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Familial Wilms tumor.

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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 129C:29 – 34 (2004)
Familial Wilms Tumor
Wilms tumor (WT), an embryonic tumor arising from undifferentiated renal mesenchyme, has been a productive
model for understanding the role of genes in both tumorigenesis and normal organogenesis. Approximately 2%
of WT patients have a family history of WT, and even sporadic WT is thought to have a strong genetic component
to its etiology. Familial WT cases generally have an earlier age of onset and an increased frequency of bilateral
disease, although there is variability among WT families, with some families displaying later than average ages at
diagnosis. One WT gene, WT1 at 11p13, has been cloned, but only a minority of tumors carry detectable
mutations at that locus, and it can be excluded as the predisposition gene in most WT families. Two familial WT
genes have been localized, FWT1 at 17q12–q21 and FWT2 at 19q13.4; lack of linkage in some WT families to
either of these loci implies the existence of at least one additional familial WT gene. Originally modeled as the
inheritance of a mutation in a tumor suppressor gene, molecular analysis of familial tumors not linked to
11p13 have provided data suggesting that this model may be overly simplistic and/or not applicable to all WT
families. Identification of the FWT1 and FWT2 genes will help clarify this and will also likely aid in our
understanding in general of the roles of the various WT genes and their genetic interactions in the development
of WT. ß 2004 Wiley-Liss, Inc.
KEY WORDS: Wilms tumor; WT1; FWT2; FWT1
Wilms tumor (WT) is a childhood
cancer of the kidney that arises from undifferentiated fetal mesenchyme and is
diagnosed in about 1 in 10,000 Caucasian children. Tumors typically display a
variable triphasic histology of blastemal,
epithelial, and stromal elements, suggestive of incomplete and aberrant differentiation of the fetal mesenchyme. The
prognosis for most children diagnosed
with WT is good, with a long-term
E. Cristy Ruteshouser is a Research Scientist in the Section of Cancer Genetics,
Department of Molecular Genetics, at The
University of Texas M. D. Anderson Cancer
Center, Houston, Texas. She is currently
pursuing the identification of the FWT2 gene
located on chromosome 19q.
Vicki Huff is an Associate Professor in the
Section of Cancer Genetics, Department of
Molecular Genetics, at the University of Texas
M. D. Anderson Cancer Center, Houston,
Texas. She has a long-standing research program in the genetics of Wilms tumor and the
role of WT1 in Wilms tumor.
*Correspondence to: Vicki Huff, Ph.D.,
Department of Molecular Genetics, The
University of Texas M.D. Anderson Cancer
Center, 1515 Holcombe Blvd, Houston, TX
77030. E-mail:
DOI 10.1002/ajmg.c.30025
ß 2004 Wiley-Liss, Inc.
survival rate of over 90% for localized
disease and over 70% for metastatic
disease [Grosfeld, 1999]. WT with diffuse
anaplasia, however, is more resistant to
conventional therapy and is associated
with a poorer prognosis.
Most cases of WTare sporadic (98–
99%) and unilateral (90–95%). Congenital anomalies, such as aniridia (AN)
and genitourinary anomalies (GU), are
observed in &1% and &3% of all WT
cases, respectively. Somatic overgrowth
syndromes, e.g., Beckwith-Wiedemann
syndrome (BWS) and Simpson-GolabiBehmel syndrome (SGB), and hemihypertrophy are observed in another &4%
of patients [Breslow et al., 1993]. WT,
along with GU anomalies (notably male
pseudohermaphrodism) and renal mesangial sclerosis resulting in early onset
renal failure, is also a feature of DenysDrash Syndrome.
The average age of WT diagnosis is
42–47 months for children with unilateral tumors and 30–33 months for
children with bilateral disease [Breslow
et al., 1993]. An earlier age at diagnosis
and an increased frequency of bilateral
disease is also observed in children with
congenital anomalies, and also, with
some notable exceptions, in WT families
[Knudson and Strong, 1972; Breslow
et al., 1993]. These data suggest that
patients with congenital anomalies or
familial WT carry a germline mutation
that predisposes to the development of
multiple tumors at an earlier age than
in the general population, as is the case
with individuals with other types of
cancer predisposition syndromes, who
exhibit early diagnosis and multiple tumors [Knudson and Strong, 1972].
As an embryonal tumor, WT has
been of interest to both developmental
biologists and geneticists as a model for
understanding normal kidney development and for understanding the role of
genetic alterations in tumorigenesis.
Unlike most adult tumors, WT is a
relatively euploid cancer [Wang-Wuu
et al., 1990; Maw et al., 1992], with no
strong environmental exposure implicated in its development. These features,
in addition to its genesis in proliferating
undifferentiated tissue, suggest that the
number of genetic alterations required
for tumorigenesis may be fewer than in
adult tumors and that the alterations that
are present are significant events. That
WT provides a tractable model for understanding the role of genetic alteration
in tumor development is underscored
by the fact that the study of WTwas key
in the development of the two-hit,
tumor suppressor gene model for tumorigenesis, which has become the
underlying framework for developing
hypotheses on the role of genetic alterations in both childhood and adult cancers. Molecular studies of WT have also
provided other precedents in cancer
genetics, such as genetic heterogeneity
in tumor predisposition, a role of imprinted genes in tumor development,
and the recognition that a ‘‘cancer’’ gene
can also play a key role in normal development [Knudson and Strong, 1972;
Schroeder et al., 1987; Grundy et al.,
1988; Huff et al., 1988; Reik and Surani,
1989; Kreidberg et al., 1993; Ogawa
et al., 1993; Rainier et al., 1993].
Approximately 2% of
Wilms tumor patients have
a family history.
Approximately 2% of Wilms tumor patients have a family history. The overwhelming majority of WT families are
small, with just two or three affected
members. A hallmark of WT families is
the presence of affected individuals,
often cousins or siblings, who are related
through an unaffected obligate carrier of
the predisposition allele; affected parentchild pairs are observed in only &10%
of familial cases [Breslow et al., 1996].
Studies of pedigrees and segregation
analyses have suggested that WT predisposition is the result of an autosomal
dominant allele that is incompletely
penetrant, and the penetrance of such
alleles has been estimated to be between 25 and 60% [Brown et al., 1972;
Knudson and Strong, 1972; Matsunaga,
1981]. Males and females are equally
represented in the affected individuals. A
gender bias is also not observed in
the obligate carrier parents of affected
children, indicating that the segregating
predisposition gene is not subject to
parent-of-origin (imprinting) effects
[Breslow et al., 1996]. Consistent with
the inheritance of a predisposing mutation, an increased frequency of bilateral tumors and a concomitant earlier age
of diagnosis is observed in familial cases
overall. The average age of onset for
familial WT is &35 months for unilateral tumors and 16 months for bilateral disease, which occurs in &16% of
familial cases [Breslow et al., 1996].
Figure 1 shows a pedigree of a large
WT family that displays the increased
frequency of bilateral disease, the early
age of diagnosis, and the presence of unaffected obligate carriers that are general
features for familial WT. Interestingly,
however, WT families appear to be
heterogeneous with regard to penetrance, frequency of bilateral disease,
and age at diagnosis [Breslow et al.,
1996]. This observation may be attributable to locus heterogeneity, allelic
heterogeneity, and/or the action of a
modifying or interacting gene(s). Even
when the same locus is involved, variability is observed. For example, of four
large families linked to a predisposition
locus at 19q13.4, one shows early WT
onset (average 17 months), one shows
late onset (average 97 months), and one
displays the unusual feature of neural
elements in the tumors from all four
affected individuals [Hussong et al.,
2000] (Table I). These data are suggestive of allelic heterogeneity and/or
the effect of modifying genes.
In rare instances, WT cases have
been reported in the context of other
familial syndromes. These include familial cancer syndromes (Bloom syndrome,
Li-Fraumeni syndrome, neurofibromatosis Type 1, and hyperparathyroid-jaw
tumor syndrome) in which isolated cases
of WT have been observed [Cairney
et al., 1987; Hartley et al., 1993;
Perilongo et al., 1993; Kakinuma et al.,
1994]. WT is also observed, as noted
above, in the somatic overgrowth syndromes, BWS and SGB. Most notably,
approximately 4% of children with
BWS develop WT, and another &4%
of BWS patients develop other embryonal malignancies [Wiedemann, 1964;
Beckwith, 1969; Sotelo-Avila et al.,
1980; Wiedemann, 1983]. Mutation or
altered expression of one or more genes
in a cluster of imprinted genes at 11p15
has been observed in BWS [reviewed in
Li et al., 1998], and many of these genes
play a role, either positively and negatively, in growth control. These data,
along with the observation of nephrogenic rests—foci of undifferentiated
Figure 1. Pedigree of 19q13.4-linked family WTX524, showing incidence of WT
in this family. Age (in months) at diagnosis for each affected individual is indicated. The
arrow indicates the proband.
TABLE I. Variability of Clinical Features of WT Families Linked to FWT2 at
Mean age (months) at
diagnosis (range)
% Bilaterality
16.6 months (4–37)
43.5 months (37–57)
96.5 months (39–204)
30.0 months (7–66)
25% (2/8)
0% (0/4)
17% (1/6)
0% (0/4)
Triphasic with neural elementsb
Huff [1998].
Hussong et al. [2000].
embryonic cells—in WT patients both
with and without BWS imply that
perturbation of normal growth and
differentiation of the embryonic kidney
plays a role in WT development
[Beckwith, 1998].
Familial WT patients, however,
only rarely display features of the above
genetic syndromes. The most common,
BWS, is noted in only &3% of the WT
families in the National Wilms Tumor
Study (NWTS) population-based registry [Breslow et al., 1996]. Similarly, an
excess of tumors other than Wilms
tumor was not observed in WT families
in this registry [Felgenhauer et al., 2001].
Thus, although some genetic syndromes
are associated with WT, the association
is primarily with sporadic WT, not
familial WT.
The etiology of Wilms tumor is
genetically heterogeneous.
The etiology of Wilms tumor is
genetically heterogeneous. Although
WT was originally assumed to be
due to alteration of a single gene, it
is now known that several genes can
play roles in WT development or
progression. The only WT gene isolated to date, however, is WT1,
which was first localized by virtue of
the observation of 11p13 germline
deletions in WT/AN patients
[Francke et al., 1979].
Subsequent cloning of the 11p13
gene, WT1, revealed that it encodes a
449–amino acid protein containing four
zinc finger motifs and a regulatory domain and that it is a member of a large
family of zinc finger transcription factors
[Call et al., 1990; Gessler et al., 1992].
The WT1 transcript is alternatively
spliced, resulting in four isoforms and
four protein products that differ in their
capacity to regulate gene expression.
Many genes have been shown to be
transcriptionally activated or repressed
by WT1 [reviewed in Lee and Haber,
2001], but it is still not clear which genes’
dysregulation is essential for tumor
development following WT1 mutation.
A recent gene expression profiling study
of Wilms tumors has demonstrated
upregulation of c-myc expression in
association with mutations in WT1,
but dysregulation of additional target
genes is likely also important [Udtha
et al., 2003]. Since many of the genes
putatively repressed by WT1 function to
promote cell proliferation, a logical
model for the role of WT1 in tumorigenesis is that inactivation of WT1
results in increased expression of these
growth stimulatory genes.
The association of AN and WT is
now known to be due to deletion of two
distinct genes. In contrast, patients with
WT and GU abnormalities often carry
germline WT1 mutations [Pelletier
et al., 1991a; Huff et al., 1991b]. Tumors
from germline mutation carriers invariably have sustained inactivating mutations in both WT1 alleles [Huff, 1998],
consistent with the model of WT1 as a
tumor suppressor gene. A reduction to
homozygosity for somatic WT1 mutations is also observed in tumors from
genotypically normal individuals. WT1
mutations described to date are predominantly deletion or truncation mutations, although missense mutations at
codons encoding amino acids thought to
be functionally critical within the zinc
finger domains are also observed, most
notably in patients with Denys-Drash
syndrome [Pelletier et al., 1991b]. Interestingly, germline mutations that result
in altered ratios of normal splice isoforms
are observed in patients with a triad of
gonadoblastoma, GU anomalies, and
later onset renal failure (Frasier Syndrome) [Barbaux et al., 1997].
Germline WT1 mutations are
usually de novo mutations.
Germline WT1 mutations are usually de
novo mutations. WT1 mutational analysis of familial cases demonstrated that
only 2 out of 30 families carried an
inherited alteration in WT1 [Huff,
1998]. Germline WT1 mutations have
been identified in WT patients with no
family history. Analysis of parental DNA
from 14 such patients revealed that in
only one case was the mutation also
present in the parent; the remaining
13 germline mutations had arisen de
novo (Huff, unpublished data). Thus,
germline WT1 mutations are rarely
observed in a family context, and most
individuals with germline WT1 mutations are ‘‘sporadic’’ cases. Analysis of
tumor DNA from these patients demonstrates that, as originally reported,
tumors are homozygous for the
paternally-derived allele, indicative of a
paternal origin of the WT mutation,
similar to the predominantly paternal
origin of large de novo 11p13 deletions
[Huff et al., 1991a; Huff, 1998].
By genetic linkage analysis of WT
families, WT1 can be excluded as the
predisposition gene segregating in most
WT families [Grundy et al., 1988; Huff
et al., 1988]. Although unexpected at
the time, now that GU anomalies are
known to be a consequence of germline
WT1 mutation, the infrequent role of
WT1 in familial predisposition is not
surprising, given the paucity of GU
anomalies in WT families. Similar to the
results of the linkage analyses, direct
sequence analysis of WT1 in both large
and small WT families has indicated
that WT1 mutation is rare, being
observed in one study in only 3 out of
30 WT families [Huff, 1998], with
additional isolated case reports [Pelletier
et al., 1991a; Kaplinsky et al., 1996;
Pritchard-Jones et al., 2000].
Other WT Genes
Mutation of two genes known for their
critical role in other types of tumors, p53
and the b-catenin gene, is observed in
5% and 15% of Wilms tumors, respectively [Bardeesy et al., 1994; Koesters
et al., 1999; Maiti et al., 2000]. p53
mutation is strongly associated with an
anaplastic tumor histology and poor
prognosis [Bardeesy et al., 1994], and
b-catenin mutation is strongly associated
with additional mutation at the WT1
locus [Maiti et al., 2000]. For both genes,
the observed mutations are somatic
events, and there is little evidence to
suggest that either gene plays a role in
familial WT.
Alteration of a number of other
genes/genomic regions has been implicated in WT development by the observation of genomic regions displaying
loss of heterozygosity (LOH) in tumors.
Unlike adult tumors, Wilms tumors
display very little (<5%) ‘‘background’’
LOH [Wang-Wuu et al., 1990; Maw
et al., 1992]. Thus, the observation of
LOH at 11p, 16q, 1p, and 7p in 40%,
20%, 20%, and 15% of tumors, respectively, identified additional regions of
the genome that may harbor genes
important in tumor development. In
some tumors, 11p LOH is confined to
markers at 11p15, a region (as noted
above) known to contain a cluster of
imprinted genes that play roles, either
positively or negatively, in growth control. One such gene whose product
positively regulates growth and proliferation, IGF2, is expressed only from the
paternally-derived allele. The observa-
tion of LOH and loss of maternal 11p15
alleles in normal kidney as well as in
tumors, as a result of somatic recombination, suggests that loss of maternallyderived alleles and/or duplication of
paternally-derived 11p15 alleles (including paternally-expressed IGF2 alleles)
results in a growth advantage for both
normal and malignant cells [Chao et al.,
1993]. The observation that tumors that
do not display 11p15 LOH often alternatively show loss of imprinting (LOI)
[Ogawa et al., 1993; Rainier et al., 1993]
further underscores the notion that,
similar to BWS, altered expression of
normally imprinted genes is an important feature in the development of many
Wilms tumors. However, for the various
genomic regions displaying LOH there
is little data implicating genes at any of
these regions as playing a role in familial
predisposition, and for 11p15 and 16q
there are data ruling out these regions as
harboring familial predisposition genes
in several large families [Grundy et al.,
1988; Huff et al., 1992].
Familial Predisposition Genes
WT1 mutation is observed only
rarely in WT families, and genetic
linkage studies of large WT families
have been employed to localize genes
that more commonly predispose to
familial WT. As a result of these studies,
Two familial predisposition
genes have been mapped to the
genome: FWT1 at 17q12–q21
and FWT2 at 19q13.4.
two familial predisposition genes have
been mapped to the genome: FWT1 at
17q12-q21 [Rahman et al., 1996] and
FWT2 at 19q13.4 [McDonald et al.,
1998]. Neither gene has yet been
identified. There are also WT families
for which linkage at any ‘‘WT gene’’
locus can be ruled out, implying that
additional predisposition genes have yet
to be localized [McDonald et al., 1998;
Rahman et al., 1998].
As mentioned above, pedigree and
segregation analyses previously suggested that predisposition is the result of
an autosomal dominant allele that is
incompletely penetrant, and, following
the precedent of retinoblastoma and the
demonstrated role of WT1 as a tumor
suppressor gene, familial predisposition
to WT has been modeled as involving
a germline mutation that is reduced
to homozygosity in tumors. However,
molecular data on familial tumors indicate that this may be too simple a model.
The first suggestion of this was the
observation of LOH at the FWT2
region at 19q13.4 in tumors from families whose inherited predisposition was
not linked to FWT2 [McDonald et al.,
1998]. As shown in Figure 2, tumors
from two WT families show 19q13.4
LOH, but the alleles retained in the
tumors are not present in blood DNA of
other affected family members. Conversely, of the tumors analyzed to date
from members of FWT2-linked families, none display 19q LOH. These data
suggest that alterations at two distinct
loci are critical rate-limiting steps in
tumor development in some families.
The observation of 19q LOH in some
nonfamilial cases implies that FWT2
also plays a role in sporadic disease.
Thus, a two-locus model or a model
of a predisposition gene modified by
another gene may more accurately
reflect the molecular genetics of these
19q-involved tumors. The role of
FWT1 in familial predisposition and
tumorigenesis also may not conform to
original expectations; a tumor from a
FWT1-linked family was observed to
have lost the 17q alleles genetically
linked to predisposition in the family,
suggestive of a ‘‘hit-and-run’’ mechanism for the FWT1 predisposition gene
[Rahman et al., 1997].
The genetic model for Wilms tumorigenesis has evolved over the years.
Originally thought to follow a simple
one-locus, ‘‘two-hit’’ paradigm established by retinoblastoma, another childhood tumor, the genetic etiology of WT
pensatory pathways in fetal kidney that
are present in other tissues. Regardless
of whether familial WT genes turn out
to play critical roles in a narrow subset or
a wide range of cell types, given the
novel discoveries that have come out of
the study of WTand the unexpected data
on familial tumors, the study of WT
families is likely to provide further insight into the role in general of WT
genes in cancer development and may
even identify novel mechanisms by
which—or novel cellular pathways in
which—genetic alterations result in cancer susceptibility.
Figure 2. FWT2 LOH in tumors from WT families unlinked to FWT2. Below
each pedigree symbol, the PCR products resulting from amplification of two 19q13.4
polymorphic loci, D19S601 and D19S589, are shown. Alleles retained in the tumors
are indicated by arrows. In each family, the allele retained in the tumor is not carried by at
least one other affected individual, demonstrating nonlinkage to 19q. Pedigree symbols
are as indicated in Figure 1. TT is tumor from the indicated individual.
is now recognized to be heterogeneous
and more complex. Several genes are
now known to play a critical role in the
etiology of WT: WT1 at 11p13, FWT1
at 17q12–q21, FWT2 at 19q13.4, and at
least one additional familial WT gene.
The alteration, primarily somatic, of
other genes—11p15 imprinting loci;
p53; b-catenin; and other genes at 16q,
7p, and possibly in other genomic
regions—also plays a role in tumor development. How, or whether, alterations at
multiple ‘‘WT’’ genes act independently
or in concert is unknown. With the
exception of WT1 and b-catenin mutations that are highly associated with each
other, there is little known about the
patterns of genetic alterations that occur
in tumors.
Similarly, the data on FWT2 LOH
in tumors from non-FWT2-linked
families and the tumor-specific loss of
the linked markers in FWT1-linked
families—although difficult to interpret
without a measure of speculation, as the
predisposition genes themselves have
yet to be isolated—suggest that familial
predisposition to WT is also not as
simple as previously modeled. In fact, it
could reasonably be argued that familial
predisposition will not conform to a
single model, but may differ depending
upon the nature of the inherited mutation(s). Most familial predisposition
occurs outside of the context of congenital anomalies, genetic syndromes, or
WT1 mutation, implying that inherited
alteration of the genes involved in these
genetic entities do not play a role in
tumor predisposition. However, somatic
alteration of these genes may still play a
role in tumor progression in conjunction
with a germline predisposition allele.
There is still much to learn about
the identity, function, and possible
interaction of genes that result in familial
WTand the phenotypic variability exhibited among families. The absence of
predisposition to other types of cancers is
suggestive of a temporal and/or tissue
specificity in the expression of predisposition genes, or the absence of com-
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