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4526 Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p

Background Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. Objective To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. Design, setting, and participants Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture–based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. Outcome measurements and statistical analysis Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S−Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. Results and limitations Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2 . We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p =0.088). Conclusions Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. Patient summary In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Background Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. Methods Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. Results Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P Conclusions IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P, There is an unmet clinical need for simple, accessible biomarkers to select patients who are more likely to respond to immune checkpoint therapy. Here the authors show that a lower neutrophil-to-lymphocyte ratio is associated with better overall and progressive-free survival, as well as higher rate of response, in a multi-cancer cohort of patients treated with immune checkpoint inhibitors.

BACKGROUND: Quantifying the degree to which spinal involvement of metastatic renal cell carcinoma (mRCC) is a locoregional phenomenon vs. a hematogenous, bone-specific affinity has implications for prognosis and antimetastatic therapy. OBJECTIVE: To investigate the distribution of spinal metastasis in mRCC and to explore relationships between clinical factors and patterns of spinal spread. METHODS: Patients with mRCC and spinal involvement from June 2005 to November 2018 were identified. Clinical and biologic features including primary tumor size and degree of spinal and nonbony metastatic involvement were collected. Spinal distributions were evaluated by the permutation test, with the null hypothesis that metastases are distributed uniformly across levels. RESULTS: One hundred patients with 685 spinal levels involved by mRCC were evaluated. A nonuniform spatial distribution was observed across the cohort (P < 0.001); a preponderance of thoracolumbar involvement was noted with the mode at L3. No significant deviation in metastatic distribution from uniform was observed in right- or left-sided tumors, subgroups of distant or local metastases, or histology. Patients with smaller tumors (

Clear cell renal cell carcinoma (ccRCC) is characterized by accumulation of neutral lipids and adipogenic trans-differentiation. We assessed adipokine expression in ccRCC and found that tumor tissues and patient plasma exhibit obesity-dependent elevations of the adipokine chemerin. Attenuation of chemerin by several approaches led to significant reduction in lipid deposition, and impairment of tumor cell growth in vitro and in vivo. A multi-omics approach revealed that chemerin suppresses fatty acid oxidation, preventing ferroptosis, and maintains fatty acid levels that activate HIF2α expression. The lipid CoQ and mitochondrial complex IV, whose biogenesis are lipid-dependent, were found decreased after chemerin inhibition, contributing to lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage and diminished tumor growth, demonstrating translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology.

Dedifferentiation and acquisition of chromosomal instability in renal cell carcinoma portends dismal prognosis and aggressive clinical behavior. However, the absence of reliable experimental models dramatically impacts the understanding of mechanisms underlying malignant progression. Here we established an in vivo genetic platform to rapidly generate somatic mosaic genetically engineerd immune-competent mouse models of renal tumors, recapitulating the genomic and phenotypic features of these malignancies. Leveraging somatic chromosomal engineering, we demonstrated that ablation of the murine locus syntenic to human 9p21 drives the rapid expansion of aggressive mesenchymal clones with prominent metastatic behavior, characterized by early emergence of chromosomal instability, whole-genome duplication, and conserved patterns of aneuploidy. This model of punctuated equilibrium provides a remarkable example of cross-species convergent evolution.SignificanceTo better understand the role of 9p21 in malignant progression, we generated a somatic mosaic GEMM of renal cancer, capturing the histological, genomic and evolutionary features of human disease. With this technology we demonstrated a critica role of 9p21 loss in metastatic evolution of RCC and provide a unique tool for testing new therapeutic treatments.

The first hypotheses about how the immune system affects cancers were proposed in the early 20th century. These early concepts about cancer immunosurveillance were further developed in the decades that followed, but a detailed understanding of cancer immunity remained elusive. It was only recently, through the advent of high-throughput technologies, that scientists gained the ability to profile tumors with a resolution that allowed for granular assessment of both tumor cells and the tumor microenvironment. The advent of immune checkpoint inhibitors (ICIs), which have proven to be effective cancer therapies in many malignancies, has spawned great interest in developing biomarkers for efficacy, an endeavor that highlighted the value of dissecting tumor immunity using large-scale methods. Response to ICI therapy has been shown to be a highly complex process, where the dynamics of tumor and immune cells is key to success. The need to understand the biologic mechanisms at the tumor–immune interface has given rise to the field of cancer immunogenomics, a discipline that aims to bridge the gap between cancer genomics and classical immunology. We provide a broad overview of this emerging branch of translational science, summarizing common platforms used and recent discoveries in the field, which are having direct clinical implications. Our discussion will be centered around the genetic foundations governing tumor immunity and molecular determinants associated with clinical benefit from ICI therapy. We emphasize the importance of molecular diversity as a driver of anti-tumor immunity and discuss how these factors can be probed using genomic approaches.

Purpose: We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC). Experimental Design: A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations. Results: Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%–17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%–11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16–6.16; Fisher's P = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46–5.40; P = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors. Conclusions: RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.

440 Background: Neoadjuvant chemotherapy (NAC) has proven survival benefits for invasive urothelial carcinoma of the bladder, yet its role in upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a phase II multicenter trial of NAC with gemcitabine and cisplatin (GC) in patients with high-risk UTUC prior to extirpative surgery to evaluate major outcomes of response, survival, and tolerability. Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of GC prior to surgical resection and lymph node dissection. The primary study endpoint was pathologic response rate (defined as < pT2N0). Patients with progressive disease prior or unable to proceed to surgery were considered treatment failures. Secondary endpoints included time to disease progression (PFS), overall survival (OS), and safety and tolerability. Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response, meeting the primary endpoint of the study. A complete response was noted in 11 patients (19%), defined as pT0N0. Forty patients (70%) tolerated all four cycles of GC, and all patients proceeded to surgery. The 90-day ≥ grade 3 surgical complication rate was 7.0%. With a median follow up of 42.3 months among survivors, six patients succumbed to disease. Two and five-year PFS were 76% (95% CI 66, 89) and 61% (95% CI 47, 78). Two and five-year OS were 93% (95% CI 86, 100) and 79% (95% CI 67, 94). Patients demonstrating pathologic response had improved PFS and OS compared to those who did not (two-year PFS 91% vs 52%, log-rank p < 0.001, two-year OS 100% vs 80%, log-rank p < 0.001). Conclusions: NAC for high-risk UTUC demonstrates outcomes of favorable pathologic response, is well tolerated requiring minimal delay to surgery without significant perioperative complication risk, and thus should be considered a new standard of care option for patients with high-risk UTUC. Better survival outcomes in patients with favorable pathologic features after NAC indicate a potential clinical benefit to this approach. Clinical trial information: NCT01261728.

Sarcomatoid dedifferentiation is an uncommon feature that can occur in most histological subtypes of renal cell carcinomas (RCCs) and carries a decidedly poor prognosis. Historically, conventional treatments for sarcomatoid RCCs (sRCCs) have shown little efficacy, and median survival is commonly 6–13 months. Despite being first described in 1968, the mechanisms driving sarcomatoid dedifferentiation remain poorly understood, and information and treatment options available to physicians and patients are limited. When diagnosed at an early stage, surgical intervention remains the treatment of choice. However, preoperative identification through routine imaging or biopsy is unreliable and most patients present with advanced disease and systemic symptoms. For these patients, the role of cytoreductive nephrectomy is disputed. The expansion of immunotherapies approved for RCCs has generated a search for biomarkers that might be indicative of treatment response in sRCCs, although a proven effective systemic agent remains elusive. PDL1 expression is increased in sarcomatoid dedifferentiated renal tumours, which suggests that patients with sRCCs could benefit from PD1 and/or PDL1 immune checkpoint blockade therapy. Treatment outcomes for sarcomatoid tumours have remained relatively consistent compared with other RCCs, but further investigation of the tumour–immune cell microenvironment might yield insights into further therapeutic possibilities., In this Review, Blum et al. summarize the current knowledge on sarcomatoid renal cell carcinoma, a diagnosis characterized by the presence of sarcomatoid dedifferentiation and a poor prognosis. They discuss the origin, presentation, molecular biology and treatment of this disease., Key Points Sarcomatoid dedifferentiation is not considered to be a unique histological subtype of renal cell carcinomas (RCCs); rather, it can be present within any subtype of RCCs.Sarcomatoid dedifferentiation appears in ~4% of all RCCs, but is present in ~20% of all metastatic RCCs. According to WHO guidelines, any RCC with sarcomatoid dedifferentiation is a WHO–International Society of Urological Pathology grade 4 lesion.Sarcomatoid dedifferentiation is often heterogeneously present within RCCs, making routine imaging and biopsy unreliable for preoperative detection. Surgical resection for localized disease is the standard of care, with subsequent close monitoring of patients following surgery.In patients with metastatic disease, conventional therapies such as surgery and systemic agents have been ineffective and overall 5-year survival remains at 23.5–33%.Previous genomic analyses have failed to identify definitive mutational drivers of disease. However, sarcomatoid RCCs (sRCCs) have been shown to have higher PD1 and PDL1 expression than other subtypes of RCCs. Newer combinations of immune checkpoint inhibitor immunotherapies could yield improved responses and outcomes.Studies investigating sRCCs are limited by patient numbers owing to the low incidence of sRCCs and their advanced stage at presentation. Multi-institutional efforts to establish a consensus on treatment recommendations based on highly powered data are essential.

Mitochondrial DNA (mtDNA) encodes essential protein subunits and translational machinery for four distinct complexes of oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, we demonstrate that pathogenic mtDNA mutations arise in tumors at a rate comparable to the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumor lineages. Loss-of-function mutations accumulate at an elevated rate specifically in Complex I, and often arise at specific homopolymeric hotspots. In contrast, Complex V is depleted of all non-synonymous mutations, suggesting that mutations directly impacting ATP synthesis are under negative selection. Both common truncating mutations and rarer missense alleles are associated with a pan-lineage transcriptional program, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal adenocarcinoma patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with significant implications for patient stratification, prognosis and therapeutic development.

Introduction: We evaluated the trajectory of estimated glomerular filtration rate (eGFR) after kidney surgery in patients with kidney cancer and chronic kidney disease (CKD). Methods: We identified 1204 consecutive patients in our institutional database with preoperative CKD undergoing partial or radical nephrectomy from 1998–2016. Postoperative eGFR was tracked, with patients censored when receiving dialysis or kidney transplantation. A multivariable mixed-effects models assessed associations between preoperative baseline patient and tumor characteristics, and longitudinal eGFR. The Kaplan-Meier method and multivariable Cox regression were used to estimate overall survival, cancer-specific survival, and cumulative incidence of dialysis. Results: Preoperatively, 892 (74.1%), 271 (22.5%), and 41 (3.4%) patients had CKD stage 3a, 3b, and 4/5, respectively. There were 55 patients dialyzed and 355 deaths (99 from kidney cancer). Median followup was 8.1 years, with 25 781 postoperative eGFR measurements. Factors associated with decreasing eGFR postoperatively included radical nephrectomy, male gender, older age, increased body mass index (BMI), and cardiovascular risk factors. We observed a significant interaction effect between time from surgery and preoperative CKD stage: the eGFR of stage 3a patients improved, while stage ≥3b declined (p

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior.To comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes.We identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients.Nonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes.A higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034).CCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management.We explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients., The advancement of upper tract urothelial carcinoma (UTUC) research is hampered by the lack of disease-specific models. Here, the authors report patient derived xenograft and cell line models of UTUC, and show that these models retain the genomic and biological heterogeneity of human disease.

INTRODUCTION AND OBJECTIVE:Intraoperative analgesics may impact oncological outcomes in various malignancies, however this association has not been tested in kidney cancer. in the enhanced recovery...

INTRODUCTION AND OBJECTIVE:Patients with metastatic upper tract urothelial carcinoma (UTUC) have limited treatment options: cisplatin-based adjuvant chemotherapy has been shown to provide a surviva...

INTRODUCTION AND OBJECTIVE:We report our experience with next-generation sequencing to characterize the prevalence and genomic landscape of actionable genomic alterations in renal cell carcinoma (R...

INTRODUCTION AND OBJECTIVE:To investigate the distribution of spinal metastasis in metastatic renal cell carcinoma (mRCC) and to explore relationships between biological and clinical factors and pa...

INTRODUCTION AND OBJECTIVE:Nephrectomy, the standard of care for localized renal cell carcinoma (RCC), may lead to kidney function loss. To identify prognostic biomarkers of postoperative renal fun...

INTRODUCTION AND OBJECTIVE:Long term survival in sarcomatoid renal cell carcinoma (sRCC) is unusual with median survivals reported between 6-10 months. However, some patients live well past median ...

INTRODUCTION AND OBJECTIVE:Intraoperative anesthetic parameters, primarily intraoperative hypotension, are associated with renal function after surgeries which do not involve the kidney; few studie...

INTRODUCTION AND OBJECTIVE:Tumor necrosis has been widely acknowledged as an adverse factor in patients with renal cell carcinoma (RCC). Furthermore, it has been shown that the proportion of non-en...

SummaryTumor progression is associated with overstimulation of cytotoxic T lymphocytes (CTLs), resulting in a dysfunctional state of exhaustion. How T cell exhaustion is elicited in the tumor remains poorly understood. Here we show that tumor-associated macrophages (TAMs) present cancer cell antigen and induce CTL exhaustion through a gene expression program dependent on the transcription factor interferon regulatory factor-8 (IRF8). In a transgenic model of murine breast cancer, CTL priming was supported by IRF8-dependent dendritic cells; yet, CTL exhaustion required TAM expression of IRF8, and its ablation suppressed tumor growth. An analysis of the highly immune-infiltrated human renal cell carcinoma tumors revealed abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. The IRF8 signature co-segregated with T cell exhaustion markers and was negatively associated with long-term patient survival. Thus, CTL exhaustion is promoted by TAMs via IRF8, and this crosstalk may be disrupted in TAM-targeted therapies.

SummaryThe immune system employs two distinct defense strategies against infections: pathogen elimination typified by type 1 immunity, and pathogen containment exemplified by type 2 immunity in association with tissue repair. Akin to infectious diseases, cancer progresses with cancer cell acquisition of microorganism-like behavior propagating at the expense of the host. While immunological mechanisms of cancer cell elimination are well defined, whether immune-mediated cancer cell containment can be induced is poorly understood. Here we show that ablation of transforming growth factor-β receptor II (TGFβRII) in CD4+T cells promotes tumor tissue healing and halts cancer progression. Notably, the restorative response is dependent on the T helper 2 cytokine IL-4 fortifying vasculature organization that spares only proximal layers of cancer cells from hypoxia, nutrient starvation and death. Thus, type 2 immunity represents an effective cancer defense mechanism, and TGFβ signaling in helper T cells may be targeted for novel cancer immunotherapy.

Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.

Background: Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients benefit, there is a strong need for predictive biomarkers. The aim of this study was to analyze the predictive capacity of neutrophil-to-lymphocyte ratio (NLR) in cancer patients treated with ICI, and to analyze the predictive value of combining NLR with tumor mutational burden (TMB). Methods: Retrospective cohort study of patients treated during 2015-2018. A total of 1714 patients with 16 different cancer types, who had complete blood count within 30 days prior to first ICI infusion, and whose tumors underwent next-generation sequencing were included. Overall survival, progression-free survival, response to ICI, and clinical benefit (response or stable disease ≥6 months) were the primary endpoints. Findings: Patients with NLR in the top 20th percentile within cancer type had significantly poorer overall survival (HR = 2·17; 95% CI, 1·89-2·50; P

There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.

This cohort study examines the relative and disease-specific survival rates for patients with 10 early-stage cancers.

We evaluated the outcomes of surgical intervention and active surveillance in patients diagnosed with cystic renal cell carcinoma at our hypothesized radiological cutoff of greater than 50% cystic.We identified all 430 patients with a pathologically confirmed cystic renal mass that fit our criteria from 2000 to 2015. The 292 patients with a lack of computerized tomography, tumors less than 50% cystic on imaging, multifocal tumors and prior renal cell carcinoma were excluded from study. Patients were stratified into benign or malignant subgroups, and radiological, clinicopathological and oncologic features were determined. Univariate and multivariate associations between clinicoradiological parameters in each group were analyzed. We similarly reviewed the records of a separate cohort of patients treated with active surveillance for cystic renal cell carcinoma.Of the 138 identified cases of cystic renal cell carcinoma 102 (73.9%) were renal cell carcinoma and 36 (26.1%) were benign masses. Of the tumors 77.5% were Fuhrman grade 1-2, 83.4% were stage pT2 or less and 65.9% showed clear cell histology. On univariate analysis male gender, a solid component and increasing Bosniak classification were significant for malignancy. In a separate cohort we identified 38 patients on active surveillance. The growth rate was 1.0 mm per year overall and 2.3 mm per year for the solid component. At a median followup of more than 4 years in all cohorts there was no evidence of recurrence or metastasis of cystic renal cell carcinoma.Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection.

Purpose: Salivary gland carcinomas (SGC) are rare, aggressive cancers with high rates of recurrence and distant metastasis. These factors, and a lack of active systemic therapies, contribute to poor clinical outcome. Response rates with immune checkpoint blockade have been low, although clinical data remain sparse. To improve the efficacy of therapies, a more comprehensive understanding of relevant molecular alterations and immunologic processes is needed. Experimental Design: To characterize the immune microenvironment and neoantigen landscape of SGCs, we performed RNA sequencing (RNA-seq) in 76 tumors representing the three most lethal histologies: adenoid cystic carcinoma (ACC), myoepithelial carcinoma (MECA), and salivary duct carcinoma (SDC). We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction. In 37 cases also undergoing exome sequencing, we analyzed somatic mutations and neoantigens. Results: SDCs exhibited high levels of immune infiltration, with corresponding higher levels of T-cell dysfunction, and higher mutational load. In contrast, ACCs were characterized by an immune-excluded microenvironment, the presence of M2-polarized macrophages and myeloid-derived suppressor cells, and very low mutational load. MECAs were more heterogeneous, with both immune-low and immune-high phenotypes represented. Across all SGCs, levels of immune infiltration were associated with mutation- and fusion-derived neoantigens, and with aggressive clinical behavior. Conclusions: These findings provide new insights into the immune microenvironment and neoantigen landscape of SGCs, showing that mechanisms of immune escape appear to differ by histology. These data nominate potential immunologic vulnerabilities and may help guide the next steps of investigation in precision immunotherapy for these difficult-to-treat cancers.

TFEB is overexpressed in TFEB-rearranged renal cell carcinomas as well as in renal tumors with amplifications of TFEB at 6p21.1. As recent literature suggests that renal tumors with 6p21.1 amplification behave more aggressively than those with rearrangements of TFEB, we compared relative TFEB gene expression in these tumors. This study included 37 TFEB-altered tumors: 15 6p21.1-amplified and 22 TFEB-rearranged (including 5 cases from The Cancer Genome Atlas data set). TFEB status was verified using a combination of fluorescent in situ hybridization (n=27) or comprehensive molecular profiling (n=13) and digital droplet polymerase chain reaction was used to quantify TFEB mRNA expression in 6p21.1-amplified (n=9) and TFEB-rearranged renal tumors (n=19). These results were correlated with TFEB immunohistochemistry. TFEB-altered tumors had higher TFEB expression when normalized to B2M (mean: 168.9%, n=28), compared with non-TFEB-altered controls (mean: 7%, n=18, P=0.005). Interestingly, TFEB expression in tumors with rearrangements (mean: 224.7%, n=19) was higher compared with 6p21.1-amplified tumors (mean: 51.2%, n=9; P=0.06). Of note, classic biphasic morphology was only seen in TFEB-rearranged tumors and when present correlated with 6.8-fold higher TFEB expression (P=0.00004). Our results suggest that 6p21.1 amplified renal tumors show increased TFEB gene expression but not as much as t(6;11) renal tumors. These findings correlate with the less consistent/diffuse expression of downstream markers of TFEB activation (cathepsin K, melan A, HMB45) seen in the amplified neoplasms. This suggests that the aggressive biological behavior of 6p21.1 amplified renal tumors might be secondary to other genes at the 6p21.1 locus that are co-amplified, such as VEGFA and CCND3, or other genetic alterations.

Background The purpose of the study was to identify patient and disease characteristics that have an adverse effect on renal function after partial nephrectomy. Patients and Methods We conducted a retrospective review of 387 patients who underwent partial nephrectomy for renal tumors between 2006 and 2014. A line plot with a locally weighted scatterplot smoothing was generated to visually assess renal function over time. Univariable and multivariable longitudinal regression analyses incorporated a random intercept and slope to evaluate the association between patient and disease characteristics with renal function after surgery. Results Median age was 60 years and most patients were male (255 patients [65.9%]) and white (343 patients [88.6%]). In univariable analysis, advanced age at surgery, larger tumor size, male sex, longer ischemia time, history of smoking, and hypertension were significantly associated with lower preoperative estimated glomerular filtration rate (eGFR). In multivariable analysis, independent predictors of reduced renal function after surgery included advanced age, lower preoperative eGFR, and longer ischemia time. Length of time from surgery was strongly associated with improvement in renal function among all patients. Conclusion Independent predictors of postoperative decline in renal function include advanced age, lower preoperative eGFR, and longer ischemia time. A substantial number of subjects had recovery in renal function over time after surgery, which continued past the 12-month mark. These findings suggest that patients who undergo partial nephrectomy can experience long-term improvement in renal function. This improvement is most pronounced among younger patients with higher preoperative eGFR.

Background The genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications. Methods We collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours. Results The cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases. Conclusions These data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.

Background Parallel development of preclinical models that recapitulate treatment response observed in patients is central to the advancement of personalized medicine. Objective To evaluate the use of biopsy specimens to develop patient-derived xenografts and the use of corresponding cell lines from renal cell carcinoma (RCC) tumors for the assessment of histopathology, genomics, and treatment response. Design, setting, and participants A total of 74 tumor specimens from 66 patients with RCC were implanted into immunocompromised NOD- SCID IL2Rg −/− mice. Four cell lines generated from patients' specimens with clear cell pathology were used for comparative studies. Outcome measurements and statistical analysis Preclinical models were established and assessed. Engraftment rates were analyzed using chi-square testing. Analysis of variance (two-way analysis of variance) was conducted to assess tumor growth. Results and limitations Overall, 33 RCC mouse xenograft models were generated with an overall engraftment rate of 45% (33 of 74). Tumor biopsies engrafted comparably with surgically resected tumors (58% vs 41%; p =0.3). Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response. Engraftment rates from metastatic tumors were higher but not more significant than primary tumors (54% vs 34%; p =0.091). Our engraftment rate using metastases or biopsies was comparable with recent reports using resected primary tumors. In stark contrast to corresponding cell lines, all tested xenografts recapitulated patients' clinical response to sunitinib. Conclusions Patient-derived xenograft models can be effectively established from tumor biopsies. Preclinical xenograft models but not matched cell lines reflected clinical responses to sunitinib. Patient summary Matched patient-derived clear cell renal cell carcinoma xenografts and cell lines from responsive and refractory patients treated with sunitinib were established and evaluated for pharmacologic response to anti–vascular endothelial growth factor treatment. Both models accurately reflected the genetic characteristics of original tumors, but only xenografts recapitulated drug responses observed in patients. These models could serve as a powerful platform for precision medicine.

Background Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. Patients and Methods This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next-generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan–Meier method. Results The median age in the cohort was 28 (range, 12-72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1-10.9) and for 12 patients who received platinum-based therapy, median progression-free survival was 2.5 months (95% CI, 1.2-not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next-generation targeted sequencing showed no recurring mutations. Conclusions Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions.

Purpose To describe the unique clinical features, determine the genomics, and investigate the metabolic derangement of an extremely rare form of a hereditary lethal kidney cancer syndrome. Patients and Methods Three patients with lethal kidney cancer (age 19, 20, and 37 years) exhibiting persistent (1 to 3 months) extremely high levels of blood lactate (> 5 mM) despite normal oxygen perfusion, highly avid tumors on [18F]fluorodeoxyglucose positron emission tomography (PET), and pleomorphic histopathologic features were identified and treated in a single institute. Integrated studies including whole-genome sequencing (WGS), targeted sequencing, immunohistochemistry, cell-based assays, and 18F-glutamine PET imaging were performed to investigate this rare kidney cancer syndrome. Results All three patients with kidney cancer were initially given various diagnoses as a result of diverse tumor histopathology and atypical clinical presentations. The correct diagnoses of these SDHB-mutated renal cell carcinomas were first made based on cancer genomics. Genomic studies of the blood and tumors of these patients identified three different kinds of germline loss-of-function mutations in the SDHB gene and the common loss of heterozygosity in the remaining SDHB allele thorough somatic chromosome 1p deletion. In one patient, WGS revealed that a germline mutation of SDHB coupled with loss of heterozygosity was the sole genetic event. Cancer evolution analysis of SDHB tumors based on WGS demonstrated that SDHB in kidney epithelium fulfills the Knudson two-hit criteria as a major tumor suppressor gene. SDHB−/− tumor cells displayed increase in glucose uptake and lactate production, alteration in mitochondrial architecture, and defect in oxidative respiration. 18F-Glutamine PET imaging studies demonstrated increased glutamine metabolism. Conclusion SDHB-deficient metastatic renal cell carcinoma is a rare, aggressive form of kidney cancer that manifests with clinical evidence of a severe Warburg effect, and genomic studies demonstrated two genetic hits at SDHB genes during kidney tumorigenesis.

Background Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. Objective To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. Design, setting, and participants DNA sequencing data were pooled from three collaborative genomic cohorts ( n =754) and our institutional database ( n =295). All patients had clinical data and identification of somatic mutations from their primary tumors. Outcome measurements and statistical analysis Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing ( q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. Results and limitations Association with tumor size was found for mutations in BAP1 ( q =0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 ( q =0.004) and TP53 ( q =0.001) were associated with decreased CSS in a multivariable model; only TP53 ( q =0.005) remained significant when SSIGN score was included. SETD2 mutations ( q =0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. Conclusions In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53 . After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. Patient summary Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence.

Molecular features associated with risk of metachronous metastases (MM) in clear cell renal cell carcinoma (ccRCC) are poorly defined. Here, we performed systematic genomic and molecular analysis of 192 ccRCC primary tumors with extended clinical follow-up for development of MM. Whole-exome sequencing analysis revealed no association between somatic mutations and development of MM. However, chromosomal deletions at 1p33 were more prevalent in tumors that later progressed with MM. We inferred immune cell infiltrates and found that depletion of regulatory T cells and M1 macrophages were associated with development of MM. Next, we used bulk tumor transcriptome deconvolution to estimate cancer (malignant) and stromal (non-malignant) cell gene expression differences between MM and indolent primary tumors. Downregulation of the Crumbs complex component PATJ (1p31) in cancer cells of MM tumors suggested loss of apicobasal cell polarity as a risk factor in metastatic progression. We also identified downregulation of fatty acid degradation in cancer cells of MM tumors. Overall, our results nominate novel genomic and molecular features underpinning metachronous metastasis in ccRCC. Citation Format: Marjan Mojtabavi Naeini, Neha Rohatgi, Umesh Ghoshdastider, Ari A. Hakimi, Anders Jacobsen Skanderup. Genomic and molecular features of metachronous metastasis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB241.

Objectives To review perioperative, renal functional, and oncological outcomes of the kidney split technique in performing partial nephrectomy (PN) to resect completely endophytic renal tumors. Methods All consecutive patients who underwent open PN with kidney split between 2015 and 2019 at our institution were included. In this approach the kidney is incised along Brodel's line in an avascular plane to locate and then resect the endophytic tumor. Clinicopathologic data, perioperative metrics, complications, renal function, recurrence, and mortality were analyzed using descriptive statistics. Results Forty-two open PN with kidney split were performed in 40 patients. No patients required conversion to radical nephrectomy. Most tumors were pT1a renal cell carcinoma (76%), with no recurrences or deaths after a median follow-up of 15 months. All patients had tumors of moderate or high complexity by R.E.N.A.L. nephrometry score. Median cold ischemia time, operative time, estimated blood loss, and inpatient length-of-stay were 34 minutes, 152 minutes, 225 ml, and 2 days, respectively. No patients experienced any Clavien-Dindo grade 4 or 5 complications. Postoperative estimated glomerular filtration rate (eGFR) at last follow-up was >30 ml/min/1.73m2 in all but one patient, and no patients required dialysis. Conclusions The kidney split represents an effective PN technique to resect complex, endophytic renal tumors. In our experience, this technique affords acceptable perioperative outcomes, preserved renal function, and no short-term recurrences or mortality events. Our series highlights the importance of adapting classical surgical techniques, using cold ischemia, and relying on preoperative and intraoperative ultrasonography to effectively guide this complex kidney-sparing operation.

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

Background Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. Objective To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. Design, setting, and participants Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). Outcome measurements and statistical analysis Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. Results and limitations Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1 , BAP1 , and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. Conclusions PBRM1 , BAP1 , and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. Patient summary Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.