Furuya Mitsuko, Hong Seung-Beom, Tanaka Reiko, Kuroda Naoto, Nagashima Yoji, Nagahama Kiyotaka, Suyama Takahito, Yao Masahiro, Nakatani Yukio
Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Cancer Sci. 2015 Mar;106(3):315-23. doi: 10.1111/cas.12601. Epub 2015 Feb 17.
Birt-Hogg-Dubé syndrome (BHD) is an inherited disorder associated with a germline mutation of the folliculin gene (FLCN). The affected families have a high risk for developing multiple renal cell carcinomas (RCC). Diagnostic markers that distinguish between FLCN-related RCC and sporadic RCC have not been investigated, and many patients with undiagnosed BHD fail to receive proper medical care. We investigated the histopathology of 27 RCCs obtained from 18 BHD patients who were diagnosed by genetic testing. Possible somatic mutations of RCC lesions were investigated by DNA sequencing. Western blotting and immunohistochemical staining were used to compare the expression levels of FLCN and glycoprotein non-metastatic B (GPNMB) between FLCN-related RCCs and sporadic renal tumors (n = 62). The expression of GPNMB was also evaluated by quantitative RT-PCR. Histopathological analysis revealed that the most frequent histological type was chromophobe RCC (n = 12), followed by hybrid oncocytic/chromophobe tumor (n = 6). Somatic mutation analysis revealed small intragenic mutations in six cases and loss of heterozygosity in two cases. Western blot and immunostaining analyses revealed that FLCN-related RCCs showed overexpression of GPNMB and underexpression of FLCN, whereas sporadic tumors showed inverted patterns. GPNMB mRNA in FLCN-related RCCs was 23-fold more abundant than in sporadic tumors. The distinctive expression patterns of GPNMB and FLCN might identify patients with RCCs who need further work-up for BHD.
Birt-Hogg-Dubé综合征（BHD）是一种与卵泡抑素基因（FLCN）种系突变相关的遗传性疾病。患病家族患多发性肾细胞癌（RCC）的风险很高。尚未对区分FLCN相关RCC和散发性RCC的诊断标志物进行研究，许多未确诊BHD的患者未能得到适当的医疗护理。我们对18例经基因检测确诊的BHD患者的27例RCC进行了组织病理学研究。通过DNA测序研究了RCC病变可能的体细胞突变。采用蛋白质免疫印迹法和免疫组织化学染色法比较FLCN相关RCC与散发性肾肿瘤（n = 62）之间FLCN和糖蛋白非转移性B（GPNMB）的表达水平。还通过定量逆转录聚合酶链反应评估GPNMB的表达。组织病理学分析显示，最常见的组织学类型是嫌色细胞性RCC（n = 12），其次是嗜酸细胞/嫌色细胞混合性肿瘤（n = 6）。体细胞突变分析显示6例存在小的基因内突变，2例存在杂合性缺失。蛋白质免疫印迹法和免疫染色分析显示，FLCN相关RCC表现为GPNMB过表达和FLCN低表达，而散发性肿瘤则呈现相反的模式。FLCN相关RCC中的GPNMB mRNA比散发性肿瘤丰富23倍。GPNMB和FLCN独特的表达模式可能有助于识别需要进一步检查是否患有BHD的RCC患者。
