Detecting TSC2 mutation in patients with early RCC onset would be beneficial and mTOR inhibitor could be a therapeutic option for TSC2 mutation-induced RCC.
This Review describes important advances in the TSC field and highlights several remaining critical knowledge gaps: the factors that promote aggressive behaviour by a subset of TSC-associated RCCs; the molecular mechanisms underlying early-onset cystogenesis in TSC2-PKD1 contiguous gene deletion syndrome; the effect of early, long-term mTORC1 inhibition on the development of TSC renal disease; and the identification of the cell or cells of origin of angiomyolipomas.
Using capture-based and amplicon-based next-generation sequencing, we now demonstrate the consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8/9 cases) and adult ESC RCC (6/6 cases).
Knockdown of TSC2 in Caki-2 cells had similar results to 786-O cells, and mTOR silencing in 786-O cells rescued the inhibitory effect of betulin, indicating that betulin inhibited RCC cell proliferation in an mTOR-dependent manner.
These data suggest that Akt/tuberin/mTOR pathway plays an important role in the regulation DNA damage and repair pathways that may predispose diabetic kidneys to pathogenesis of renal cell carcinoma.
Germline mutations in the MET and fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC.
Here, we will address the genetic, cellular and biochemical mechanisms that may contribute to the unusually broad spectrum of renal disease in cells with TSC1 or TSC2 mutations, and consider how the TSC signaling pathways may be linked to other renal diseases such as polycystic kidney disease and renal cell carcinoma.
Here, we will review the clinical association of RCC in TSC, consider the factors that have led to its under-emphasis within the RCC field, address the cellular and biochemical mechanisms that may contribute to RCC in cells with TSC1 or TSC2 mutations, and finally discuss the ways in which the TSC signaling pathways may be linked to sporadic RCC in the general population.
TSC1 and TSC2 mutations are related to various phenotypic manifestations and risks of malignancy, such as an increased incidence of the TSC2 mutation in patients with renal cell carcinoma.
The Eker (Tsc2 gene mutant) rat model of hereditary renal carcinoma (RC) is an example of Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal.