IKCS 2022: Somatic Testing Considerations

(UroToday.com) The tenth session of the 2022 International Kidney Cancer Symposium (IKCS): North America meeting focused on the genetics of renal cell carcinoma (RCC). In this context, Dr. Henske presented on considerations regarding somatic genetic testing in the context of Tuberous Sclerosis Complex (TSC) and Birt Hogg Dube (BHD) syndrome.


She began by noting that tuberous sclerosis can affect nearly every organ in the body. However, renal manifestations are among the most common and are the most common cause of death. The most common renal tumor in patients with TSC is benign angiomyolipomas. However, there are distinct clinical and histologic features of renal cell carcinoma (RCC) in TSC. This was only relatively recently recognized – 2014. At that time, two reports from the Cleveland Clinic and from MGH identified a relatively young age at diagnosis (mean 36 years) and female predominance (2:1). In terms of pathology, reports from the Cleveland clinic identified a chromophobe-like appearance while those from MGH noted a TSC-associated papillary RCC and the hybrid oncocytic-chromophobe tumor (HOCT). Notably, HOCT can also occur in Birt Hogg Dube.

Dr. Henske noted that there is a relative absence of sporadic counterparts to TSC-associated RCC. While TSC1 and TSC2 mutations occur uncommonly in clear cell and chromophobe RCC, there is evidence that they are relatively common in some uncommon histologies – eosinophilic solid cystic (ESC)-RCC (90%), RCC with leiomyomatous stroma (RCC-LMS) (80%), and eosinophilic vacuolated tumors (EVT) (57%).

She then moved to discuss the role of TFEB in RCC associated with TSC and BHD. Mouse tumors in a model of tuberous sclerosis (TSC2 mutant) have increased lysosomes. Cellular models also show an increase in genes associated with lysosomes in TSC deficient cells, including NPC1. There is also evidence of a corollary in human tumors with increased NPC1 (a hallmark lysosomal gene) in TSC associated renal tumors. Dr. Henske said that, in her hands, this is “one of the best markers” of AMLs. TFEB is a master regulator of lysosomal biogenesis, part of the microphthalmia-associated family including MITF and TFE3, along with TFEB. As a transcription factor, she noted that TFEB can activate mTOR. In cell models, shuttling to nucleus shows that both TFEB and TFE3 may be drivers of disease in TSC1/2 deficient HeLa cells.

Dr. Henske noted that there are two features in common between TSC and BHD: unusual renal cell carcinoma and pulmonary manifestations.

Birt Hogg Dube.jpg

She noted that loss of folliculin also causes nuclear localization of the same transcription factors, through a shared pathway. Down-regulation of both TSC2 and FLCN causes increases in TFEB, suggesting a potential driving effect in both conditions. In mouse models, while FLCN knockout is associated with the development of renal tumors, double knockout of FLCN and TFEB abrogated this effect. She, therefore, suggested that these transcription factors may be missing the link between TSC and BHD associated renal carcinomas.

Dr. Henske then highlighted the case of a woman with a large chromophobe RCC. She noted that high GSH levels are a hallmark of chromophobe RCC, with hypersensitivity to cysteine deprivation leading to ferroptotic cell death. She noted that NPC1, a TFEB target, is highly expressed in chromophobe RCC.

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Further, she noted that the lysosome pathway is upregulated in chromophobe kidney cancer. Thus, she suggested that TFEB/TFE3 may be the missing link between rare forms of RCC, including TSC-RCC, BHD-RCC, chromophobe RCC, translocation RCC, and eosinophilic and cystic RCC.

In conclusion, Dr. Henske noted that RCC in TSC and BHD demonstrate hybrid oncocytic and chromophobe histology and upregulation of lysosomal targets of the TFEB/TFE3 transcription factors.

Presented by: Elizabeth Henske, MD, Brigham and Women’s Hospital, Boston, MA

Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2022 International Kidney Cancer Symposium (IKCS) North America, November 4-5, Austin, Texas, USA

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