Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD.
Urology. 2021 Mar;149:89-97. doi: 10.1016/j.urology.2020.11.025. Epub 2020 Nov 24.
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 Polymerase chain reaction. 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.
描述小眼畸形相关转录因子（MITF）家族转录因子基因成员引起的家族性肾细胞癌（RCC）的临床特征、基因组改变、病理表型和临床管理。
在此评估并报告了临床表现、家族史、肿瘤组织病理学和手术管理情况。对血液 DNA、肿瘤 DNA 和从相邻正常肾组织中提取的 DNA 进行 DNA 测序。通过实时聚合酶链反应对肿瘤和正常组织进行拷贝数和基因表达分析。使用 TCGA 基因表达数据进行比较分析。通过免疫组织化学评估蛋白表达和亚细胞定位。
种系基因组分析在一名双侧、多灶性 1 型乳头状 RCC 患者和 RCC 家族史中发现了 MITF p.E318K 变体。所有肿瘤均显示 MITF 变体，并伴有 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 MITF p.E318K 变体导致转录活性改变，MiT 家族成员的下游靶标，如 GPNMB，在肿瘤中失调。
该家族中致病性 MITF 变体与双侧和多灶性 1 型乳头状 RCC 的关联支持其作为 RCC 发生的风险等位基因的作用，并强调了无论 RCC 组织学亚型如何，筛选 MITF 变体的重要性。本研究确定了疾病的潜在生物标志物，如 GPNMB 表达，这可能有助于为受 MITF 相关 RCC 影响的患者开发靶向治疗。
