Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations
Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations
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DOI：
10.1210/jc.2006-0183
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发表时间：
2006-08-01
影响因子：
5.8
通讯作者：
Tomlinson, Ian P. M.
中科院分区：
文献类型：
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作者：
Carvajal-Carmona, Luis G.;Alam, N. Afrina;Tomlinson, Ian P. M.
背景：间质细胞肿瘤是最常见的睾丸非生殖细胞肿瘤。LCT通常具有荷尔蒙活性，可导致性早熟或成年女性化。我们从一个遗传性子宫肌瘤病和肾细胞癌(HLRCC)家系中发现了一个LCT和一个富马酸水合酶(FH)胚系突变(N64T)。目的：我们的目的是研究FH突变在LCT易感性中的作用。设计：我们测试了N64T突变的致病作用，并对另外29个未选择的成人LCT进行了FH改变的筛选。我们还检测了这些LCT中两个基因的突变，即促黄体生成素/绒毛膜促性腺激素受体(LHCGR)和与LCT肿瘤发生有关的鸟氨酸核苷酸结合蛋白α(GNAS)。结果：在GNAS中没有发现突变，其中一个肿瘤存在LHCGR体细胞替代。除了具有N64T胚系FH突变的HLRCC病例外，我们还发现了另一例具有以前未报道的FH突变(M411I)的LCT。这些患者的LCT均显示野生型FH等位基因缺失。免疫组织化学和原位杂交分析表明，不仅在FH突变携带者的肿瘤中，缺氧/血管生成途径被激活，而且在其他几个突变阴性的LCT中也是激活的。结论：我们的研究表明，一些LCT是由FH突变引起的，这是首次报道任何类型的成人睾丸肿瘤的生殖系突变。
Context: Leydig cell tumors (LCTs) are the most common non-germ-cell neoplasms of the testis. LCTs are often hormonally active and can result in precocious virilization or in adult feminization. We identified an LCT in an affected individual from a kindred with hereditary leiomyomatosis and renal cell cancer (HLRCC) and a germline fumarate hydratase (FH) mutation (N64T).Objective: Our objective was to investigate the role of FH mutations in predisposition to LCTs.Design: We tested for pathogenic effects of the N64T mutation and screened an additional 29 unselected adult LCTs for FH alterations. We also tested these LCTs for mutations in two genes, the LH/choriogonadotropin receptor ( LHCGR) and the guanine nucleotide-binding protein alpha (GNAS) that had been implicated in LCT tumorigenesis.Results: No mutations were found in GNAS, and one tumor had a LHCGR somatic substitution. In addition to the HLRCC case with the N64T germline FH mutation, we identified one other LCT with a previously unreported FH mutation (M411I). Both LCTs from these patients showed loss of the wild-type FH allele. Immunohistochemical and in situ hybridization analyses demonstrated activation of the hypoxia/angiogenesis pathway not only in the tumors belonging to the FH mutation carriers but also in several other mutation-negative LCTs.Conclusions: Our study shows that some LCTs are caused by FH mutations and represents one of the first reports of germline mutations in any type of adult testicular tumor.