PRDM10 RCC: A Birt-Hogg-Dubé-like Syndrome Associated With Lipoma and Highly Penetrant, Aggressive Renal Tumors Morphologically Resembling Type 2 Papillary Renal Cell Carcinoma

作者：Laura S. Schmidt, Cathy D. Vocke, Christopher J. Ricketts, Zoë Blake, Kristin K. Choo, Deborah L. Nielsen, Rabindra Gautam, Daniel R. Crooks, Krista L. Reynolds, Janis L. Krolus, Meena Bashyal, Baktiar Karim, Edward W. Cowen, Ashkan A. Malayeri, Maria J. Merino, Ramaprasad Srinivasan, Mark W. Ball, Berton Zbar, W. Marston Linehan · 发表于：Urology · 年份：2023 · DOI：10.1016/j.urology.2023.04.035 · 被引用次数：17 · 研究领域：Renal cell carcinoma treatment、Bladder and Urothelial Cancer Treatments、Renal and related cancers

OBJECTIVE: To characterize the clinical manifestations and genetic basis of a familial cancer syndrome in patients with lipomas and Birt-Hogg-Dubé-like clinical manifestations including fibrofolliculomas and trichodiscomas and kidney cancer. METHODS: Genomic analysis of blood and renal tumor DNA was performed. Inheritance pattern, phenotypic manifestations, and clinical and surgical management were documented. Cutaneous, subcutaneous, and renal tumor pathologic features were characterized. RESULTS: Affected individuals were found to be at risk for a highly penetrant and lethal form of bilateral, multifocal papillary renal cell carcinoma. Whole genome sequencing identified a germline pathogenic variant in PRDM10 (c.2029 T>C, p.Cys677Arg), which cosegregated with disease. PRDM10 loss of heterozygosity was identified in kidney tumors. PRDM10 was predicted to abrogate expression of FLCN, a transcriptional target of PRDM10, which was confirmed by tumor expression of GPNMB, a TFE3/TFEB target and downstream biomarker of FLCN loss. In addition, a sporadic papillary RCC from the TCGA cohort was identified with a somatic PRDM10 mutation. CONCLUSION: We identified a germline PRDM10 pathogenic variant in association with a highly penetrant, aggressive form of familial papillary RCC, lipomas, and fibrofolliculomas/trichodiscomas. PRDM10 loss of heterozygosity and elevated GPNMB expression in renal tumors indicate that PRDM10 alteration leads to reduced FLCN expression, driving TFE3-induc...