The following is a summary of “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,” published in the SEPTEMBER 2023 issue of Urology by Schmidt, et al.

For a study, researchers sought to provide a comprehensive characterization of a familial cancer syndrome observed in patients presenting with lipomas, as well as clinical manifestations resembling Birt-Hogg-Dubé syndrome (BHD), including fibrofolliculomas, trichodiscomas, and kidney cancer.

The study involved a detailed genomic analysis of both blood and renal tumor DNA. They documented the inheritance pattern, phenotypic manifestations, and clinical and surgical management. They carefully examined the pathological features of cutaneous, subcutaneous, and renal tumors.

The investigation revealed that affected individuals were at significant risk of developing a highly penetrant and aggressive form of bilateral, multifocal papillary renal cell carcinoma (RCC). Through whole genome sequencing, a pathogenic germline variant in PRDM10 (c.2029 T>C, p.Cys677Arg) was identified, and it was shown to cosegregate with the disease. Furthermore, loss of heterozygosity in PRDM10 was observed in kidney tumors. It was predicted that this PRDM10 variant could abolish the expression of FLCN, which is a known transcriptional target of PRDM10. This prediction was confirmed through the tumor’s expression of GPNMB, a biomarker for FLCN loss, regulated by TFE3 and TFEB. Additionally, the study identified a sporadic papillary RCC in the TCGA cohort with a somatic PRDM10 mutation.

The study established the connection between a germline PRDM10 pathogenic variant and a highly penetrant, aggressive familial papillary RCC. Patients with this variant displayed a spectrum of symptoms, including lipomas and BHD-like manifestations such as fibrofolliculomas and trichodiscomas. The loss of FLCN expression due to PRDM10 alteration and the consequent TFE3-driven tumor formation were identified as key underlying mechanisms. The research highlighted the importance of screening individuals with BHD-like features and subcutaneous lipomas, especially if they lack a pathogenic germline FLCN variant. Furthermore, it suggested that patients with a PRDM10 variant and kidney tumors should undergo surgical resection instead of active surveillance.

Source: goldjournal.net/article/S0090-4295(23)00501-0/fulltext