源自肾上腺和肾上腺外副神经节的肿瘤中的端粒酶逆转录酶启动子突变
Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia.
作者信息
Papathomas Thomas G, Oudijk Lindsey, Zwarthoff Ellen C, Post Edward, Duijkers Floor A, van Noesel Max M, Hofland Leo J, Pollard Patrick J, Maher Eamonn R, Restuccia David F, Feelders Richard A, Franssen Gaston J H, Timmers Henri J, Sleijfer Stefan, de Herder Wouter W, de Krijger Ronald R, Dinjens Winand N M, Korpershoek Esther
机构信息
Department of PathologyJosephine Nefkens Institute, Erasmus MC, Rotterdam, The NetherlandsDepartment of Pediatric Oncology-HematologyErasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsSector of EndocrinologyDepartment of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsCancer Biology and Metabolism GroupInstitute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge, UKDepartment of SurgeryErasmus MC, Rotterdam, The NetherlandsDivision of EndocrinologyDepartment of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The NetherlandsDepartment of Medical OncologyErasmus MC, Rotterdam, The NetherlandsDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
Department of PathologyJosephine Nefkens Institute, Erasmus MC, Rotterdam, The NetherlandsDepartment of Pediatric Oncology-HematologyErasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsSector of EndocrinologyDepartment of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsCancer Biology and Metabolism GroupInstitute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge, UKDepartment of SurgeryErasmus MC, Rotterdam, The NetherlandsDivision of EndocrinologyDepartment of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The NetherlandsDepartment of Medical OncologyErasmus MC, Rotterdam, The NetherlandsDepartment of PathologyReinier de Graaf Hospital, Delft, The NetherlandsDepartment of PathologyJosephine Nefkens Institute, Erasmus MC, Rotterdam, The NetherlandsDepartment of Pediatric Oncology-HematologyErasmus MC-Sophia Children's Hospital, Rotterdam, The NetherlandsSector of EndocrinologyDepartment of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsCancer Biology and Metabolism GroupInstitute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UKDepartment of Medical GeneticsUniversity of Cambridge, Cambridge, UKDepartment of SurgeryErasmus MC, Rotterdam, The NetherlandsDivision of EndocrinologyDepartment of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The NetherlandsDepartment of Medical OncologyErasmus MC, Rotterdam, The NetherlandsDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
出版信息
Endocr Relat Cancer. 2014 Aug;21(4):653-61. doi: 10.1530/ERC-13-0429. Epub 2014 Jun 20.
Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.
最近有报道称，端粒酶逆转录酶（TERT）基因启动子中的热点突变存在于人类癌症中，并被认为是端粒酶激活的一种新机制。为了探究源自肾上腺和肾上腺外副神经节的肿瘤中的TERT启动子突变情况，我们选取了一组253个肿瘤（38例肾上腺皮质癌（ACC）、127例嗜铬细胞瘤（PCC）、18例肾上腺外副神经节瘤（ea PGL）、37例头颈部副神经节瘤（HN PGL）和33例外周神经母细胞瘤）以及16个人类神经母细胞瘤（NBL）和2个ACC细胞系，采用桑格测序法评估TERT启动子突变情况。所有检测到的突变均通过SNaPshot分析进行确认。此外，还纳入了36例胃肠道间质瘤（GIST），以探究TERT启动子突变与SDH缺陷之间的关联。在289个肿瘤中有7个以及18个人类细胞系中有3个检测到TERT启动子突变；38例ACC中有4个C228T突变（10.5%），18例ea PGL中有2个C228T突变（11.1%），36例GIST中有1个C250T突变（2.8%），16个人类NBL细胞系中有3个C228T突变（18.75%）。在PCC、HN PGL、神经母细胞瘤以及ACC细胞系中未检测到突变。TERT启动子突变优先发生在SDH缺陷的情况下（P = 0.01），47个SDH缺陷肿瘤中有3个（6.4%）存在突变，而171个SDH完整肿瘤中未检测到突变（0%）。我们得出结论，TERT启动子突变发生在ACC和ea PGL中。此外，初步证据表明SDH缺陷肿瘤中TERT启动子突变的获得可能存在潜在关联。
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