Ewing Tumors That Do Not Overexpress BMI-1 Are a Distinct Molecular Subclass with Variant Biology: A Report from the Children's Oncology Group

• Published in: Clinical cancer research 2011, Vol.17 (1), p.56-66
• Main Authors: COOPER, Aaron, VAN DOORNINCK, John, TRICHE, Timothy J, SPOSTO, Richard, LAWLOR, Elizabeth R, LINGYUN JI, RUSSELL, Darren, LADANYI, Marc, SHIMADA, Hiroyuki, KRAILO, Mark, WOMER, Richard B, HSU, Jessie Hao-Ru, THOMAS, Dafydd
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Child; Child, Preschool; Diseases of the osteoarticular system; Female; Gene Expression Regulation, Neoplastic; Humans; Infant; Infant, Newborn; Male; Medical sciences; Middle Aged; Nuclear Proteins - genetics; Pharmacology. Drug treatments; Phenotype; Polycomb Repressive Complex 1; Prognosis; Proto-Oncogene Proteins - genetics; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Repressor Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sarcoma, Ewing - classification; Sarcoma, Ewing - diagnosis; Sarcoma, Ewing - genetics; Tumors of striated muscle and skeleton; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-1417

Ewing sarcoma family tumors (ESFT) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. In several human cancers, high expression of the polycomb protein BMI-1 is associated with poor outcome. We have assessed the potential clinical significance of BMI-1 expression level in ESFT. BMI-1 expression was assessed in 130 tumors by immunostaining and associations with clinical features and outcome determined. The molecular signatures of BMI-1-low and BMI-1-high tumors were compared using microarrays and differentially activated canonical pathways identified by gene-specific enrichment analysis. Automated quantitative analysis of phosphoproteins was used to assess relative levels of pathway activation. Sensitivity to IGF1-R inhibition was determined using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays. BMI-1 is overexpressed by the vast majority of ESFTs. However, in 20% of cases, BMI-1 levels are low to undetectable. Significantly, although clinical presentation and outcome were similar between BMI-1-high and BMI-1-low tumors, whole genome expression array analysis showed marked differences in their respective gene expression profiles. Gene-specific enrichment analysis identified that several cancer-associated canonical biological pathways, including IGF1, mTOR, and WNT, are significantly downregulated in BMI-1-low compared with BMI-1-high tumors. Consistent with these in vivo data, the response to IGF1-R inhibition in vitro was diminished in BMI-1-low compared with BMI-1-high ESFT cells. ESFT that do not overexpress BMI-1 represent a novel subclass with a distinct molecular profile and altered activation of and dependence on cancer-associated biological pathways.