Molecular genetics of clear-cell renal cell carcinoma

Abstract

Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.

Fig 1.

Interplay between VHL and mTORC1 pathways. In the presence of growth factors, transphosphorylation by the intracellular domains of receptor tyrosine kinases leads to recruitment of the regulatory subunit of class IA PI3K, p85 (either directly or through adaptor proteins like IRS) and releases its inhibition of the catalytic subunit (p110α; encoded by the PIK3CA gene), which phosphorylates phosphatidylinositol-4,5-trisphosphate to generate phosphatidylinositol-3,4,5-trisphosphate (PIP₃). PIP₃ recruits interacting proteins to the plasma membrane, such as Akt, which is phosphorylated and activated by PDK1 and mTORC2 (mTOR complex 2). Akt phosphorylates TSC2, which is in a complex with TSC1 and TBC1D7, releasing its inhibition on Rheb. Activated Rheb binds to and activates mTORC1. mTORC1 is inhibited by PRAS40, and this inhibition is also released by AKT activation. mTORC1 is also inhibited by REDD1 in a manner that requires TSC1/TSC2. REDD1 is transcriptionally induced by both HIF-1 and HIF-2, which are activated following the inactivation of the VHL complex through mutations in either VHL or TCEB1 (encoding Elongin C). mTORC1 is inhibited by temsirolimus and everolimus, which interact with FKBP12 and subsequently bind to mTORC1. Brown ovals, oncoproteins activated by mutation in ccRCC; blue ovals, tumor-suppressor proteins inactivated by mutation in ccRCC.

Fig 2.

PBRM1- and BAP1-mutant tumors are associated with different biology, pathologic features, and outcomes, setting the foundation for a molecular genetic classification of clear-cell renal cell carcinoma (ccRCC). (A) BAF180 (encoded by the PBRM1 gene) contains six tandem bromodomains that bind to acetylated lysine residues in histone tails, thereby localizing the PBAF chromatin remodeling complex to specific chromatin regions and regulating gene expression. (B) BAP1 interacts with HCF-1 and functions to deubiquitinate proteins, including histone H2AK119ub1. By deubiquitinating its substrates, BAP1 may inhibit protein degradation or, in the case of H2A, alter gene expression. PBRM1- and BAP1-mutant tumors are associated with different gene expression signatures, pathologic features, mTORC1 activation, and outcomes (Kapur et al). (C) Pie chart representation of ccRCC subtypes and their approximate frequencies. HR, hazard ratio; other, tumors without detectable mutations in PBRM1 and BAP1.

Fig 3.

Model for clear-cell renal cell carcinoma (ccRCC) development. The genes VHL, BAP1, and PBRM1 are all located on chromosome (Chr) 3p (SETD2 is also in this region; not shown). Following an intragenic mutation in VHL, loss of 3p, which is observed in the majority of ccRCCs, inactivates the remaining VHL allele along with one allele of BAP1 and PBRM1. Subsequent mutation in the remaining PBRM1 or BAP1 allele results in ccRCC with different pathologic features and outcomes.