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In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non‐small‐cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: In this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed 10 uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N‐lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser, and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N‐lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N‐lobe‐mutated MET variants were found to trigger a common HGF‐stimulation‐dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N‐lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations. MET variants in the N‐lobe of the kinase domain, found in hereditary papillary renal cell carcinoma, require ligand stimulation to promote cell transformation, in contrast to other RTK variants. This suggests that HGF expression in the microenvironment is important for tumor growth in such patients. Their sensitivity to MET inhibitors opens the way for use of targeted therapies in these patients.

SETD2-dependent H3 Lysine-36 trimethylation (H3K36me3) has been recently linked to the deposition of de-novo DNA methylation. SETD2 is frequently mutated in cancer, however, the functional impact of SETD2 loss and depletion on DNA methylation across cancer types and tumorigenesis is currently unknown. Here, we perform a pan-cancer analysis and show that both SETD2 mutation and reduced expression are associated with DNA methylation dysregulation across 21 out of the 24 cancer types tested. In renal cancer, these DNA methylation changes are associated with altered gene expression of oncogenes, tumour suppressors, and genes involved in neoplasm invasiveness, including TP53, FOXO1 , and CDK4 . This suggests a new role for SETD2 loss in tumorigenesis and cancer aggressiveness through DNA methylation dysregulation. Moreover, using a robust machine learning methodology, we develop and validate a 3-CpG methylation signature which is sufficient to predict SETD2 mutation status with high accuracy and correlates with patient prognosis.

Background In this article, we report a case of renal cell carcinoma metastasis to the thyroid gland. Occult lesions of the thyroid were treated with a thyroidectomy. The case history presented below describes the patient’s pathway and subsequent results. Case presentation A routine medical examination of a 58-year-old Ukrainian woman revealed lesions in her thyroid gland. In total, two nodules 3.5 cm and 1.5 cm wide were found in the gland using ultrasound. Features of thyroid nodules were classified as Thyroid Imaging Reporting and Data System 3. A fine-needle aspiration biopsy showed Bethesda category IV thyroid nodules. Before this, the patient had a right-sided nephrectomy. The histopathology report confirmed renal cell carcinoma. The patient underwent a total thyroidectomy 13 years ago with confirmed metastatic renal cell carcinoma to the thyroid gland. Subsequent surgeries aimed at removing the local recurrences and distant metastases of the primary site. The patient got six cycles of Sunitinib (Sutent™, Pfizer) chemotherapy for renal cell carcinoma. Today, she lives in another country as a refugee and visits home occasionally. The patient takes thyroxine and waits for a suitable treatment option to cure advanced renal cell carcinoma. Conclusion A comprehensive investigation of the patient’s case history is crucial for determining a correct diagnosis. In our case, metastases to the thyroid were found 13 years after the initial renal cell carcinoma diagnosis. Moreover, foci of renal cancer cells in other organs indicates advanced disease with subsequent recurrence and distant metastases. Renal cell carcinoma may cause thyroid nodules.

Objective To evaluate the survival outcomes of patients with local recurrence after radical nephrectomy (RN) and to test the effect of surgery, as monotherapy or in combination with systemic treatment, on cancer-specific mortality (CSM). Methods Patients with local recurrence after RN were abstracted from an international dataset. The primary outcome was CSM. Cox’s proportional hazard models tested the main predictors of CSM. Kaplan–Meier method estimates the 3-year survival rates. Results Overall, 96 patients were included. Of these, 44 (45.8%) were metastatic at the time of recurrence. The median time to recurrence after RN was 14.5 months. The 3-year cancer-specific survival rates after local recurrence were 92.3% (± 7.4%) for those who were treated with surgery and systemic therapy, 63.2% (± 13.2%) for those who only underwent surgery, 22.7% (± 0.9%) for those who only received systemic therapy and 20.5% (± 10.4%) for those who received no treatment ( p  < 0.001). Receiving only medical treatment (HR: 5.40, 95% CI 2.06–14.15, p  = 0.001) or no treatment (HR: 5.63, 95% CI 2.21–14.92, p  = 0.001) were both independently associated with higher CSM rates, even after multivariable adjustment. Following surgical treatment of local recurrence 8 (16.0%) patients reported complications, and 2/8 were graded as Clavien–Dindo ≥ 3. Conclusions Surgical treatment of local recurrence after RN, when feasible, should be offered to patients. Moreover, its association with a systemic treatment seems to warrantee adjunctive advantages in terms of survival, even in the presence of metastases.

The Birt-Hogg-Dubé (BHD) disease is a genetic cancer syndrome. The responsible gene, BHD, has been identified by positional cloning and thought to be a novel tumor suppressor gene. BHD mutations cause many types of diseases including renal cell carcinomas, fibrofolliculomas, spontaneous pneumothorax, lung cysts, and colonic polyps/cancers. By combining Gateway Technology with the Ksp-Cre gene knockout system, we have developed a kidney-specific BHD knockout mouse model. BHD(flox/flox)/Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. The affected BHD(flox/flox)/Ksp-Cre mice died of renal failure at approximate three weeks of age, having blood urea nitrogen levels over tenfold higher than those of BHD (flox/+)/Ksp-Cre and wild-type littermate controls. We further demonstrated that these phenotypes were caused by inactivation of BHD and subsequent activation of the mTOR pathway. Application of rapamycin, which inhibits mTOR activity, to the affected mice led to extended survival and inhibited further progression of cystogenesis. These results provide a correlation of kidney-targeted gene inactivation with renal carcinoma, and they suggest that the BHD product FLCN, functioning as a cyst and tumor suppressor, like other hamartoma syndrome-related proteins such as PTEN, LKB1, and TSC1/2, is a component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation.

Renal cell carcinoma (RCC) is a common form of urologic tumor that originates from the highly heterogeneous epithelium of renal tubules. Over the last decade, targeting therapies to renal cancer cells have transformed clinical care for RCC. Recently, it was proposed that renal cancer stem cells (CSCs) isolated from renal carcinomas were responsible for driving tumor growth and resistance to conventional chemotherapy and radiotherapy, according to the theory of CSCs; this has provided the rationale for therapies targeting this aggressive cell population. Precise identification of renal CSC populations and the complete cell hierarchy will accurately inform characterization of disease subtypes. This will ultimately contribute to more personalized and targeted therapies. Here, we summarize potential targeting strategies for renal cancer cells and renal CSCs, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTOR), interleukins, CSC marker inhibitors, bone morphogenetic protein-2, antibody drug conjugates, and nanomedicine. In conclusion, targeting therapies for RCC represent new directions for exploration and clinical investigation and they plant a seed of hope for advanced clinical care.

The BAP1 gene (BRCA1-associated protein 1) is a tumour suppressor gene that encodes a deubiquitinating enzyme (DUB), regulating key cellular pathways, including cell cycle, cellular differentiation, transcription and DNA damage response. Germline BAP1 mutations cause a novel cancer syndrome characterised by early onset of multiple atypical Spitz tumours and increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma and various other malignancies. Recognising the clinicopathological features of specific BAP1-deficient tumours is crucial for early screening/tumour detection, with significant impact on patient outcome.

PurposeHereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is associated with an aggressive form of renal cell carcinoma with high risk of metastasis, even in small primary tumors with unequivocal imaging findings. In this study, we compare the performance of ultra-high b-value diffusion-weighted imaging (DWI) sequence (b = 2000 s/mm2) to standard DWI (b = 800 s/mm2) sequence in identifying malignant lesions in patients with HLRCC.MethodsTwenty-eight patients (n = 18 HLRCC patients with 22 lesions, n = 10 controls) were independently evaluated by three abdominal radiologists with different levels of experience using four combinations of MRI sequences in two separate sessions (session 1: DWI with b-800, session 2: DWI with b-2000). T1 precontrast, T2-weighted (T2WI), and apparent diffusion coefficient (ADC) sequences were similar in both sessions. Each identified lesion was subjectively assessed using a six-point cancer likelihood score based on individual sequences and overall impression.ResultsThe ability to distinguish benign versus malignant renal lesions improved with the use of b-2000 for more experienced radiologists (Reader 1 AUC: Session 1—0.649 and Session 2—0.938, p = 0.017; Reader 2 AUC: Session 1—0.781 and Session 2—0.921, p = 0.157); whereas no improvement was observed for the less experienced reader (AUC: Session 1—0.541 and Session 2—0.607, p = 0.699).ConclusionThe inclusion of ultra-high b-value DWI sequence improved the ability of classification of renal lesions in patients with HLRCC for experienced radiologists. Consideration should be given toward incorporation of DWI with b-2000 s/mm2 into existing renal MRI protocols.

RNA modification is a post-transcriptional level of regulation that is widely distributed in all types of RNAs, including mRNA, tRNA, rRNA, miRNA, and lncRNA, where N6-methyladenine (m 6 A) is the most abundant mRNA methylation modification. Significant evidence has depicted that m 6 A modifications are closely related to human diseases, especially cancer, and play pivotal roles in RNA transcription, splicing, stabilization, and translation processes. The most common urological cancers include prostate, bladder, kidney, and testicular cancers, accounting for a certain proportion of human cancers, with an ever-increasing incidence and mortality. The recurrence, systemic metastasis, poor prognosis, and drug resistance of urologic tumors have prompted the identification of new therapeutic targets and mechanisms. Research on m 6 A modifications may provide new solutions to the current puzzles. In this review, we provide a comprehensive overview of the key roles played by RNA modifications, especially m 6 A modifications, in urologic cancers, as well as recent research advances in diagnostics and molecularly targeted therapies.

Background Xanthogranulomatous pyelonephritis (XGP) is an uncommon form of chronic pyelonephritis. Most patients of XGP are diffuse in radiology and the clinical features are typical. Case presentation We present a case of 24-year-old female with the absence of symptoms and normal laboratory examinations. Contrast computed tomography and intravenous pyelography demonstrate infiltrative renal mass and renal cell carcinoma is presumed. Laparoscopic right radical nephrectomy is performed, but the final pathological result shows XGP. Conclusions As far as we know, this is the first case report of XGP without any symptoms/signs and with normal laboratory examinations. The diagnosis of atypical XGP is challenging and preoperative renal mass biopsy should be considered in special cases.