Histopathological analysis of aggressive renal cell carcinoma harboring a unique germline mutation in fumarate hydratase
Histopathological analysis of aggressive renal cell carcinoma harboring a unique germline mutation in fumarate hydratase
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DOI：
10.1111/pin.12684
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发表时间：
2018-08-01
影响因子：
2.2
通讯作者：
Furuya, Mitsuko
中科院分区：
文献类型：
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作者：
Matsumoto, Kana;Udaka, Naoko;Furuya, Mitsuko
遗传性平滑肌瘤病和肾细胞癌（HLRCC）是一种罕见的遗传性疾病，以皮肤和子宫平滑肌瘤病合并RCC为特征。这种疾病是由富马酸水合酶（FH）基因的种系突变引起的，该基因编码三羧酸（TCA）循环的一种重要酶。这种突变将HLRCC与散发性rcc区分开来。在此，我们研究了一个32岁男性的HLRCC病例，他为治疗左肾的实体囊性肿瘤而接受了肾切除术。组织病理学显示为乳头状、管状和筛网状的杂色结构，由细胞核增大和嗜酸性核仁的高级别肿瘤细胞组成。免疫染色和western blotting未见FH在肿瘤中表达。基因组DNA测序发现一个杂合突变，涉及FH基因（c.251_267+7delTGACAGAACGCATGCCAGTAAGTG）外显子2的3'端和内含子2的缺失，RT-PCR证实FH mRNA中外显子2跳变。肿瘤的体细胞FH基因状态仅显示突变等位基因，表明杂合性丧失是抑癌基因失活的“第二次打击”。这些数据支持涉及剪接位点的FH突变导致外显子跳变，改变蛋白质的构象，并在TCA循环中FH功能受损时加速致癌级联反应。
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis with RCC. This disorder is caused by a germline mutation in the fumarate hydratase (FH) gene, which encodes an important enzyme of the tricarboxylic acid (TCA) cycle. This mutation distinguishes HLRCC from sporadic RCCs. Herein, we investigated a case of HLRCC in a 32-year-old man who underwent nephrectomy for treatment of a solid-cystic tumor in the left kidney. Histopathology demonstrated a variegated architecture of papillary, tubulocystic and cribriform patterns composed of high-grade tumor cells with enlarged nuclei and eosinophilic nucleoli. Immunostaining and western blotting revealed no FH expression in the tumor. Genomic DNA sequencing identified a heterozygous mutation involving deletion of the 3' end of exon 2 and intron 2 of the FH gene (c.251_267+7delTGACAGAACGCATGCCAGTAAGTG), and RT-PCR confirmed exon 2 skipping in FH mRNA. The somatic FH gene status of the tumor showed only the mutated allele, indicating loss of heterozygosity as the "second hit" of tumor suppressor gene inactivation. These data support that an FH mutation involving the splice site causes exon skipping, changing the conformation of the protein and accelerating carcinogenic cascades under impaired FH functioning in the TCA cycle.