High Prognostic Value of p16INK4 Alterations in Gastrointestinal Stromal Tumors

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Abstract
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 p16INK4 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 p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. Results: p16INK4 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. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P < .01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P = .02). There was a high predictive value for p16INK4 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 p16INK4 alterations, tumor size, mitotic index, and overall survival (P < .02), whereas multivariate Cox’s analysis confirmed only p16INK4 alterations as an independent prognostic factor. Conclusion: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.