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Abstract Background Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. Methods Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. Results Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. Conclusions These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment. Trial registration The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.

Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.

Metastatic primary cutaneous extramammary Paget disease (EMPD) is a rare clinical entity with a 5-year survival

Renal medullary carcinoma (RMC) is a highly aggressive disease associated with sickle hemoglobinopathies and universal loss of the tumor suppressor gene SMARCB1. RMC has a relatively low rate of incidence compared with other renal cell carcinomas (RCCs) that has hitherto made molecular profiling difficult. To probe this rare disease in detail we performed an in-depth characterization of the RMC tumor microenvironment using a combination of genomic, metabolic and single-cell RNA-sequencing experiments on tissue from a representative untreated RMC patient, complemented by retrospective analyses of archival tissue and existing published data. Our study of the tumor identifies a heterogenous population of malignant cell states originating from the thick ascending limb of the Loop of Henle within the renal medulla. Transformed RMC cells displayed the hallmarks of increased resistance to cell death by ferroptosis and proteotoxic stress driven by MYC-induced proliferative signals. Specifically, genomic characterization of RMC tumors provides substantiating evidence for the recently proposed dependence of SMARCB1-difficient cancers on proteostasis modulated by an intact CDKN2A-p53 pathway. We also provide evidence that increased cystine-mTORC-GPX4 signaling plays a role in protecting transformed RMC cells against ferroptosis. We further propose that RMC has an immune landscape comparable to that of untreated RCCs, including heterogenous expression of the immune ligand CD70 within a sub-population of tumor cells. The latter could provide an immune-modulatory role that serves as a viable candidate for therapeutic targeting.

Abstract Backgound Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a subtype of RCC that is increasingly recognized pathologically. The aim of this study was to evaluate the imaging features of FH-RCC on computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG PET), and to determine the pre-operative diagnostic potential of imaging. Methods This single-site retrospective study included patients with histologically confirmed FH-RCC or with a renal cancer and known germline FH mutation; imaging of the renal mass before treatment with contrast-enhanced CT, contrast-enhanced MRI, or FDG PET/CT between October 2007 and May 2019. Clinical information, pathological data, and imaging features were analyzed and reported descriptively. Results Sixteen patients with sixteen tumors were included (median age 46 years, interquartile range 38–53 years; 31 % female). Almost all tumors were unifocal (15/16, 94 %). Most tumors had infiltrative margins (14/16, 88 %); few were circumscribed (2/16, 12 %). A large cystic tumor component (> 75 % of tumor volume) was seen in 8/16 (50 %) of tumors. Involvement of renal sinus fat was seen in 13/16 (81 %) of tumors, involvement of the hilar collecting system in 8/16 (50 %), and renal vein tumor thrombus in 6/16 (38 %). All 12 tumors (100 %) imaged with MRI had heterogenous tumor enhancement and heterogenous T2 signal. Of those patients that had diffusion-weighted imaging, 11/11 (100 %) of tumors had diffusion restriction in the solid portions of the tumor. Of the patients who had PET, 3/3 (100 %) tumors showed high metabolic activity with mean maximum standardized uptake value (SUVmax) of 16.4 (range 9.6–21.9). Patients presented with retroperitoneal nodal metastases in 69 % of cases and distant metastases in 75 %. Of those four patients without metastatic disease at presentation, three (75 %) developed metastases within 4 years of diagnosis. Conclusions In our study, the majority of tumors (≥ 75 %) were unifocal, had an infiltrative margin, invaded the renal sinus fat, and presented with distant metastases. On MRI, most tumors had heterogenous T2 signal and diffusion restriction in their solid components. The small number of cases that had PET imaging showed high metabolic activity.

Abstract Background Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), caused by heterozygous germline pathogenic variants in the FH, confers an increased risk for cutaneous and uterine leiomyomas and renal cancer. Methods About 13,722 advanced cancer patients, including 560 with renal cell carcinoma, had germline analysis performed in the context of tumor‐normal sequencing under an IRB approved protocol. Results We report two unrelated individuals with early onset kidney cancer who both carried the c.914C > T (p.Phe305Ser) germline variant in the FH. Both tumors exhibited loss of FH staining by immunohistochemistry and/or positive 2SC staining. Subsequent familial testing discovered that a daughter of a proband who carried the variant had both cutaneous and uterine leiomyomas. Conclusion This combination of evidence suggests that the FH c.914C > T (p.Phe305Ser) is pathogenic for HLRCC.

Cell lines are central to cancer research, but knowing which cell lines are the best representative of actual tumours is a major challenge. Here the authors provide a resource assessment of 65 renal cell lines to assist researchers in selecting suitable lines for studying specific renal carcinoma subtypes.

While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.

A subset of renal cell carcinomas have uncertain histology and are aggressive in nature. Here, the authors examine this group of unclassified renal cancers using genomics techniques and identify further subclasses of the tumours that have differing prognoses.

To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

We are presenting a compelling case of a 61-year-old female with a history of appendiceal mucinous adenocarcinoma (AMA) with a new complaint of irritative lower urinary tract symptoms. Magnetic resonance imaging (MRI) showed a semi-circumferential, T2 hyperintense, rim enhancing, and lacking restricted diffusion lesion involving the urethra and infiltrating the right perineal and internal obturator muscles. The suspected differential diagnosis was urethral malignancy, based on her cancer history and MRI findings. After interdisciplinary consensus, the patient underwent excision of the lesion, and pathology was consistent with metastasis from the primary tumor. The urethra is a rare site of primary malignancy and metastatic disease. In particular, a non-contiguous metastatic disease involving the urethra is exceedingly rare. To the best of our knowledge, this is the first report of an AMA metastasizing to the urethra., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)