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 study 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 significance, the authors studied INK4A deletion in 41 ES samples from 39 patients.


METHODS
Using Southern blot analysis with an INK4A p16 cDNA probe, the intensity of the INK4A bands in ES DNA samples was normalized to that of a control probe and compared with nondeleted control DNA; > 50% signal reduction was scored as evidence of deletion. All ES tumor DNA samples previously were confirmed 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 survival in univariate analysis (P = 0.001) and in multivariate analysis including stage (relative risk = 6; P = 0.001).


CONCLUSIONS
INK4A deletions appear to be the most frequent secondary molecular genetic alteration found to date in ES. Their possible clinical usefulness in identifying a subset of ES patients with poor prognosis merits systematic prospective analysis. [See related article on pages 783-92.]
Wei
G
G
Department of Orthopaedic Surgery, People's Hospital, Beijing, China.
Antonescu
C R
CR
de Alava
E
E
Leung
D
D
Huvos
A G
AG
Meyers
P A
PA
Healey
J H
JH
Ladanyi
M
M
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001859:Bone Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002352:Carrier Proteins / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D006801:Humans; D008297:Male; D011379:Prognosis; D012512:Sarcoma, Ewing / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16