997). CGH analysis identified mostly gains. Chromo- somes affected in more than 30% of the cases included 1, 2, 7, 8, and 17 (Steenman et al., 1999).
Epigenetics of Hepatoblastomas
When determining the parental origin of 11p alleles lost in HBs, it became clear that in this BWS-associated tumor LOH at 11p15.5 was exclu- sively of maternal origin (Albrecht et al., 1994). When looking directly at the imprinting status of the IGF2 and H19 genes, biallelic expression was detected. Two studies showed LOI of IGF2 with normal imprinting of H19 in 1/3 of HBs (Li et al., 1995) and in 1/5 of HBs (Montagna et al., 1994). A third study showed LOI of both genes in 1/5 of cases (Rainier et al., 1995).
COMMON GENETIC PATHWAYS
When reviewing all genetic and epigenetic data, it becomes clear that the most evident abnormality found in all BWS-associated tumors affects 11p15 (Table 1). This is the region to which the syn- drome has been linked. All four tumor types show LOH of markers in this region, with loss of the maternal allele and retention of the paternal allele. This suggests the involvement of genomic imprint- ing. Indeed, abnormal imprinting was found for these tumors as it was for BWS: they display LOI of the maternally imprinted IGF2 gene. Therefore, this growth factor may play a central role in the development of the overgrowth syndrome and its associated tumors. Increased expression has been noted for WT, ACC, and E-RMS, and LOI of IGF2
| Duplications | WT | ACC | E-RMS | HB |
|---|---|---|---|---|
| +1q | A | NA | NA | A |
| +2q | NA | NA | A | A |
| +7q | A | NA | A | A |
| +8 | A | NA | A | A |
| +12q | A | A | A | NA |
| +17q | A | NA | A | A |
| +18 | A | NA | A | NA |
| +19 | NA | A | A | NA |
| Translocations/loss of genetic material | ||||
| LOHª/translocation | ||||
| 1p | A | NA | A | A |
| Translocation/-3p | NA | A | A | NA |
| LOH 11p | A | A | A | A |
| LOH 16q | A | NA | A | NA |
| -17p | A | A | NA | NA |
| -22q | A | A | NA | NA |
| Imprinting/expression abnormalities | ||||
| LOIb IGF2 | A | A | A | A |
| Increased expression | ||||
| IGF2 | A | A | A | NA |
| LOI H19 | A | NA | NA | A |
| Decreased expression | ||||
| H19 | A | A | A | NA |
| Mutation | ||||
| TP53 | A | A | A | A |
*Abnormalities are shown in the left column. WT, Wilms’ tumor; ACC, adrenocortical carcinoma; E-RMS, embryonal rhabdomyosarcoma; HB, hepatoblastoma. A indicates that the abnormality has been found in the tumors. NA indicates that the abnormality was not found in the tumors or that the tumors were not analyzed for the presence of that particular abnormality.
ªLOH, loss of heterozygosity. bLOI, loss of imprinting.
has been associated with decreased expression of the supposed tumor suppressor gene H19.
There is an additional genetic abnormality com- mon among all four types of neoplasms. They all show mutations in the TP53 gene. However, this is found in a large proportion of all cancers and there- fore is not considered to be specific for the devel- opment of tumors associated with the BWS.
Besides genetic evidence, there are also patho- logical data indicating an association among these tumors. Both WT and HB may contain rhabdomyo- matous tissue, whereas primary tumors of the liver have been shown to consist of ACC and RMS (Koufos et al., 1985).
There are also several chromosome aberrations found in a subset of these tumors. When consider- ing abnormalities found in three of the four tumor types, there seems to be a strong connection be-
tween WT, E-RMS, and HB. As shown in Table 1, they share seven common genetic abnormalities. Besides the abnormalities already mentioned above, they all may contain extra copies of 7q, 8, and 17q. Therefore, these chromosome regions may contain genes that play a role in the normal embryonal development of the affected tissues. Because these affected regions are large, it would be very difficult to identify the genes involved. More interesting therefore is the abnormality of 1p that was found in these tumors. This presented either as LOH or a structural abnormality of the short arm of chromosome 1. Because these aberra- tions affect small(er) regions of the chromosome, they may be very helpful in the identification of genes. This applies especially to the analysis of translocation breakpoint regions, as has been shown for the regions involved in BWS.
Extra copies of chromosome 12 have been iden- tified in the subset consisting of WT, ACC, and E-RMS. These tumors are also characterized by increased expression of IGF2 and decreased ex- pression of H19.
When analyzing the published data, it becomes clear that WT and E-RMS share most genetic ab- errations, a total of 12 (Table 1). Therefore, the genetic relationship is most evident between these two tumor types. In addition to the abnormalities already mentioned, they have both been shown to contain extra copies of chromosome 18, and in both tumor types decreased expression of H19 has been found. Further elucidation of the common genetic pathways involved in the etiology of the BWS- associated tumors awaits identification of the genes involved.
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