%0 Journal Article
%T 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.
%A Schmidt LS
%A Vocke CD
%A Ricketts CJ
%A Blake Z
%A Choo KK
%A Nielsen D
%A Gautam R
%A Crooks DR
%A Reynolds KL
%A Krolus JL
%A Bashyal M
%A Karim B
%A Cowen EW
%A Malayeri AA
%A Merino MJ
%A Srinivasan R
%A Ball MW
%A Zbar B
%A Marston Linehan W
%J Urology
%V 179
%N 0
%D 2023 09 16
%M 37331486
%F 2.633
%R 10.1016/j.urology.2023.04.035
%X 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.<BR>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.<BR>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.<BR>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-induced tumor formation. These findings suggest that individuals with Birt-Hogg-Dubé-like manifestations and subcutaneous lipomas, but without a germline pathogenic FLCN variant, should be screened for germline PRDM10 variants. Importantly, kidney tumors identified in patients with a pathogenic PRDM10 variant should be managed with surgical resection instead of active surveillance.