title: TERT promoter mutations are a rare event in gastrointestinal stromal tumors.
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.
authors.affiliation: Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan ; Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Akaike
authors.affiliation: Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan ; Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Toda-Ishii
authors.affiliation: Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suehara
authors.affiliation: Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan ; Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Mukaihara
authors.affiliation: Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kubota
authors.affiliation: Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Mitani
authors.affiliation: Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takagi
authors.affiliation: Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.affiliation: Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
keywords: ATRX; DAXX; Gastrointestinal stromal tumor; TERT promoter; Telomere dysregulation