Looijenga Leendert H J, de Leeuw Hubert, van Oorschot Monique, van Gurp Ruud J H L M, Stoop Hans, Gillis Ad J M, de Gouveia Brazao Carlos A, Weber Rob F A, Kirkels Wim J, van Dijk Thamar, von Lindern Marieke, Valk Peter, Lajos Geczy, Olah Edit, Nesland Jahn M, Fosså Sophie D, Oosterhuis J Wolter
Pathology/Laboratory for Experimental Patho-Oncology, Erasmus MC, University Medical Center Rotterdam, den Hoed Cancer Center, Nefkens Institute, Building Be, Room 430b, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.
Cancer Res. 2003 Nov 15;63(22):7674-8.
Testicular germ-cell tumors (TGCTs) of adolescents and adults originate from intratubular germ cell neoplasia (ITGCN), which is composed of the malignant counterparts of embryonal germ cells. ITGCN cells are characterized, among others, by the presence of stem cell factor receptor c-KIT. Once established, ITGCN will always progress to invasiveness. Approximately 2.5-5% of patients with a TGCT will develop bilateral disease and require complete castration, resulting in infertility, a need for lifelong androgen replacement, and psychological stress. To date, the only way to predict a contralateral tumor is surgical biopsy of the contralateral testis to demonstrate ITGCN. We did a retrospective study of 224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three independently collected series in Europe) for the presence of activating c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In the two wild-type bilateral tumors for which ITGCN was available, the preinvasive cells contained the mutation. The mutations were somatic in origin and identical in both tumors. We conclude that somatic activating codon 816 c-KIT mutations are associated with development of bilateral TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies patients at risk for bilateral disease. These patients may undergo tailored treatment to prevent the development of bilateral disease, with retention of testicular hormonal function.
青少年和成人的睾丸生殖细胞肿瘤（TGCT）起源于管内生殖细胞肿瘤（ITGCN），后者由胚胎生殖细胞的恶性对应物组成。ITGCN细胞的特征之一是存在干细胞因子受体c-KIT。一旦形成，ITGCN总会发展为侵袭性肿瘤。约2.5%-5%的TGCT患者会发生双侧病变，需要进行双侧睾丸切除，从而导致不育、终身需要雄激素替代治疗以及心理压力。迄今为止，预测对侧肿瘤的唯一方法是对侧睾丸的手术活检以证实存在ITGCN。我们对224例单侧和61例经证实的双侧TGCT（来自欧洲三个独立收集系列中的46例患者）进行了回顾性研究，以检测激活型c-KIT密码子816突变的存在情况。在3例单侧TGCT中发现了c-KIT密码子816突变（1.3%），在57例双侧TGCT中发现了该突变（93%；P<0.0001）。在有ITGCN的2例野生型双侧肿瘤中，侵袭前细胞含有该突变。这些突变起源于体细胞，且在两个肿瘤中相同。我们得出结论，体细胞激活型密码子816 c-KIT突变与双侧TGCT的发生有关。在单侧TGCT中检测c-KIT密码子816突变可识别有双侧病变风险的患者。这些患者可接受针对性治疗以预防双侧病变的发生，同时保留睾丸的激素功能。
