Journal of Oncology

Journal of Oncology / 2010 / Article

Review Article | Open Access

Volume 2010 |Article ID 397632 |

R. L. Randall, S. L. Lessnick, K. B. Jones, L. G. Gouw, J. E. Cummings, L. Cannon-Albright, J. D. Schiffman, "Is There a Predisposition Gene for Ewing's Sarcoma?", Journal of Oncology, vol. 2010, Article ID 397632, 6 pages, 2010.

Is There a Predisposition Gene for Ewing's Sarcoma?

Academic Editor: Frederic G. Barr
Received25 Aug 2009
Revised14 Dec 2009
Accepted08 Feb 2010
Published15 Mar 2010


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 sarcoma has been reported as a 2nd malignancy after retinoblastoma, significant associations of Ewing's sarcoma with classic tumor 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.

1. Introduction

The analysis of cancer predisposition syndromes has been an important approach towards the identification of oncogenes 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 [1]. 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 primarily at risk for Wilms tumor [2, 3]. The identification of 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 [6], the cell of origin of Ewing’s sarcoma remains unknown. James Ewing himself initially described this disease as an endothelioma of bone, and later suggested that it arises from perivascular lymphatic endothelium [7, 8]. Since that time, other investigators have suggested myriad cells of origin, including hematologic [9], 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 [1416]. 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 known, the molecular genetics of the tumor are better understood. 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, 1921]. This Ewing’s sarcoma-specific translocation generates an EWS/ETS fusion protein [17, 1921]. The Ewing’s sarcoma fusion proteins contain a strong transcriptional activation domain fused to an ETS type DNA binding domain and thus function as aberrant transcription factors that dysregulate target genes contributing to oncogenic transformation [22]. A number of genes that are dysregulated by EWS/FLI have been identified, and their roles in the oncogenic process are under active investigation [2329]. 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 [3033]. 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 p and p 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 [3842]. Ewing’s sarcoma does not appear to be a component of other tumor susceptibility syndromes, either.

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 [43], 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 [38].

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 percent of the African population [44].It is hypothesized that (Alu elements are preferential sites for genetic recombinations in cancer [45]. Beyond the observation of different rates by ethnicity, Ewing’s sarcoma is considered to be nonfamilial, with no genetic lineage predisposition.

2. Search Strategy and Selection 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 described below.

2.1. Ewing’s Sarcoma and Related 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 [46]. 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 these tumor types harbor the identical t(11;22) translocation. Because of the consistent genetic lesion, we will continue to refer to this entire group as Ewing’s sarcoma.

There are currently no known cancer syndromes of which 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, ninety 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 also do less well than females. The pelvis is the most common location, followed by the femur, tibia, humerus, and scapula. However, Ewing’s sarcoma can be found in any part in the body.

Several reports have highlighted the general association of Ewing’s sarcoma and parental exposure to pesticides, solvents, and farming or agricultural occupation [4751]. Hernia, both inguinal and umbilical have also been linked to Ewing’s sarcoma [47, 48, 52, 53]. Valery et al. [53] surmised that Ewing’s sarcoma and hernia have common embryologic neuroectodermal pathways. Interestingly, these cases arose in farming families perhaps suggesting some unknown environmental influence the link of the two entities [53]. At least one report discounts this association [54]. In a case-control study, Winn et al. [54] 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 [5561].

The ethnic epidemiology of Ewing’s Sarcoma is fascinating as it uniquely follows racial boundaries, similar to Wilms’ tumor. Ewing’s Sarcoma has a strong predilection for Caucasians, being far more common than in Asians and those of African descent [44, 6265]. 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 [44]. Alu elements are a type of SINE, or Short INterspersed Element, and are approximately 300 bp 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 [45]. Perhaps in families with Ewing’s sarcoma probands that develop remote Ewing’s sarcoma in their descendents, increased genomic predominance of Alu elements leads to subsequent rechimerization of EWS/FLI and related translocations. Large-scale studies on 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 [66].The previous studies had explored the association between advanced maternal and paternal age with congenital syndromes (including several which predispose to cancer) [67] and a handful of other reports had provided preliminary support of an association between older parental age and an increased risk of some childhood cancers [68, 69]. Johnson et al. [66] 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, birth year, and state. Johnson et al. report that older maternal 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 [66]. 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 [70], some as early as 1952 [71]. Reporting on the Mayo clinic experience with Ewing’s, McCormack et al. [71] noted that 9 of 80 patients (11%) were 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. [72]. 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 [73]. Hutter et al. [73] 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. [74] 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 contributions also cannot be ruled out. It is also interesting to note that these isolated siblings with familial Ewing’s sarcoma 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. [42] 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. [40], via meta-analysis, found that while Ewing’s has been reported after a number of different malignancies. 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.

2.5. Microsatellites and Ewing’s Sarcoma Risk

The mechanisms by which oncogenic ETS fusion proteins, which are DNA-binding transcription factors, target genes necessary for tumorigenesis are not well understood. Gangwal et al. analyzed promoters of these target genes and described a significant overrepresentation of highly repetitive GGAA-containing elements (microsatellites) [77]. They also reported that EWS/FLI uses GGAA microsatellites to regulate the expression of target genes, and that the ability to do so depends on the number of consecutive GGAA motifs. Gangwal 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 [78]. 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 [25]. 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 microsatellite size and frequency are now required to support these findings.

3. Future Investigation

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 multi-institutional collaborations.

4. Conclusion

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 Sarcoma Fund, the Liddy Shriver Sarcoma Initiative, the Sunbeam 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 Foundation and the St. Baldrick’s Foundation.


  1. D. Malkin, F. P. Li, L. C. Strong et al., “Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms,” Science, vol. 250, no. 4985, pp. 1233–1238, 1990. View at: Google Scholar
  2. A. Drash, F. Sherman, W. H. Hartmann, and R. M. Blizzard, “A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease,” The Journal of Pediatrics, vol. 76, no. 4, pp. 585–593, 1970. View at: Google Scholar
  3. R. W. Miller, J. F. Fraumeni Jr., and M. D. Manning, “Association of Wilms's tumor with aniridia, hemihypertrophy and other congenital malformations,” The New England Journal of Medicine, vol. 270, pp. 922–927, 1964. View at: Google Scholar
  4. L. Granowetter, R. Womer, M. Devidas et al., “Dose-intensified compared with standard chemotherapy for nonmetastatic ewing sarcoma family of tumors: a children's oncology group study,” Journal of Clinical Oncology, vol. 27, no. 15, pp. 2536–2541, 2009. View at: Publisher Site | Google Scholar
  5. H. E. Grier, M. D. Krailo, N. J. Tarbell et al., “Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone,” The New England Journal of Medicine, vol. 348, no. 8, pp. 694–701, 2003. View at: Publisher Site | Google Scholar
  6. C. R. Walkley, R. Qudsi, V. G. Sankaran et al., “Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease,” Genes and Development, vol. 22, no. 12, pp. 1662–1676, 2008. View at: Publisher Site | Google Scholar
  7. J. Ewing, “Diffuse endothelioma of bone,” Proceedings of the New York Pathological Society, vol. 21, pp. 17–24, 1921. View at: Google Scholar
  8. J. Ewing, “Further report on endothelial myeloma of bone,” Proceedings of the New York Pathological Society, vol. 24, pp. 93–101, 1924. View at: Google Scholar
  9. M. E. Kadin and K. G. Bensch, “On the origin of Ewing's tumor,” Cancer, vol. 27, no. 2, pp. 257–273, 1971. View at: Google Scholar
  10. P. S. Dickman, L. A. Liotta, and T. J. Triche, “Ewing's sarcoma. Characterization in established cultures and evidence of its histogenesis,” Laboratory Investigation, vol. 47, no. 4, pp. 375–382, 1982. View at: Google Scholar
  11. J. J. Navas-Palacios, R. Aparicio-Duque, and M. D. Valdes, “On the histogenesis of Ewing's sarcoma. An ultrastructural, immunohistochemical, and cytochemical study,” Cancer, vol. 53, no. 9, pp. 1882–1901, 1984. View at: Google Scholar
  12. M. Lipinski, K. Braham, and I. Philip, “Neuroectoderm-associated antigens on Ewing's sarcoma cell lines,” Cancer Research, vol. 47, no. 1, pp. 183–187, 1987. View at: Google Scholar
  13. A. O. Cavazzana, J. S. Miser, J. Jefferson, and T. J. Triche, “Experimental evidence for a neural origin of Ewing's sarcoma of bone,” American Journal of Pathology, vol. 127, no. 3, pp. 507–518, 1987. View at: Google Scholar
  14. N. Riggi, L. Cironi, P. Provero et al., “Development of Ewing's sarcoma from primary bone marrow-derived mesenchymal progenitor cells,” Cancer Research, vol. 65, no. 24, pp. 11459–11468, 2005. View at: Publisher Site | Google Scholar
  15. N. Riggi, M.-L. Suva, D. Suva et al., “EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells,” Cancer Research, vol. 68, no. 7, pp. 2176–2185, 2008. View at: Publisher Site | Google Scholar
  16. F. Tirode, K. Laud-Duval, A. Prieur, B. Delorme, P. Charbord, and O. Delattre, “Mesenchymal stem cell features of Ewing tumors,” Cancer Cell, vol. 11, no. 5, pp. 421–429, 2007. View at: Publisher Site | Google Scholar
  17. P. H. B. Sorensen, S. L. Lessnick, D. Lopez-Terrada, X. F. Liu, T. J. Triche, and C. T. Denny, “A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG,” Nature Genetics, vol. 6, no. 2, pp. 146–151, 1994. View at: Publisher Site | Google Scholar
  18. C. Turc-Carel, A. Aurias, F. Mugneret et al., “Chromosomes in Ewing's sarcoma. I. An evaluation of 85 cases and remarkable consistency of t(11;22)(q24;q12),” Cancer Genetics and Cytogenetics, vol. 32, no. 2, pp. 229–238, 1988. View at: Google Scholar
  19. I.-S. Jeon, J. N. Davis, B. S. Braun et al., “A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1,” Oncogene, vol. 10, no. 6, pp. 1229–1234, 1995. View at: Google Scholar
  20. M. Peter, J. Couturier, H. Pacquement et al., “A new member of the ETS family fused to EWS in Ewing tumors,” Oncogene, vol. 14, no. 10, pp. 1159–1164, 1997. View at: Google Scholar
  21. O. Delattre, J. Zucman, B. Plougastel et al., “Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours,” Nature, vol. 359, no. 6391, pp. 162–165, 1992. View at: Publisher Site | Google Scholar
  22. S. L. Lessnick, B. S. Braun, C. T. Denny, and W. A. May, “Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene,” Oncogene, vol. 10, no. 3, pp. 423–431, 1995. View at: Google Scholar
  23. B. S. Braun, R. Frieden, S. L. Lessnick, W. A. May, and C. T. Denny, “Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis,” Molecular and Cellular Biology, vol. 15, no. 8, pp. 4623–4630, 1995. View at: Google Scholar
  24. M. Kinsey, R. Smith, and S. L. Lessnick, “NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's sarcoma,” Molecular Cancer Research, vol. 4, no. 11, pp. 851–859, 2006. View at: Publisher Site | Google Scholar
  25. W. Luo, K. Gangwal, S. Sankar, K. M. Boucher, D. Thomas, and S. L. Lessnick, “GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance,” Oncogene, vol. 28, no. 46, pp. 4126–4132, 2009. View at: Publisher Site | Google Scholar
  26. L. A. Owen and S. L. Lessnick, “Identification of target genes in their native cellular context: an analysis of EWS/FLI in Ewing's sarcoma,” Cell Cycle, vol. 5, no. 18, pp. 2049–2053, 2006. View at: Google Scholar
  27. G. Potikyan, R. O. V. Savene, J. M. Gaulden et al., “EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins,” Cancer Research, vol. 67, no. 14, pp. 6675–6684, 2007. View at: Publisher Site | Google Scholar
  28. R. Smith, L. A. Owen, D. J. Trem et al., “Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma,” Cancer Cell, vol. 9, no. 5, pp. 405–416, 2006. View at: Publisher Site | Google Scholar
  29. J. P. Zwerner and W. A. May, “PDGC-C is an EWS/FLI induced transforming growth factor in Ewing family tumors,” Oncogene, vol. 20, no. 5, pp. 626–633, 2001. View at: Publisher Site | Google Scholar
  30. H.-Y. Huang, P. B. Illei, Z. Zhao et al., “Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse,” Journal of Clinical Oncology, vol. 23, no. 3, pp. 548–558, 2005. View at: Publisher Site | Google Scholar
  31. H. Komuro, Y. Hayashi, M. Kawamura et al., “Mutations of the p53 gene are involved in Ewing's sarcomas but not in neuroblastomas,” Cancer Research, vol. 53, no. 21, pp. 5284–5288, 1993. View at: Google Scholar
  32. A. Patino-Garcia and L. Sierrasesumaga, “Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients,” Cancer Genetics and Cytogenetics, vol. 98, no. 1, pp. 50–55, 1997. View at: Publisher Site | Google Scholar
  33. T. Tsuchiya, K. Sekine, S. Hinohara, T. Namiki, T. Nobori, and Y. Kaneko, “Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma,” Cancer Genetics and Cytogenetics, vol. 120, no. 2, pp. 91–98, 2000. View at: Publisher Site | Google Scholar
  34. M. Ladanyi, R. Lewis, S. C. Jhanwar, W. Gerald, A. G. Huvos, and J. H. Healey, “MDM2 and CDK4 gene amplification in Ewing's sarcoma,” Journal of Pathology, vol. 175, no. 2, pp. 211–217, 1995. View at: Publisher Site | Google Scholar
  35. G. Wei, C. R. Antonescu, E. De Alava et al., “Prognostic impact of INK4A deletion in Ewing sarcoma,” Cancer, vol. 89, no. 4, pp. 793–799, 2000. View at: Publisher Site | Google Scholar
  36. B. Deneen and C. T. Denny, “Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation,” Oncogene, vol. 20, no. 46, pp. 6731–6741, 2001. View at: Publisher Site | Google Scholar
  37. S. L. Lessnick, C. S. Dacwag, and T. R. Golub, “The Ewing's sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts,” Cancer Cell, vol. 1, no. 4, pp. 393–401, 2002. View at: Publisher Site | Google Scholar
  38. L. A. G. Ries, M. P. Eisner, and C. L. Kosary, Eds., SEER Cancer Statistics Review, 1973–1998, National Cancer Institute, Bethesda, Md, USA, 2001.
  39. H. M. Ceha, A. J. Balm, D. de Jong et al., “Multiple malignancies in a patient with bilateral retinoblastoma,” Journal of Laryngology and Otology, vol. 112, no. 2, pp. 189–192, 1998. View at: Google Scholar
  40. J. U. Cope, M. Tsokos, and R. W. Miller, “Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms,” Medical and Pediatric Oncology, vol. 36, no. 2, pp. 290–294, 2001. View at: Publisher Site | Google Scholar
  41. B. G. Mohney, D. M. Robertson, P. J. Schomberg, and D. O. Hodge, “Second nonocular tumors in survivors of heritable retinoblastoma and prior radiation therapy,” American Journal of Ophthalmology, vol. 126, no. 2, pp. 269–277, 1998. View at: Publisher Site | Google Scholar
  42. S. L. Spunt, C. Rodriguez-Galindo, C. E. Fuller et al., “Ewing sarcoma-family tumors that arise after treatment of primary childhood cancer,” Cancer, vol. 107, no. 1, pp. 201–206, 2006. View at: Publisher Site | Google Scholar
  43. J. G. Gurney, A. R. Swensen, and M. Bultreys, “Malignant bone tumors,” in Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975–1995, L. A. G. Ries, M. A. Smith, J. G. Gurney et al., Eds., pp. 99–110, National Institutes of Health, Bethesda, Md, USA, 1999. View at: Google Scholar
  44. J. Zucman-Rossi, M. A. Batzer, M. Stoneking, O. Delattre, and G. Thomas, “Interethnic polymorphism of EWS intron 6: genome plasticity mediated by Alu retroposition and recombination,” Human Genetics, vol. 99, no. 3, pp. 357–363, 1997. View at: Publisher Site | Google Scholar
  45. E. Kolomietz, M. S. Meyn, A. Pandita, and J. A. Squire, “The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors,” Genes Chromosomes and Cancer, vol. 35, no. 2, pp. 97–112, 2002. View at: Publisher Site | Google Scholar
  46. J. Whang-Peng, T. J. Triche, T. Knutsen et al., “Chromosome translocation in peripheral neuroepithelioma,” The New England Journal of Medicine, vol. 311, no. 9, pp. 584–585, 1984. View at: Google Scholar
  47. I. T. J. Ferris, O. Berbel Tornero, J. A. Ortega Garcia et al., “Risk factors for pediatric malignant bone tumors,” Anales de Pediatria, vol. 63, no. 6, pp. 537–547, 2005. View at: Google Scholar
  48. E. A. Holly, D. A. Aston, D. K. Ahn, and J. J. Kristiansen, “Ewing's bone sarcoma, paternal occupational exposure, and other factors,” American Journal of Epidemiology, vol. 135, no. 2, pp. 122–129, 1992. View at: Google Scholar
  49. P. C. Valery, W. McWhirter, A. Sleigh, G. Williams, and C. Bain, “Farm exposures, parental occupation, and risk of Ewing's sarcoma in Australia: a national case-control study,” Cancer Causes and Control, vol. 13, no. 3, pp. 263–270, 2002. View at: Publisher Site | Google Scholar
  50. P. C. Valery, W. McWhirter, A. Sleigh, G. Williams, and C. Bain, “A national case-control study of Ewing's sarcoma family of tumours in Australia,” International Journal of Cancer, vol. 105, no. 6, pp. 825–830, 2003. View at: Publisher Site | Google Scholar
  51. P. C. Valery, G. Williams, A. C. Sleigh, E. A. Holly, N. Kreiger, and C. Bain, “Parental occupation and Ewing's sarcoma: pooled and meta-analysis,” International Journal of Cancer, vol. 115, no. 5, pp. 799–806, 2005. View at: Publisher Site | Google Scholar
  52. L. Hum, N. Kreiger, and M. M. Finkelstein, “The relationship between parental occupation and bone cancer risk in offspring,” International Journal of Epidemiology, vol. 27, no. 5, pp. 766–771, 1998. View at: Publisher Site | Google Scholar
  53. P. C. Valery, E. A. Holly, A. C. Sleigh, G. Williams, N. Kreiger, and C. Bain, “Hernias and Ewing's sarcoma family of tumours: a pooled analysis and meta-analysis,” Lancet Oncology, vol. 6, no. 7, pp. 485–490, 2005. View at: Publisher Site | Google Scholar
  54. D. M. Winn, F. P. Li, L. L. Robison, J. J. Mulvihill, A. E. Daigle, and J. F. Fraumeni Jr., “A case-control study of the etiology of Ewing's sarcoma,” Cancer Epidemiology Biomarkers and Prevention, vol. 1, no. 7, pp. 525–532, 1992. View at: Google Scholar
  55. G. Bacci, S. Ferrari, P. Rosito et al., “Ewing's sarcoma of the bone. Anatomoclinical study of 424 cases,” Minerva Pediatrica, vol. 44, no. 7-8, pp. 345–359, 1992. View at: Google Scholar
  56. J. D. Buckley, T. W. Pendergrass, C. M. Buckley et al., “Epidemiology of osteosarcoma and Ewing's sarcoma in childhood: a study of 305 cases by the children's cancer group,” Cancer, vol. 83, no. 7, pp. 1440–1448, 1998. View at: Publisher Site | Google Scholar
  57. S. J. Cotterill, C. M. Wright, M. S. Pearce, and A. W. Craft, “Stature of young people with malignant bone tumors,” Pediatric Blood and Cancer, vol. 42, no. 1, pp. 59–63, 2004. View at: Google Scholar
  58. J. F. Fraumeni Jr., “Stature and malignant tumors of bone in childhood and adolescence,” Cancer, vol. 20, no. 6, pp. 967–973, 1967. View at: Google Scholar
  59. D. B. Glasser, K. Duane, J. M. Lane, J. H. Healey, and B. Caparros-Sison, “The effect of chemotherapy on growth in the skeletally immature individual,” Clinical Orthopaedics and Related Research, no. 262, pp. 93–100, 1991. View at: Google Scholar
  60. E. A. Operskalski, S. Preston-Martin, B. E. Henderson, and B. R. Visscher, “A case-control study of osteosarcoma in young persons,” American Journal of Epidemiology, vol. 126, no. 1, pp. 118–126, 1987. View at: Google Scholar
  61. C.-H. Pui, R. K. Dodge, S. L. George, and A. A. Green, “Height at diagnosis of malignancies,” Archives of Disease in Childhood, vol. 62, no. 5, pp. 495–499, 1987. View at: Google Scholar
  62. W. Guo, W. Xu, A. G. Huvos, J. H. Healey, and C. Feng, “Comparative frequency of bone sarcomas among different racial groups,” Chinese Medical Journal, vol. 112, no. 12, pp. 1101–1104, 1999. View at: Google Scholar
  63. E. G. Olisa, R. Chandra, and M. A. Jackson, “Malignant tumors in American black and Nigerian children: a comparative study,” Journal of the National Cancer Institute, vol. 55, no. 2, pp. 281–284, 1975. View at: Google Scholar
  64. T. Ozaki, K.-L. Schaefer, D. Wai et al., “Population-based genetic alterations in Ewing's tumors from Japanese and European Caucasian patients,” Annals of Oncology, vol. 13, no. 10, pp. 1656–1664, 2002. View at: Publisher Site | Google Scholar
  65. A. P. Polednak, “Primary bone cancer incidence in black and white residents of New York State,” Cancer, vol. 55, no. 12, pp. 2883–2888, 1985. View at: Google Scholar
  66. K. J. Johnson, S. E. Carozza, E. J. Chow et al., “Parental age and risk of childhood cancer,” Epidemiology, vol. 20, no. 4, pp. 475–483, 2009. View at: Publisher Site | Google Scholar
  67. J. F. Crow, “The origins, patterns and implications of human spontaneous mutation,” Nature Reviews Genetics, vol. 1, no. 1, pp. 40–47, 2000. View at: Google Scholar
  68. J. D. Dockerty, G. Draper, T. Vincent, S. D. Rowan, and K. J. Bunch, “Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers,” International Journal of Epidemiology, vol. 30, no. 6, pp. 1428–1437, 2001. View at: Google Scholar
  69. B. H. Yip, Y. Pawitan, and K. Czene, “Parental age and risk of childhood cancers: a population-based cohort study from Sweden,” International Journal of Epidemiology, vol. 35, no. 6, pp. 1495–1503, 2006. View at: Publisher Site | Google Scholar
  70. J. Ji and K. Hemminki, “Familial risk for histology-specific bone cancers: an updated study in Sweden,” European Journal of Cancer, vol. 42, no. 14, pp. 2343–2349, 2006. View at: Publisher Site | Google Scholar
  71. C. L. McCormack, M. B. Dockerty, and R. K. Ghormley, “Ewing's sarcoma,” Cancer, vol. 5, no. 1, pp. 85–99, 1952. View at: Google Scholar
  72. R. W. Huntington, D. J. Sheffel, M. Iger, and C. Henkelmann, “Malignant bone tumors in siblings: Ewing's tumor and an unusual tumor perhaps a variant of Ewing's tumor,” The Journal of Bone and Joint Surgery, vol. 42, pp. 1065–1075, 1960. View at: Google Scholar
  73. R. V. P. Hutter, K. C. Francis, and F. W. Foote Jr., “Ewing's sarcoma in siblings. Report of the second known occurrence,” The American Journal of Surgery, vol. 107, no. 4, pp. 598–603, 1964. View at: Google Scholar
  74. M. J. Joyce, D. C. Harmon, H. J. Mankin et al., “Ewing's sarcoma in female siblings. A clinical report and review of the literature,” Cancer, vol. 53, no. 9, pp. 1959–1962, 1984. View at: Google Scholar
  75. K. J. Helton, B. D. Fletcher, L. E. Kun, J. J. Jenkins III, and C. B. Pratt, “Bone tumors other than osteosarcoma after retinoblastoma,” Cancer, vol. 71, no. 9, pp. 2847–2853, 1993. View at: Google Scholar
  76. R. Mittal, S. Al Awadi, O. Sahar, and A. M. Behbehani, “Ewing's sarcoma as second malignant neoplasm after retinoblastoma: a case report,” Medical Principles and Practice, vol. 17, no. 1, pp. 84–85, 2008. View at: Publisher Site | Google Scholar
  77. K. Gangwal, S. Sankar, P. C. Hollenhorst et al., “Microsatellites as EWS/FLI response elements in Ewing's sarcoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 29, pp. 10149–10154, 2008. View at: Publisher Site | Google Scholar
  78. K. Gangwal and S. L. Lessnicke, “Microsatellites are EWS/FLI response elements: genomic “junk” is EWS/FLI's treasure,” Cell Cycle, vol. 7, no. 20, pp. 3127–3132, 2008. View at: Google Scholar

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