Tuberous sclerosis complex-associated renal cell carcinoma, an underappreciated form of familial renal cancer, is characterized by activation of the TFEB/TFE3 pathway

Abstract Objective To describe the genetic, phenotypic, and pathologic manifestations of patients presenting with inherited kidney cancer and germline variants of the Tuberous Sclerosis Complex (TSC) genes. Materials and Methods Inherited kidney cancer patients were screened for germline RCC susceptibility gene variants and patient histories and clinical evaluations were performed. Renal tumors were evaluated for somatic genetic alterations by DNA sequencing and mRNA expression analysis by RNAseq and immunohistochemical analyses were performed. Results Nine distinct germline TSC1/TSC2 variants were identified in 13 patients, including seven known or likely pathogenic alterations. Five patients presented with a clinical diagnosis of TSC, and eleven patients had a genetic diagnosis of TSC. Nine patients had bilateral RCC and nine had multifocal RCC. The average initial age at diagnosis of RCC was 47 years old. The TSC-associated tumors demonstrated a variety of histologies including ccRCC, RCC with clear cell and papillary features, chromophobe RCC, and oncocytoma; with ccRCC being the most prevalent. Loss of heterozygosity or secondary somatic alteration of TSC1/TSC2 was observed in ~ 37% of tumors. RNAseq analysis demonstrated specific expression patterns associated within histologically defined tumor clusters and increased expression of CLEAR genes activated by the TFE3/TFEB transcription factors, including GPNMB and NPC1 which were confirmed with immunohistochemistry. Conclusion This study confirms the importance of screening individuals with a family history of kidney cancer for TSC1/TSC2 germline variants, even in the absence of canonical TSC manifestations, and indicates a critical role of TFE3 and TFEB as drivers of human TSC-deficient renal cell carcinoma.