Koelsche Christian, Renner Marcus, Hartmann Wolfgang, Brandt Regine, Lehner Burkhard, Waldburger Nina, Alldinger Ingo, Schmitt Thomas, Egerer Gerlinde, Penzel Roland, Wardelmann Eva, Schirmacher Peter, von Deimling Andreas, Mechtersheimer Gunhild
Department of General Pathology, Institute of Pathology, University Hospital, Im Neuenheimer Feld 224, Heidelberg D-69120, Germany.
J Exp Clin Cancer Res. 2014 Apr 11;33(1):33. doi: 10.1186/1756-9966-33-33.
Recently, recurrent point mutations in the telomerase reverse transcriptase (TERT) promoter region have been found in many human cancers, leading to a new transcription factor binding site, increased induction of TERT and subsequently to telomere maintenance. We determined the prevalence of TERT promoter mutations in soft tissue sarcomas of 341 patients comprising 16 entities and in 16 sarcoma cell lines covering 7 different soft tissue sarcoma types.
The sarcoma tissue samples were collected from the archives of the Institute of Pathology, University of Heidelberg and were composed of 39 myxoid liposarcomas (MLS), 61 dedifferentiated liposarcomas, 15 pleomorphic liposarcomas, 27 leiomyosarcomas, 25 synovial sarcomas (SS), 35 malignant peripheral nerve sheath tumors (MPNST), 40 undifferentiated pleomorphic sarcomas, 17 myxofibrosarcomas, 9 low grade fibromyxoid sarcomas, 10 cases of dermatofibrosarcoma protuberans, 31 solitary fibrous tumors (SFT), 8 extraskeletal myxoid chondrosarcomas, 9 angiosarcomas, 6 alveolar soft part sarcomas, 5 clear cell sarcomas and 4 epithelioid sarcomas. Sarcoma cell lines were obtained from the raising laboratories. A 193 bp fragment of the TERT promoter region covering the hot-spot mutations C228T and C250T was amplified, and direct sequencing of the PCR products was performed.
TERT promoter mutations were detected in 36/341 sarcomas. They were highly recurrent in MLS (29/39; 74%) and were in the present MLS series not associated with the phenotype (myxoid vs. round cell variant), tumor grade, tumor site and patients' median age or gender. In the remaining cases, TERT promoter mutations were found only in 7/302 sarcoma samples and confined to SFTs (4/31; 13%), MPNSTs (2/35; 6%), and SSs (1/25; 4%). Within the collection of sarcoma cell lines examined, TERT promoter mutations were detected in two MLS and in one of three MPNST cell lines.
TERT promoter mutations are frequent in MLSs including their round cell variants, representing the most prevalent mutation identified in this sarcoma entity to date, and in a minor fraction of SFTs, MPNSTs and SSs. The majority of sarcomas are devoid of TERT promoter hotspot mutations. These data suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis especially of MLS.
最近，在许多人类癌症中发现了端粒酶逆转录酶（TERT）启动子区域的复发性点突变，导致新的转录因子结合位点，TERT诱导增加并随后维持端粒。我们确定了341例包括16种实体的软组织肉瘤患者以及16种覆盖7种不同软组织肉瘤类型的肉瘤细胞系中TERT启动子突变的发生率。
肉瘤组织样本取自海德堡大学病理学研究所的档案，包括39例黏液样脂肪肉瘤（MLS）、61例去分化脂肪肉瘤、15例多形性脂肪肉瘤、27例平滑肌肉瘤、25例滑膜肉瘤（SS）、35例恶性外周神经鞘瘤（MPNST）、40例未分化多形性肉瘤、17例黏液纤维肉瘤、9例低级别纤维黏液样肉瘤、10例隆突性皮肤纤维肉瘤、31例孤立性纤维性肿瘤（SFT）、8例骨外黏液样软骨肉瘤、9例血管肉瘤、6例肺泡软组织肉瘤、5例透明细胞肉瘤和4例上皮样肉瘤。肉瘤细胞系来自培养实验室。扩增覆盖热点突变C228T和C250T的TERT启动子区域的193bp片段，并对PCR产物进行直接测序。
在341例肉瘤中检测到36例TERT启动子突变。它们在MLS中高度复发（29/39；74%），在目前的MLS系列中与表型（黏液样与圆形细胞变体）、肿瘤分级、肿瘤部位以及患者年龄中位数或性别无关。在其余病例中，仅在302例肉瘤样本中的7例中发现TERT启动子突变，且仅限于SFT（4/31；13%）、MPNST（2/35；6%）和SS（1/25；4%）。在所检测的肉瘤细胞系中，在两个MLS细胞系和三个MPNST细胞系中的一个中检测到TERT启动子突变。
TERT启动子突变在MLS中很常见，包括其圆形细胞变体，是该肉瘤实体中迄今为止发现的最普遍的突变，在一小部分SFT、MPNST和SS中也有发现。大多数肉瘤没有TERT启动子热点突变。这些数据表明，通过增加端粒酶表达来维持端粒在发病机制中起重要作用，尤其是在MLS中。
