Advances in Ewing's Sarcoma Research: Where Are We Now and What Lies Ahead?

Ordóñez, José Luis; Osuna, Daniel; Blanco‐Herrero, David; Álava, Enrique de; Madoz‐Gúrpide, Juan

doi:10.1158/0008-5472.can-08-4041

Cited by 110 publications

(112 citation statements)

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“…50 FUS and EWSR1 (along with TAF15, another member of the FET family) are rearranged with various transcription factor genes in sarcomas and more rarely in hematopoietic and epithelial cancers. 51 FUS can serve as an alternative to EWSR1 in other sarcomas (eg, FUS-ERG in Ewing sarcoma 51 and acute myeloid leukemia 52 and FUS-DDIT3 in myxoid liposarcoma), 53,54 and EWSR1 and FUS appear to serve as alternative 5 0 partners with the ATF1 gene. 47 EWSR1-CREB1 is the most frequently described gene fusion to date, having been described in more than 90% of cases, 43,44 although EWSR1-ATF1 appears to be more common in AFH occurring in extrasomatic soft tissue sites.…”

Section: Histopathologymentioning

confidence: 99%

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

Thway

Fisher

2015

Archives of Pathology &Amp; Laboratory Medicine

120

134

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Context.-Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the superficial extremities of children and young adults. While it has characteristic histologic features of nodular distributions of ovoid and spindle cells with blood-filled cystic cavities and a surrounding dense lymphoplasmacytic infiltrate, there is a significant morphologic spectrum, which coupled with its rarity and lack of specific immunoprofile can make diagnosis challenging. Angiomatoid fibrous histiocytoma is associated with 3 characteristic gene fusions, EWSR1-CREB1 and EWSR1-ATF1, which are also described in other neoplasms, and rarely FUS-ATF1. Angiomatoid fibrous histiocytoma is now recognized at an increasing number of sites and is known to display a variety of unusual histologic features.Objective.-To review the current status of AFH, discussing putative etiology, histopathology with variant morphology and differential diagnosis, and current genetics, including overlap with other tumors harboring EWSR1-CREB1 and EWSR1-ATF1 fusions.Data Sources.-Review of published literature, including case series, case reports, and review articles, in online medical databases.Conclusions.-The occurrence of AFH at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its small risk of metastasis and death. This highlights the importance of diagnostic recognition, ancillary molecular genetic confirmation, and close clinical follow-up of patients with AFH. Further insight into the genetic and epigenetic changes arising secondary to the characteristic gene fusions of AFH will be integral to understanding its tumorigenic mechanisms.

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Section: Histopathologymentioning

confidence: 99%

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

Thway

Fisher

2015

Archives of Pathology &Amp; Laboratory Medicine

120

134

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“…Although there is an extensive knowledge about EWS-ETS chimeric proteins (considered the initiating molecular event in the pathogenesis of the disease) (Ordon˜ez et al, 2009), few studies have evaluated the role of secondary genetic alterations in the oncogenesis and/or progression of ES. TP53 mutations and CDKN2A deletions are known to confer poor prognosis but are infrequent in this tumor entity (around 13% percent of cases) (Huang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma

et al. 2011

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Despite extensive characterization of the role of the EWS-ETS fusions, little is known about secondary genetic alterations and their clinical contribution to Ewing sarcoma (ES). It has been demonstrated that the molecular structure of EWS-ETS lacks prognostic value. Moreover, CDKN2A deletion and TP53 mutation, despite carrying a poor prognosis, are infrequent. In this scenario identifying secondary genetic alterations with a significant prevalence could contribute to understand the molecular mechanisms underlying the most aggressive forms of ES. We screened a 67 ES tumor set for copy number alterations by array comparative genomic hybridization. 1q gain (1qG), detected in 31% of tumor samples, was found markedly associated with relapse and poor overall and disease-free survival and demonstrated a prognostic value independent of classical clinical parameters. Reanalysis of an expression dataset belonging to an independent tumor set (n ¼ 37) not only validated this finding but also led us to identify a transcriptomic profile of severe cell cycle deregulation in 1qG ES tumors. Consistently, a higher proliferation rate was detected in this tumor subset by Ki-67 immunohistochemistry. CDT2, a 1q-located candidate gene encoding a protein involved in ubiquitin ligase activity and significantly overexpressed in 1qG ES tumors, was validated in vitro and in vivo proving its major contribution to this molecular and clinical phenotype. This integrative genomic study of 105 ES tumors in overall renders the potential value of 1qG and CDT2 overexpression as prognostic biomarkers and also affords a rationale for the application of already available new therapeutic compounds selectively targeting the protein-ubiquitin machinery.

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“…Молекулярные маркеры неопласти-ческого процесса на сегодняшний день рассма-триваются в качестве как прогностических факто-ров, так и объектов целевой (таргетной) терапии. Ангиогенез -процесс формирования опухолью собственной сосудистой сети -является абсолют-ным условием развития и распространения ново-образования [9,10]. Ранее мы установили [11] Целью настоящего исследования была интенси-фикация лечения пациентов с прогнозируемым на основании уровня маркеров ангиогенеза неблаго-приятным исходом заболевания посредством бло-кады ангиогенеза.…”

Section: обоснованиеunclassified