Hindawi Publishing Corporation
Journal of Oncology
Volume 2010, Article ID 397632, 6 pages
IsTherea PredispositionGeneforEwing’s Sarcoma?
R.L.Randall,1S.L.Lessnick,2K.B. Jones,1L.G.Gouw,3J. E.Cummings,4
L.Cannon-Albright,5,6and J. D.Schiffman2
1Sarcoma Services, Department of Orthopaedics, Huntsman Cancer Institute and Primary, Children’s Medical Center,
The University of Utah, Utah, UT 84112, USA
2Department of Oncological Sciences, Division of Pediatric Hematology/Oncology, Center for Children’s Cancer Research,
Huntsman Cancer Institute, The University of Utah, Utah, UT 84112, USA
3Division of Medical Oncology, The University of Utah, Utah, UT 84112, USA
4Department of Orthopaedics, Indiana University, Indiana, IN 46202, USA
5Division of Genetic Epidemiology, Department of Internal Medicine, The University of Utah, Utah, UT 84112, USA
6George E. Wallen Department, Veterans Affairs Medical Center, Salt Lake City, The University of Utah, Utah, UT 84148, USA
Correspondence should be addressed to R. L. Randall, firstname.lastname@example.org
Received 25 August 2009; Revised 14 December 2009; Accepted 8 February 2010
Academic Editor: Frederic G. Barr
Copyright © 2010 R. L. Randall et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ewing’s sarcoma is a highly malignant tumor of children and young adults. The molecular mechanisms that underlie Ewing’s
Sarcoma development are beginning to be understood. For example, most cases of this disease harbor somatic chromosomal
translocations that fuse the EWSR1 gene on chromosome 22 with members of the ETS family. While some cooperative genetic
events have been identified, such as mutations in TP53 or deletions of the CDKN2A locus, these appear to be absent in the vast
majority of cases. It is therefore uncertain whether EWS/ETS translocations are the only consistently present alteration in this
tumor, or whether there are other recurrent abnormalities yet to be discovered. One method to discover such mutations is to
identify familial cases of Ewing’s sarcoma and to then map the susceptibility locus using traditional genetic mapping techniques.
Although cases of sibling pairs with Ewing’s sarcoma exist, familial cases of Ewing’s sarcoma have not been reported. While Ewing’s
susceptibility syndromes have not been identified. We will review the current evidence, or lack thereof, regarding the potential of
a heritable condition predisposing to Ewing’s sarcoma.
The analysis of cancer predisposition syndromes has been
an important approach towards the identification of onco-
genes and tumor suppressor genes. Some hereditary cancer
syndromes, such as Li-Fraumeni Syndrome, are caused by
the mutation of critical tumor suppressor genes (TP53)
and lead to wide-spread tumorigenesis including many
different tumor types . However, other hereditary cancer
syndromes appear to have a more limited tumor spectrum.
For example, individuals with syndromes such as WAGR
(Wilms tumor, aniridia, genitourinary abnormalities, and
mental retardation syndrome) and Denys-Drash Syndrome
have mutations in the WT1 gene, and these patients are
an underlying genetic mutation or predisposition to develop
specific cancers is helpful not only to family members
with that syndrome, but also to many other individuals
who develop cancer without known risk factors. Knowledge
of how specific tumors arise can be applied to targeted
prevention, surveillance, and even therapeutic strategies.
Ewing’s sarcoma, first described by James Ewing in
1921, is the second most common pediatric bone cancer
after osteosarcoma. It is an aggressive cancer of children
and young adults, with 30%–60% survival depending on
tumor site and the presence or absence of metastases at
diagnosis [4, 5]. While osteosarcoma is thought to arise
from bone cell progenitors , the cell of origin of Ewing’s
sarcoma remains unknown. James Ewing himself initially
described this disease as an endothelioma of bone, and
2 Journal of Oncology
later suggested that it arises from perivascular lymphatic
endothelium [7, 8]. Since that time, other investigators
have suggested myriad cells of origin, including hematologic
, mesenchymal/fibroblastic [10, 11], and neural crest
derivatives [12, 13]. More recently, emerging evidence has
suggested that Ewing’s sarcoma arises from a mesenchymal
stem or progenitor cell [14–16]. A definitive answer to the
cell of origin question will require additional analyses.
While the cell of origin of Ewing’s sarcoma is not yet
stood. Ewing’s sarcomas are highly associated with a limited
set of recurring, somatic chromosomal rearrangements.
The most common of these, t(11;22)(q24;q12), is found
in approximately 85% of cases, while t(21;22)(q22;q12) is
found in 10% of cases [17, 18]. The remaining translocations
are found in <5% each [19, 20]. These translocations fuse
the EWSR1 gene on chromosome 22 with an ETS family
member, most commonly the FLI1 gene on chromosome
11 [17, 19–21]. This Ewing’s sarcoma-specific translocation
generates an EWS/ETS fusion protein [17, 19–21]. The
Ewing’s sarcoma fusion proteins contain a strong tran-
scriptional activation domain fused to an ETS type DNA
binding domain and thus function as aberrant transcrip-
tion factors that dysregulate target genes contributing to
oncogenic transformation . A number of genes that are
dysregulated by EWS/FLI have been identified, and their
roles in the oncogenic process are under active investigation
[23–29]. The presence of EWS/ETS translocations is specific
to Ewing’s sarcoma, and the presence of an EWS/ETS fusion
protein can be used clinically to diagnose patients with
Ewing’s sarcoma who have small round blue cell tumors.
Two main cooperating mutations have been identified in
Ewing’s sarcoma: p53 and RB pathway mutations [30–33].
Mutations in TP53 (encoding the p53 protein) occur with
a frequency of 5%–20% in Ewing’s sarcoma, amplifications
of MDM2 occur in 0%–10% of cases, and deletions of the
CDKN2A locus (encoding overlapping p16INK4Aand p14ARF
transcripts) occur in about 15% of cases [30, 32, 34, 35].
Thus, a significant percentage of Ewing’s sarcoma have p53
pathway alterations. A similar percentage of Ewing’s sarcoma
tumors also have alterations in the RB pathway [30, 32, 33].
Alterations in these pathways may be required to bypass a
growth inhibitory effect mediated by the EWS/ETS fusion
protein [36, 37]. Although alterations in the p53 and/or
RB pathways may cooperate with EWS/ETS fusion proteins
to induce Ewing’s sarcoma, this disease is not traditionally
considered to be a part of the Li-Fraumeni syndrome and
has rarely been reported as a second tumor in patients with
heritable retinoblastoma [38–42]. Ewing’s sarcoma does not
appear to be a component of other tumor susceptibility
There are no well-documented environmental causes of
this disease and only a handful of epidemiological studies
have focused on Ewing’s sarcoma. While Ewing’s sarcoma is
not common, with an incidence of about 3 per one million
people under 20 years of age , it remains uniformly
deadly when untreated. Ewing’s sarcoma has a slightly higher
incidence in males. Interestingly, Ewing’s sarcoma has a
strong predilection for Caucasians, being far more common
in this population than in Asians and ten times more
common than in those of African descent. This Caucasian
predilection is true globally .
A molecular postulate has been proposed for the racial
predilection noted: intron 6, near the molecular breakpoint
region, is at least fifty percent smaller due to diminished
interspersed repeat sequences (Alu elements) in about 10
(Alu elements are preferential sites for genetic recombina-
with no genetic lineage predisposition.
2.SearchStrategy andSelection Criteria
We reviewed the English literature to find any evidence
in the demographics and epidemiology of Ewing’s sarcoma
to suggest a familial predisposition. We considered cases
of consanguinity and any onco-syndromic conditions that
might imply a predisposition genotype. Our results are
2.1.Ewing’s SarcomaandRelated Tumors. Additional tumors
beyond classic Ewing’s sarcoma have been found to have
similar histologic and molecular phenotypes, including the
specific t(11; 22) translocation. Ewing’s sarcoma and another
small round blue cell malignancy often seen in soft tissues,
termed primitive neuroectodermal tumor (PNET), were
found to not only have similar histologic features but also
to contain the identical translocation in greater than 95%
of cases . PNET is approximately 10-fold less common
than Ewing’s sarcoma. Some investigators have used the term
“Ewing’s Sarcoma Family of Tumors” to encompass Ewing’s
sarcoma, PNET, as well as atypical Ewing’s sarcoma and
Askin tumor (Ewing’s sarcoma of the chest wall). All of
Because of the consistent genetic lesion, we will continue to
refer to this entire group as Ewing’s sarcoma.
Ewing’s sarcoma tumors are included, and Ewing’s sarcoma
tumors do not seem to be associated with any other types of
tumors either in pediatric or adult oncology.
2.2. Demographics and Epidemiology. Chronologically, nine-
ty percent of cases occur in patients between 5 and 25 years
of age. After age 25, it is relatively rare. About 25% of cases
occur before age 10, while 65% arise between ages 10 and
20 years old. Approximately 10% of patients are older than
20 years when they are diagnosed. Boys and young men are
affected more frequently than girls and young women. Males
location, followed by the femur, tibia, humerus, and scapula.
However, Ewing’s sarcoma can be found in any part in the
Several reports have highlighted the general association
of Ewing’s sarcoma and parental exposure to pesticides,
solvents, and farming or agricultural occupation [47–51].
Hernia, both inguinal and umbilical have also been linked
Journal of Oncology3
to Ewing’s sarcoma [47, 48, 52, 53]. Valery et al. 
surmised that Ewing’s sarcoma and hernia have common
embryologic neuroectodermal pathways. Interestingly, these
cases arose in farming families perhaps suggesting some
. At least one report discounts this association . In
a case-control study, Winn et al.  matched 208 Ewing’s
cases with one sibling control and one age matched regional
population control. Although hernia was seen 6 times more
frequently among Ewing’s patients compared to regional
controls, sibling controls experienced hernias with the same
frequency as Ewing’s patients. Reports of patient height and
onset of pubertal growth have been varied with no clear
or consistent pattern developing in their association with
Ewing’s sarcoma [55–61].
The ethnic epidemiology of Ewing’s Sarcoma is fascinat-
tumor. Ewing’s Sarcoma has a strong predilection for Cau-
casians, being far more common than in Asians and those
of African descent [44, 62–65]. Zucman-Rossi et al. have
noted that intron 6, near the molecular breakpoint region, is
at least fifty percent smaller due to diminished interspersed
repeat sequences (Alu elements) in about 10 percent of
the African population . Alu elements are a type of
SINE, or Short INterspersed Element, and are approximately
300bp in length with approximately 1,000,000 copies in
the human genome, accounting for approximately 10% of
genetic material. Alu elements are a type of transposon. It
is hypothesized that Alu elements are preferential sites for
genetic recombinations in cancer . Perhaps in families
with Ewing’s sarcoma probands that develop remote Ewing’s
sarcoma in their descendents, increased genomic predomi-
nance of Alu elements leads to subsequent rechimerization
germline DNA from Ewing’s sarcoma patients have yet to be
performed which could support this hypothesis.
Most recently, Johnson et al. explored the association
between parental age and risk of all childhood cancers
.The previous studies had explored the association
between advanced maternal and paternal age with congenital
syndromes (including several which predispose to cancer)
support of an association between older parental age and an
al.  followed up on these investigations and performed a
pooled analysis on 17,672 childhood cancer cases diagnosed
during 1980–2004 and 57,9666 controls born during 1970–
2004. Cancer and birth registry records from New York,
Washington, Minnesota, Texas, and California were linked,
and Johnson et al. calculated logistic regression for parental
age and specific childhood cancers adjusting for sex, birth
weight, gestational age, birth order, plurality, maternal race,
age seemed to increase the risk for most common childhood
cancers. Interestingly, Ewing’s sarcoma was found to be
associated with the highest risk of all childhood cancer
subtypes in relation to a 5-year increase in both maternal age
(Odds Ratio 1.18 [1.02–1.35]) and paternal age (Odds Ratio
1.19 [1.06–1.34]). They speculate that the increased risk of
cancer in older mothers could be due to age-related increases
in de novo epimutations in oocyte genes transmitted to
offspring .A similar phenomenon in epimutations could
be occurring in the spermatocytes of older fathers. Although
limited to a single pooled analysis, this large study provides
intriguing data to suggest a slight but possible contribution
of genetic risk to the development of Ewing’s sarcoma.
2.3. Possible Consanguinity. The association between Ewing’s
sarcoma and other forms of cancer seen in a proband’s
pedigree has been reported , some as early as 1952
. Reporting on the Mayo clinic experience with Ewing’s,
noted to have close family relatives, usually a grandfather or
aunt, with some form of malignant tumor. In their series,
only 1 patient had a sibling who had experienced a bone
sarcoma. Eight years later the first reported incidence of
Ewing’s sarcoma in siblings was reported by Huntington et
al. . Two sisters, each diagnosed in their teens, eventually
died of metastatic disease. None of their other siblings (five
boys and two girls) showed any evidence of disease. A
second report of Ewing’s sarcoma in siblings was published
in 1964 . Hutter et al.  reported the case of two
siblings, both female. One sister was diagnosed at age 3
and died of metastatic disease shortly thereafter. Her sister
was diagnosed at age 16 and at the time of reporting was
alive and disease free. Interestingly, their mother was treated
for breast carcinoma, and their maternal grandfather died
of carcinoma of the colon. Joyce et al.  reported the
third case of Ewing’s sarcoma in siblings in 1983. The
first sibling was diagnosed at age 9 and treated successfully
with chemotherapy and radiation. Her sister was diagnosed
at age 19 and at the time of publication was alive with
pulmonary disease that seemed responsive to chemotherapy.
A careful history showed no reports of neoplastic disease in
the immediate or extended family.
Although isolated to case reports, these siblings with
Ewing’s sarcoma also would imply a slight but definitely
suggestible contribution of genetics to the risk of developing
Ewing’s sarcoma. However, given their limited numbers
and lack of genomic DNA for analysis, environmental
were all females.
2.4. Onco-Syndromic Considerations. Finally, several authors
have reported on the association of Ewing’s sarcoma after
diagnoses and treatment for retinoblastoma [75, 76]. Spunt
et al.  published on a cohort of 6 Ewing’s patients
diagnosed after treatment for various cancers including
lymphoma, leukemia, Wilms tumor, and retinoblastoma.
Cope et al. , via meta-analysis, found that while Ewing’s
has been reported after a number of different malignan-
cies. Only the predominance of retinoblastoma prior to
Ewing’s differs dramatically from the low frequency of
retinoblastoma among childhood cancers in the general
population. In contrast, cancers other than retinoblastoma
were proportionate to those in the general population.
4 Journal of Oncology
2.5. Microsatellites and Ewing’s Sarcoma Risk. The mech-
anisms by which oncogenic ETS fusion proteins, which
are DNA-binding transcription factors, target genes nec-
essary for tumorigenesis are not well understood. Gang-
wal et al. analyzed promoters of these target genes and
GGAA-containing elements (microsatellites) . They also
the expression of target genes, and that the ability to do so
depends on the number of consecutive GGAA motifs. Gang-
wal et al. speculated that these microsatellite polymorphisms
may contribute to differences in individual and population
susceptibility to Ewing’s sarcoma, and that this may also
be true of other diseases mediated by ETS transcription
factors . Most recently, this same group combined
transcriptional analysis, whole genome localization data,
and RNA interference knockdown to identify glutathione S-
transferase M4 (GSTM4) as a critical EWS/FLI target gene
in Ewing’s sarcoma . They found that the recurrent
Ewing’s sarcoma translocation t(11;22) directly binds and
regulates GSTM4 expression through the same GGAA-
microsatellite described above. Higher GSTM4 expression
correlated with worse clinical outcome. Microsatellite sizes
differ between individuals, and so in addition to possible
genetic contribution to Ewing’s sarcoma susceptibility, there
may be inherited differences in Ewing’s sarcoma therapeutic
responses. Ewing’s sarcoma case-control studies analyzing
The epidemiological evidence supports a slight but possible
genetic contribution to the risk of developing Ewing’s
sarcoma. However, due to its rarity, many of these studies
lack statistical power to definitely prove or disprove a genetic
susceptibility to this sarcoma. There is no “smoking gun” to
suggest an underlying cancer predisposition in the majority
of cases of Ewing’s sarcoma. Large-scale studies investigating
the genetic epidemiology of Ewing’s sarcoma are sorely
needed to answer the question of genetic disease risk. This
will only be accomplished through group consortia and
Ewing’s sarcoma remains a deadly form of cancer in children
and young adults. Unique and specific molecular genetic
events define the pathogenesis of this tumor. It arises within
defined ethnic boundaries yet only sporadic consanguinity
has been reported. Because of its rarity, a remote familiality
may have evaded detection thus far. We believe that an in
depth investigation into the genetic epidemiology of Ewing’s
sarcoma is required to see if a predisposition gene or set
of genes might contribute to this deadly disease in some
subtle manner. This will only be accomplished through a
stringent analysis of existing Ewing’s sarcoma registries or
large population databases.
The second author is supported by the Teri Anna Perine
beam Foundation, Huntsman Cancer Institute/Huntsman
Cancer Foundation, and the American Cancer Society
(RSG0618801MGO). They also acknowledge NIH support
to the Huntsman Cancer Institute (P30 CA042014). The
seventh author is supported by the Harriet H. Samuelsson
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