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
]. 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
]. 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
]. Since that time, other investigators have suggested myriad cells of origin, including hematologic [9
], mesenchymal/fibroblastic [10
], and neural crest derivatives [12
]. More recently, emerging evidence has suggested that Ewing's sarcoma arises from a mesenchymal stem or progenitor cell [14
]. 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
]. The remaining translocations are found in <5% each [19
]. These translocations fuse the EWSR1
gene on chromosome 22 with an ETS family member, most commonly the FLI1
gene on chromosome 11 [17
]. This Ewing's sarcoma-specific translocation generates an EWS/ETS fusion protein [17
]. 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 [23
]. 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
]. 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 p16INK4A
transcripts) occur in about 15% of cases [30
]. 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
]. Alterations in these pathways may be required to bypass a growth inhibitory effect mediated by the EWS/ETS fusion protein [36
]. 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
]. 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.