In conclusion, while TSC2 is broadly downregulated in sporadic ccRCC, TSC1 expression is reduced in two subsets of these tumors, those with monoallelic VHL gene inactivation and those with concurrent low HIF-1α and high HIF-2α expression.
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 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.
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.
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.
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.
These data indicate that biallelic inactivation of TSC1 or TSC2 is not frequent in sporadic RCC and suggests that the molecular mechanisms of renal carcinogenesis in TSC are likely to be distinct.
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.
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.
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.
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).