Background Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal cell carcinoma; no effective forms of therapy for advanced disease exist. Methods We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas. Results Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene. Conclusions Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features.

Secreted Frizzled-related protein-1 (sFRP-1) contains a cysteine-rich domain homologous to the putative Wntbinding site of Frizzleds. To facilitate the biochemical and biological analysis of sFRP-1, we developed a mammalian recombinant expression system that yields ϳ3 mg of purified protein/liter of conditioned medium. Using this recombinant protein, we demonstrated that sFRP-1 and Wg (wingless) interact in enzyme-linked immunosorbent and co-precipitation assays. Surprisingly, a derivative lacking the cysteine-rich domain retained the ability to bind Wg. Cross-linking experiments performed with radioiodinated sFRP-1 provided definitive evidence that sFRP-1 and Wg bind directly to each other. Besides detecting a cross-linked complex consistent in size with 1:1 stoichiometry of sFRP-1 and Wg, we also observed a larger complex whose size suggested the presence of a second sFRP-1 molecule. The formation of both complexes was markedly enhanced by an optimal concentration of exogenous heparin, emphasizing the potential importance of heparan-sulfate proteoglycan in Wnt binding and signaling. sFRP-1 exerted a biphasic effect on Wg activity in an armadillo stabilization assay, increasing armadillo level at low concentrations but reducing it at higher concentrations. These results provide new insights about the Wnt binding and biological activity of sFRPs.

Despite nearly two decades since the discovery of gene fusions involving TFE3 or TFEB (“TFE”) in sporadic renal cell carcinoma (RCC), the molecular mechanisms underlying the renal-specific tumorigenesis remains largely unclear. The recent publication of the TCGA Network's clear cell kidney cancer paper provides further evidence for the importance of gene fusions by identifying 5 tumors harboring SFPQ-TFE3 fusions that otherwise lacked the common clear cell RCC associated mutation. Herein, we review key molecular features of TFE-fusion RCC, including candidate signaling pathways contributing to oncogenesis and a detailed overview of gene fusion isoforms based on an updated knowledge of TFE genetic organization. A total of 5 TFE3 gene fusions (PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3, NONO-TFE3, CLTC-TFE3) and 1 TFEB gene fusion (MALAT1-TFEB) have been identified in RCC tumors and characterized at the mRNA transcript level, with considerable heterogeneity in exon structure across different tumors, even for the same fusion partners. Common to all TFE3 and TFEB fusion isoforms is the retention of the wild-type protein C-terminus, including domains for DNA-binding, dimerization, and nuclear localization, but interestingly, not transcriptional activation. Despite this, the most widely accepted model explaining TFE-fusion oncogenesis remains the introduction of a constitutively active promoter leading to dysregulated TFE transcriptional activity. A multitude of molecular pathways well-implicated in carcinogenesis are regulated in part by TFE3 and/or TFEB protein, including activation of TGFβ and ETS transcription factors, E-cadherin expression, CD40L-dependent lymphocyte activation, mTORC1 signaling, insulin-dependent metabolism regulation, folliculin signaling, and Rb-dependent cell cycle arrest. Determining which pathways are most important will be critical to discovering the most promising therapeutic targets for this disease. Useful to this goal is a panel of cell lines derived from different TFE3-fusion RCC patient tumors, representing multiple fusion isoforms.

Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.