Clinical and Molecular Characterization of Microphthalmia-associated Transcription Factor (MITF)-related Renal Cell Carcinoma.
Clinical and Molecular Characterization of Microphthalmia-associated Transcription Factor (MITF)-related Renal Cell Carcinoma.
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小眼相关转录因子（MITF）相关肾细胞癌的临床和分子特征。
DOI：
10.1016/j.urology.2020.11.025
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发表时间：
2021-03
期刊：
影响因子：
2.1
通讯作者：
Linehan WM
中科院分区：
文献类型：
--
作者：
Lang M;Vocke CD;Ricketts CJ;Metwalli AR;Ball MW;Schmidt LS;Linehan WM
描述小眼相关转录因子（MITF）家族性肾细胞癌（RCC）的临床表现、基因组改变、病理表型和临床管理，该家族性肾细胞癌由转录因子基因的TFE 3、TFEB和MITF家族成员引起。本文评估并报告了临床表现、家族史、肿瘤组织病理学和手术治疗。对血液DNA、肿瘤DNA和从邻近正常肾组织提取的DNA进行DNA测序。采用Real-Time PCR方法对肿瘤组织和正常组织进行拷贝数和基因表达分析。TCGA基因表达数据用于比较分析。免疫组化检测蛋白表达和亚细胞定位。生殖系基因组分析鉴定了MITF p.E318K变异体在患有双侧、多灶性1型乳头状RCC和RCC家族史的患者中。所有肿瘤均显示MITF变异，其特征为7号和17号染色体扩增，这是1型乳头状RCC的标志。我们证明了MITF p.E318K变体导致转录活性改变，并且MiT家族成员的下游靶点（如GPNMB）在肿瘤中失调。在这个家族中，致病性MITF变异与双侧和多灶性1型乳头状肾细胞癌的关联支持其作为肾细胞癌发展的风险等位基因的作用，并强调了筛查与肾细胞癌组织学亚型无关的MITF变异的重要性。这项研究确定了该疾病的潜在生物标志物，如GPNMB表达，这可能有助于为MITF相关RCC患者开发靶向治疗。本报告描述了一个病例研究的患者与双边，多灶性1型乳头状肾细胞癌和肾细胞癌的家族史，有生殖系MITF p.E318K变异，已知易患肾癌。所有肿瘤均表现为乳头状1型组织学，对可用肿瘤的分析发现MITF转录因子的核染色增加，7号和17号染色体的体细胞扩增，以及与肿瘤发生相关的基因表达改变，包括潜在的生物标志物，如GPNMB。
To characterize the clinical presentation, genomic alterations, pathologic phenotype and clinical management of microphthalmia-associated transcription factor (MITF) familial renal cell carcinoma (RCC), caused by a member of the TFE3, TFEB and MITF family of transcription factor genes. The clinical presentation, family history, tumor histopathology, and surgical management were evaluated and reported herein. DNA sequencing was performed on blood DNA, tumor DNA and DNA extracted from adjacent normal kidney tissue. Copy number and gene expression analyses on tumor and normal tissues were performed by Real-Time PCR. TCGA gene expression data were used for comparative analysis. Protein expression and subcellular localization were evaluated by immunohistochemistry. Germline genomic analysis identified the MITF p.E318K variant in a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC. All tumors displayed the MITF variant and were characterized by amplification of chromosomes 7 and 17, hallmarks of type 1 papillary RCC. We demonstrated that MITF p.E318K variant results in altered transcriptional activity and that downstream targets of MiT family members, such as GPNMB, are dysregulated in the tumors. Association of the pathogenic MITF variant with bilateral and multifocal type 1 papillary RCC in this family supports its role as a risk allele for the development of RCC and emphasizes the importance of screening for MITF variants irrelevant of the RCC histologic subtype. This study identifies potential biomarkers for the disease, such as GPNMB expression, that may facilitate the development of targeted therapies for patients affected with MITF-associated RCC. This report describes a case study of a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC that has the germline MITF p.E318K variant, known to predispose to kidney cancer. All tumors demonstrated a papillary type 1 histology and analyses of available tumors identified increased nuclear staining for the MITF transcription factor, somatic amplification of chromosomes 7 and 17, and altered expression of genes associated with tumorigenesis, including potential biomarkers, such as GPNMB.
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影响因子：
64.8
作者：
Bertolotto, Corine;Lesueur, Fabienne;Bressac-de Paillerets, Brigitte
通讯作者：
Bressac-de Paillerets, Brigitte
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
2.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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