Abstract
Recently, the impact of telomere dysregulation on malignant progression has been reported in many cancers. A few studies have examined TERT promoter mutations in gastrointestinal stromal tumors (GISTs). Irregular telomerase activation can be maintained by TERT hot spot alterations and alternative lengthening of telomeres (ALT) characterized by inactivation of either the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain–associated protein (DAXX). To elucidate the clinicopathological impact of telomere dysregulation in GISTs, we examined 92 cases of GISTs for TERT promoter hot spot mutations along with immunohistochemical analysis of ATRX and DAXX expression, and compared these findings with the clinicopathological features. Univariate clinicopathological analysis revealed that tumor site, smaller tumor size, presence of necrosis, higher mitotic rate (>5/50 high-power fields) and risk classification were prognostic factors for either disease-free survival or overall survival. Two of 92 informative cases (2.2 %) were found to have heterozygous TERT promoter mutations (C228T), and these mutations occurred in a low-risk and a high-risk tumor, respectively. On immunohistochemical analysis for ATRX and DAXX, 16 (17.4 %) and 3 (3.3 %) of 92 cases showed loss of expression of ATRX and DAXX, respectively. Loss of expression of ATRX and DAXX were mutually exclusive except for one case. TERT promoter mutations were also mutually exclusive of the ALT phenotype. Telomere dysregulation was not associated with patient survival; however, telomere dysregulation was frequently observed in tumors of extra-gastric origin, which have an adverse outcome compared to those of gastric origin.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1606-2) contains supplementary material, which is available to authorized users.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract occurring in stomach (50–60 %), small intestine (30– 35 %), colon and rectum (5 %), esophagus (
Clinicopathological and survival analysis of telomere dysregulation Given that any cases with telomerase reverse transcriptase (TERT) promoter mutations or loss of either alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or DAXX expression were regarded as exhibiting telomere dysregulation, we examined the relationship between telomere dysregulation and clinicopathological features including age, sex, tumor size, tumor location, risk classification, presence of necrosis, and occurrence of metastasis or recurrence
The impact of telomere dysregulation on aggressive behavior has been reported in many malignancies (Shay and Bacchetti 1997; Horn et al 2013; Koelsche et al 2013; Landa et al 2013; Nault et al 2013; Fig. 2 TERT promoter mutations in gastrointestinal stromal tumors (GISTs)
Summary
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract occurring in stomach (50–60 %), small intestine (30– 35 %), colon and rectum (5 %), esophagus (
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