Department of Pathology, Creighton University School of Medicine, Omaha, NE 68131, USA.
Hum Pathol. 2011 Dec;42(12):1979-88. doi: 10.1016/j.humpath.2011.02.026. Epub 2011 Jul 5.
Chromosomal abnormalities and gene mutations have become major determinants in the classification of kidney carcinomas. Most renal medullary carcinomas develop in patients with hereditary sickle cell disease, but sporadic cases unassociated with sickle cell disease have also been described, for which underlying genetic abnormality is unknown. We evaluated 3 patients with renal medullary carcinoma (1 patient with sickle cell disease and 2 patients without sickle cell disease) for germ line and somatic mutations in genes commonly involved in pathogenesis of renal carcinomas using denaturing high-performance liquid chromatography and direct sequencing. Chromosomal abnormalities were studied by the conventional cytogenetic and SNP arrays analysis. Expression of hypoxia-inducible factor 1α was examined using immunohistochemistry. Two new mutations in the gene for fumarate hydratase were identified in 1 case of medullary renal carcinoma without sickle cell disease: a germ line mutation in exon 6 (R233H) and an acquired (somatic) mutation in exon 8 (P374S). No fumarate hydratase mutations were identified in the other 2 patients. The second sporadic case of renal medullary carcinoma harbored double somatic mutations in von Hippel-Lindau gene, and renal medullary carcinoma in the patient with sickle cell disease showed von Hippel-Lindau gene promoter methylation (epigenetic silencing). No consistent pattern of chromosomal abnormalities was found between 2 cases tested. All 3 cases showed increased hypoxia-inducible factor 1α expression. Medullary renal carcinomas from patients with or without sickle cell disease show involvement of genes important in hypoxia-induced signaling pathways. Generalized cellular hypoxia (in sickle cell disease) or pseudohypoxia (in tumors with fumarate hydratase and von Hippel-Lindau mutations or epigenetic silencing) may act alone or in concert at the level of medullary tubular epithelium to promote development of this rare type of renal carcinoma, which could then be genetically reclassified as either fumarate hydratase-associated renal carcinomas or high-grade clear cell renal cell carcinomas.
染色体异常和基因突变已成为肾癌分类的主要决定因素。大多数肾髓质癌发生在遗传性镰状细胞病患者中，但也有描述散发性与镰状细胞病无关的病例，其潜在的遗传异常尚不清楚。我们使用变性高效液相色谱法和直接测序法评估了 3 例肾髓质癌患者（1 例镰状细胞病患者和 2 例非镰状细胞病患者）的常涉及肾癌发病机制的基因的种系和体细胞突变。染色体异常通过常规细胞遗传学和 SNP 阵列分析进行研究。使用免疫组织化学检查缺氧诱导因子 1α 的表达。在 1 例非镰状细胞病的肾髓质癌患者中发现了 2 个新的延胡索酸水合酶基因突变：外显子 6 中的种系突变（R233H）和外显子 8 中的获得性（体细胞）突变（P374S）。在其他 2 名患者中未发现延胡索酸水合酶突变。第二个散发性肾髓质癌病例携带有 von Hippel-Lindau 基因的双重体细胞突变，镰状细胞病患者的肾髓质癌表现出 von Hippel-Lindau 基因启动子甲基化（表观遗传沉默）。在测试的 2 例病例中均未发现染色体异常的一致模式。所有 3 例病例均显示缺氧诱导因子 1α表达增加。镰状细胞病或无镰状细胞病患者的肾髓质癌均涉及缺氧诱导信号通路中重要的基因。全身性细胞缺氧（镰状细胞病）或假性缺氧（延胡索酸水合酶和 von Hippel-Lindau 突变或表观遗传沉默的肿瘤）可能单独或协同作用于髓质管状上皮，促进这种罕见类型的肾癌的发展，然后可以将其遗传上重新归类为延胡索酸水合酶相关的肾细胞癌或高级别透明细胞肾细胞癌。
