P53 mutations in gastrointestinal stromal tumor: Pattern and prognostic significance

Abstract

9026 Background: Mutational activation of c-kit gene is recognized as a relatively early event in GIST tumorigenesis, and additional genetic alteration is needed for malignant transformation of GIST. The objective of this study was to evaluate the pattern and prognostic significance of p53 mutation as an additional genetic change. Methods: Previously, we analyzed c-kit mutations and clinical characteristics of 86 localized GISTs which were curatively resected between Jan 1990 and Dec 2001, and observed that presence of c-kit mutation and mitosis ≥ 5/50 HPF were independent poor prognostic factors for relapse-free survival (Kim, et al. Proc ECCO 2003). For these cases, clinical data were updated, and mutation analyses for p53 exons 4, 5, 6, 7, and 8 were performed with PCR and direct sequencing. Results: In 64 cases, p53 mutations were fully analyzed at exons 4, 5, 6, 7, and 8. Polymorphism at exon 4 was observed in 27 cases. P53 mutations were found in 19 (29.7%) cases; 4 in exon 4, 3 in exon 5, 6 in exon 6, 2 in exon 7, and 4 in exon 8, respectively. All were missense mutations in a single amino acid. Fifteen (31.3%) out of 48 patients with c-kit mutation and 4 (25.0%) out of 16 patients without c-kit mutation had p53 mutation (p = 0.785). By univariate analyses for relapse-free survival, mitosis (< 5/50 HPF vs. ≥ 5/50 HPF), tumor size (< 5cm vs. ≥ 5cm), c-kit mutation (presence vs. absence), cell type (spindle cell vs. others), necrosis (presence vs. absence), and cellularity (dense vs. sparse) were statistically significant factors. Multivariate analysis including p53 mutation (presence vs. absence) and above factors showed that mitosis ≥ 5/50 HPF (p = 0.0001), presence of c-kit mutation (p =0.02), presence of p53 mutation (p = 0.002) were significant independent poor prognostic factors for relapse-free survival. Conclusions: P53 mutation was found in a proportion of GISTs, and evenly distributed from exon 4 to exon 8 without any specific hot spots. P53 mutation was identified as an independent poor prognostic factor for relapse in addition to c-kit mutation and high mitosis in localized GISTs. P53 mutation may have a role in the malignant transformation of GISTs. No significant financial relationships to disclose.