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High Prognostic Value of p16^INK4 Alterations in Gastrointestinal Stromal Tumors

Regine Schneider-Stock, Carsten Boltze, Jerzy Lasota, Markku Miettinen, Brigitte Peters, Matthias Pross, Albert Roessner, Thomas Günther

From the Department of Pathology, Department of Biometrics, Department of General Surgery, Otto-von-Guericke University, Magdeburg, Germany; and Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC.

Address reprint requests to Regine Schneider-Stock, PhD, Department of Pathology, Otto-von-Guericke University, Leipziger Str 44, 39120 Magdeburg, Germany; email: regine.schneider-stock{at}medizin.uni-magdeburg.de.

Purpose: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16^INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival.

Material and Methods: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16^INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16^INK4 protein in 43 GISTs in 39 patients.

Results: p16^INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16^INK4 alterations were correlated with a loss of p16^INK4 protein expression (P < .01). Patients who had tumors with p16^INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P = .02). There was a high predictive value for p16^INK4 alterations only in the group of benign and borderline GISTs (P < .01) with regard to clinical outcome. Univariate Cox’s proportional hazard regression analysis revealed a strong correlation between p16^INK4 alterations, tumor size, mitotic index, and overall survival (P < .02), whereas multivariate Cox’s analysis confirmed only p16^INK4 alterations as an independent prognostic factor.

Conclusion: We believe that the evaluation of p16^INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.

Supported in part by Mildred-Scheel Foundation grant no. 10-1501.

We thank Hiltraud Scharfenort and Antje Schinlauer for their expert technical assistance.

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