Prognostic impact of INK4A deletion in Ewing sarcoma

BACKGROUND. The primary genetic alteration in > 95% of Ewing sarcomas (ES) is a specific fusion of EWS with FLI1 or ERG. Secondary genetic alterations possibly involved in progression of ES are not well understood. A recent s tudy found loss of the negative cell cycle regulator gene INK4A in 8 of 27 ES samples (30%). To confirm these findings and evaluate their prognostic s ignificance, the authors studied INK4A deletion in 41 ES samples from 39 pa tients. METHODS. Using Southern blot analysis with an INK4A p16 cDNA probe, the int ensity of the INK4A bands in ES DNA samples was normalized to that of a con trol probe and compared with nondeleted control DNA; > 50% signal reduction was scored as evidence of deletion. All ES tumor DNA samples previously we re cofirmed to have EWS rearrangements on the same Southern blots, using a cDNA probe spanning the EWS breakpoint region. RESULTS. Tumors from 7 patients (18%) showed INK4A deletion independent of disease stage (localized or metastatic) or sample source (primary tumor or metastasis). INK4A was a strong negative factor for disease specific surviv al in univariate analysis (P = 0.001) and in multivariate analysis includin g stage (relative risk = 6; P = 0.001). CONCLUSIONS. INK4A deletions appear to be the most frequent secondary molec ular genetic alteration found to date in ES. Their possible clinical useful ness in identifying a subset of ES patients with poor prognosis merits syst ematic prospective analysis. [See related article on pages 783-92.] (C) 200 0 American Cancer Society.