Characterization Of Renal Cell Carcinoma Research Articles

Abstract 1846: Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell carcinoma

Abstract Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conduct comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. RCC tumors are distinctly separated from corresponding normal tissues through multi-omics clustering, a distinction further supported by pathway analysis. In addition, various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest adaptive immune response and angiogenesis with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways and alteration in VHL (100.0%) along with BAP1 (24.0%) genes. C3 (N=19) was associated with enrichment in inflammatory response with dismal prognosis and therapeutic resistance to tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. Transglutaminase 2 (TGM2), a crosslinking enzyme, is identified as a potential marker with therapeutic implication for ccRCC. Collectively, this study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Citation Format: Woo Sun Kwon, Chang Gon Kim, Harim Koo, Woo Kyun Bae, Eu Chang Hwang, Won Sik Ham, Nam Hoon Cho, Jason K. Sa, Jong Bae Park, Sun Young Rha. Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1846.

TRB CDR3-cancer testis antigen chemical complementarity scoring for identifying productive immune responses in renal cell carcinoma.

Immunogenomics approaches to the characterization of renal cell carcinoma (RCC) have helped to better our understanding of the features of RCC immune dysfunction. However, much is still unknown with regard to specific immune interactions and their impact in the tumor microenvironment. This study applied chemical complementarity scoring for the TRB complementarity determining region-3 (CDR3) amino acid sequences and cancer testis antigens (CTAs) to determine whether such complementarity correlated with survival and the expression of immune marker genes. TRB recombination reads from RCC tumor samples from RNAseq files obtained from two separate databases, Moffitt Cancer Center and The Cancer Genome Atlas (TCGA), were evaluated. Chemical complementarity scores (CSs) were calculated for TRB CDR3-CTA pairs and survival assessments based on those CSs were performed. Moffitt Cancer Center and TCGA cases representing the upper 50th percentile of chemical CSs for TRB CDR3 amino acid sequences and the CTA POTEA were found to be associated with a better overall survival (OS) Also, greater tumor RNA expression of multiple immune signature genes, including granzyme A, granzyme B, and interferon-gamma were correlated with the higher chemical CSs. These results indicate that TRB CDR3-CTA chemical complementarity scoring may be useful in distinguishing RCC cases with a productive, anti-tumor immune response from cases where basic immune parameter assessments are inconsistent with a productive immune response.

Evaluation of a novel Re-VASC score to differentiate malignant and benign T1a renal masses.

e16548 Background: Early characterization of renal cell carcinoma (RCC) is pertinent for cancer prognosis and patient treatment. However, characterization of renal masses as benign or malignant on computed tomography (CT) remains a difficult clinical challenge. Angiogenesis plays a major role in RCC progression and assessing neovascularity in tumor-burdened kidneys with Re-VASC scoring has been shown to aptly predict tumor pathology and staging. In the current study, we evaluated if Re-VASC can reliably differentiate between malignant T1a ( < 4cm) RCC and benign T1a renal masses. Methods: All eligible patients had a diagnosis of T1a from pathologic or clinical evaluation. The inclusion criteria for malignant masses included a diagnosis of RCC by pathology after partial or radical nephrectomy. Our T1a benign group was comprised of patients with a diagnosis of a non-malignant renal mass (angiomyolipoma or oncocytoma) established via histopathology or CT imaging (fat containing lesions). Re-VASC score was calculated on axial preoperative contrast enhanced CT utilizing the system described below: 0 = No visible neovascularization 1 = visualized single new vessel < 3mm in diameter 2 = visualized single new vessel ≥3mm in diameter 3 = visualized multiple new vessels < 3mm in diameter 4 = visualized multiple new vessels and at least one vessel ≥3mm in diameter. Results: A total of 64 benign and 69 malignant T1a tumors were included. Comparison of the two groups demonstrated no significant differences with regards to age, sex, ASA, and BMI. The average Re- VASC scores was 0.159 and 0.753 for benign and malignant masses respectively (p < 0.001). Additionally, the tumor size for benign masses was 2.373 and for malignant masses was 2.546 (p = 0.210). There was no significant difference in Re-VASC score between the contralateral kidneys of malignant and benign kidney masses (p < 0.508). Additionally, the sensitivity, specificity and positive predictive values were 26%, 86% and 74% respectively, when utilizing a Re-VASC score of 1 as a cutoff for malignancy. Conclusions: Our results show a significantly higher Re-VASC score in T1a malignant tumors and T1a benign tumors. While biopsy remains the gold standard for confirmation of malignant tumors such as RCC, radiological evaluation with tumor scoring systems like Re-VASC may offer a useful clinical decision-making tool in a less-invasive manner. Because renal biopsy carries non-negligible risk of complications, reducing volume of biopsies among low-risk patients may lead to better overall care. The Re-VASC score shows potential as a confirmatory test with a specificity of 86%. We would like to apply the Re-VASC score to an expanded multi-center trial, in order to assess its translatability to the general population.

Abstract 722: Epidemiological characterization of renal cell carcinoma in Hispanics: A single US center cohort study

Abstract Background: Annually, there are over 400,000 new cases of renal cell carcinoma (RCC) and more than 170,000 deaths worldwide. RCC is one of the top ten more prevalent malignancies in the United States, with 76,000 new cases each year and almost 14,000 deaths. Over the past half-century, RCC has more than doubled in incidence. RCC seems to have a greater incidence among Hispanics with a nearly three-fold increase. The epidemiology of RCC in the Caucasian population has been previously studied. However, there is a knowledge gap on disparities in RCC on minority populations. Studying the epidemiology of RCC in Hispanics is integral to our community where Hispanics make up 70%. Methods: We conducted a retrospective cohort study to describe the characteristics and rates of recurrence of RCC among patients treated at Sylvester Comprehensive Cancer Center in Miami (which serves four counties in South Florida) between June 2010 to June 2022. We identified ethnicity as Hispanic/Latino (HL) or non-Hispanic/Latino (NHL). Clinical presentation was classified based on the last encounter as local RCC without recurrence, metastatic RCC after nephrectomy, and metastatic RCC at diagnosis/de novo. Results: We analyzed a total of 2049 patients aged 18 and older diagnosed with RCC, from which 1014 patients (47.90%) were identified as NHL and 933 (48.02%) as HL. A subtotal of 435 patients (22.86%) had metastatic RCC at diagnosis/de novo, from which 245 (55.60%) were NHL, and 176 (40.57%) were HL. A subtotal of 1614 patients (77.14%) were diagnosed with local RCC and underwent nephrectomy, from which 769 (45.61%) were identified as NHL and 787 (50.22%) as HL. From the NHL group that underwent nephrectomy, 223 patients (28.28%) had recurrent disease, and 546 patients (71.72%) did not. From the HL group, 176 patients (21.81%) had recurrent disease, and 611 (78.19%) did not. Overall, 409 patients had metastasis after nephrectomy, of which 176 (44.5%) were HL, and 203 (52.42%) were NHL. Conclusions: In this cohort of patients with RCC, almost 50% of patients diagnosed with metastasis were HL. NHL appeared to have more disease recurrence after nephrectomy and higher rates of metastatic disease at diagnosis compared to Hispanics. Further histopathological differences, clinical outcomes, genomic characterization, and rates of clinical trial participation between the NHL and HL cohorts will be presented at the meeting, along with comparisons between US and foreign-born HLs. Citation Format: Abner A. Murray, Jesus A. Ocejo Gallegos, Sandra Jones, Jose Noy, Rosa L. Frias, Leticia E. Campoverde, Jaime R. Merchan. Epidemiological characterization of renal cell carcinoma in Hispanics: A single US center cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 722.

Shear wave elastography in the characterization of renal cell carcinoma and angiomyolipoma.

Detection and characterization of renal lesions are common in daily clinical practice. To investigate the effectiveness of shear wave elastography (SWE), a novel radiological examination technique, in the characterization of renal masses. The study included a total of 68 patients (33 men, 35 women; mean age = 57.71 ± 12.08 years; age range = 19-83 years) who underwent SWE. SWE measurements were obtained at depths of 2-8 cm from the probe surface in two different positions from an analysis window of approximately 0.5 × 1.0 cm on ultrasound. The cutoff SWE was calculated for the differentiation of renal cell carcinoma (RCC) and angiomyolipoma (AML) by receiver operating characteristic (ROC) analysis. When the result was statistically significant, the sensitivity, specificity, accuracy, and positive and negative predictive values of the test were calculated. Mass-to-parenchyma SWE ratios of RCCs were significantly higher than those of AMLs (P = 0.003). In ROC curve analysis, the SWE cutoff was 1.215 m/s to differentiate RCCs from AMLs. The area under the ROC curve was calculated as 0.74 (95% CI = 0.610-0.871, sensitivity = 70.7%, specificity = 70.6%, positive predictive value = 87.8%, negative predictive value = 44.4%). The SWE technique is increasingly used and may be useful in distinguishing RCC and AML lesions, and especially clear cell and non-clear cell RCCs.

Proteomic Characterization of Renal Cell Carcinoma Using MALDI-MS Imaging

Proteomic Characterization of Renal Cell Carcinoma Using MALDI-MS Imaging

Molecular characterization of renal cell carcinoma with venous tumor thrombus: Genomic aberrations with renal vein wall invasion.

385 Background: Renal cell carcinoma (RCC) patients with tumor thrombus (TT) have been observed distinct phenotypes of TT: deeply invading into the wall of renal vein/inferior vena cava (IVC) (DITT) or minimal/non-invasion (NITT), with different surgical strategy and post-thrombectomy outcome. However, the molecular characters of DITT/NITT have not been investigated, due to operational challenges and limited patient access. Methods: In this study, primary tumor and TT samples from 68 patients having IVC thrombectomy were prospectively collected for DNA mutation profiling and RNA expression profiling, using Predicine panel-based next generation sequencing and transcriptome RNA-SEQ, respectively. Next-generation sequencing and bioinformatics data analysis was conducted in Colleges of American Pathologist (CAP)-accredited laboratory in Shanghai, China (Huidu Shanghai Medical Sciences Ltd.). Kaplan–Meier survival analysis was performed to analyze the correlation between DITT/NITT and clinical outcome, and p-values were calculated using log-rank test. Results: When metastasis was detected, patients with DITT showed significantly shorter overall survival comparing to patients with NITT (P < 0.05, log-rank test). However, this difference was not observed in non-metastatic group. Successful sequencing has been achieved in 100% (68/68) patients. NITT tumor bulks more frequently carried mutations in PTEN, TP53 and epigenetic regulators such as SETD2, PBRM1 and KDM5C and had higher expression of cell cycle related pathway genes. In contrast, DITT had lower expression of genes encoding cell adhesion and extracellular matrix molecules such as ADAM33, NCAM1 and FLRT2, which could contribute to higher invasiveness. Conclusions: To our knowledge, this is the first large study to systematically interrogate genomic landscape and molecular features of different TT phenotypes in RCC patients. The differential genomic mutation and gene expression landscapes across the two groups may reflect biologic differences and clinical implications such as tumor invasiveness and aggressiveness.

P0542 - Comprehensive molecular characterization of renal cell carcinoma in the Chinese population

P0542 - Comprehensive molecular characterization of renal cell carcinoma in the Chinese population

Application of diffusion kurtosis tensor MR imaging in characterization of renal cell carcinomas with different pathological types and grades

BackgroundTo probe the feasibility and reproducibility of diffusion kurtosis tensor imaging (DKTI) in renal cell carcinoma (RCC) and to apply DKTI in distinguishing the subtypes of RCC and the grades of clear cell RCC (CCRCC).MethodsThirty-eight patients with pathologically confirmed RCCs [CCRCC for 30 tumors, papillary RCC (PRCC) for 5 tumors and chromophobic RCC (CRCC) for 3 tumors] were involved in the study. Diffusion kurtosis tensor MR imaging were performed with 3 b-values (0, 500, 1000s/mm2) and 30 diffusion directions. The mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr) values and mean diffusity (MD) for RCC and contralateral normal parenchyma were acquired. The inter-observer agreements of all DKTI metrics of contralateral renal cortex and medulla were evaluated using Bland-Altman plots. Statistical comparisons with DKTI metrics of 3 RCC subtypes and between low-grade (Furman grade I ~ II, 22 cases) and high-grade (Furman grade III ~ IV, 8 cases) CCRCC were performed with ANOVA test and Student t test separately. Receiver operating characteristic (ROC) curve analyses were used to compare the diagnostic efficacy of DKTI metrics for predicting nuclear grades of CCRCC. Correlations between DKTI metrics and nuclear grades were also evaluated with Spearman correlation analysis.ResultsInter-observer measurements for each metric showed great reproducibility with excellent ICCs ranging from 0.81 to 0.87. There were significant differences between the DKTI metrics of RCCs and contralateral renal parenchyma, also among the subtypes of RCC. MK and Ka values of CRCC were significantly higher than those of CCRCC and PRCC. Statistical difference of the MK, Ka, Kr and MD values were also obtained between CCRCC with high- and low-grades. MK values were more effective for distinguishing between low- and high- grade CCRCC (area under the ROC curve: 0.949). A threshold value of 0.851 permitted distinction with high sensitivity (90.9%) and specificity (87.5%).ConclusionOur preliminary results suggest a possible role of DKTI in differentiating CRCC from CCRCC and PRCC. MK, the principle DKTI metric might be a surrogate biomarker to predict nuclear grades of CCRCC.Trial registrationChiCTC, ChiCTR-DOD-17010833, Registered 10 March, 2017, retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=17559.

A "Lymphocyte MicroRNA Signature" as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastatic Renal Cell Carcinoma: Pointing towards Epigenetic Reprogramming.

Simple SummaryMicroRNAs are small molecules of non-coding RNAs which regulate gene expression at the post-transcriptional level. Normal miRNA expression and function can be deregulated in cancer. The comprehensive molecular characterization of Renal Cell Carcinoma shows several genes silenced and signaling pathways deregulated by epigenetic modifications, such as the abnormal expression of miRNAs. They can be secreted from malignant cells in whole-blood, plasma, serum, and urine samples, making miRNAs potential non-invasive tumor biomarkers. However, if a single miRNA can show low discriminatory power, the combination of miRNAs in a “miRNA signature”, identified in the peripheral lymphocytes of patients, could function better with much higher probability to predict the response to immunotherapy and to discriminate responders from non-responders patients already at therapy baseline.Introduction of checkpoint inhibitors resulted in durable responses and improvements in overall survival in advanced RCC patients, but the treatment efficacy is widely variable, and a considerable number of patients are resistant to PD-1/PD-L1 inhibition. This variability of clinical response makes necessary the discovery of predictive biomarkers for patient selection. Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC. Based on this biological background, we hypothesized that a miRNA expression profile directly identified in the peripheral lymphocytes of the patients before and after the nivolumab administration could represent a step toward a real-time monitoring of the dynamic changes during cancer evolution and treatment. Interestingly, we found a specific subset of miRNAs, called “lymphocyte miRNA signature”, specifically induced in long-responder patients (CR, PR, or SD to nivolumab >18 months). Focusing on the clinical translational potential of miRNAs in controlling the expression of immune checkpoints, we identified the association between the plasma levels of soluble PD-1/PD-L1 and expression of some lymphocyte miRNAs. These findings could help the development of novel dynamic predictive biomarkers urgently needed to predict the potential response to immunotherapy and to guide clinical decision-making in RCC patients.

203P Characterization of renal cell carcinoma (RCC) with VHL mutation

VHL is one of the most commonly mutated oncogene in RCC. However, different co-mutated genes and VHL mutation types are associated with different prognoses and treatments. A more comprehensive understanding of the genomic landscape relative to different VHL variant subsets will help guide therapeutic development. Molecular profiles of 322 RCC samples were obtained using next-generation sequencing of 808 genes (Acornmed Corporation) and classified based on the presence and types of VHL variant. Incidence of VHL mutations was noted across the cohort. Co-occurring genomic alterations and tumor mutational burden (TMB) were analyzed by VHL mutation type. Across the entire cohort, 163 VHL mutations were detected among 154 patients(47.8%). Frameshift mutations were the most prevalent mutation type, accounting for the 42.9%(70/163), followed by missense, nonsense, splicing mutation, copy number loss(42.4%(69/163), 9.2%(15/163), 4.3%(7/163) and 1.2%(2/163) respectively). These mutations were classified into structural variant(58.4%) and non-structural variant(41.6%) based on the effects of variants on protein structure. PBRM1, SETD2, BAP1, KDM5C were commonly co-occurring with VHL(all p<0.05). SETD2 and KDM5C mutations were more common in VHL-nosv RCC, followed by VHL-sv and the VHL-wt. BAP1 has a similar mutation frequency in cases of VHL-sv and VHL-nosv, while VHL-wt had a lower frequency. PBRM1 was mutated in 10.1% of VHL wild type RCC but more frequently noted in both VHL subtype, with the higher rate in VHL-sv (43.3%) and lower in VHL-nosv(29.7%). TMB-H was defined by >12.8 mutations/Mb(upper quartile of the cohort). TMB-H varied across the different VHL mutation subset, most common in VHL-sv (31.1%) and least common in VHL wild type(VHL-wt) (22.2%). VHL mutations are relatively common in Renal cell Carcinoma and VHL structural variant is the most common type. The different VHL mutation has different co-occurring mutations and a different genomic landscape. VHL-sv was associated with the highest rate of TMB and PBRM1 frequency. These different clinical correlates in terms of therapeutic interventions need to be investigated.

Network-based metabolic characterization of renal cell carcinoma

An emerging hallmark of cancer is metabolic reprogramming, which presents opportunities for cancer diagnosis and treatment based on metabolism. We performed a comprehensive metabolic network analysis of major renal cell carcinoma (RCC) subtypes including clear cell, papillary and chromophobe by integrating transcriptomic data with the human genome-scale metabolic model to understand the coordination of metabolic pathways in cancer cells. We identified metabolic alterations of each subtype with respect to tumor-adjacent normal samples and compared them to understand the differences between subtypes. We found that genes of amino acid metabolism and redox homeostasis are significantly altered in RCC subtypes. Chromophobe showed metabolic divergence compared to other subtypes with upregulation of genes involved in glutamine anaplerosis and aspartate biosynthesis. A difference in transcriptional regulation involving HIF1A is observed between subtypes. We identified E2F1 and FOXM1 as other major transcriptional activators of metabolic genes in RCC. Further, the co-expression pattern of metabolic genes in each patient showed the variations in metabolism within RCC subtypes. We also found that co-expression modules of each subtype have tumor stage-specific behavior, which may have clinical implications.

PET/MR Characterization of Renal Cell Carcinomas

PET/MR Characterization of Renal Cell Carcinomas

Abstract 2658: Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature

Abstract Introduction and Objective: With 10% survival at 5-years, metastatic disease presents poor prognosis for renal cell carcinoma (RCC) patients. Prognosis can be improved if biomarkers that predict disease outcome are identified and validated. Aberrantly expressed microRNAs (miRs) promote (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, consensus of a clinically significant miRNA signature has not been established. The objective of this study was to identify a miRNA signature for predicting clinical outcome in RCC patients using a four-pronged interconnected discovery and validation approach. Methods: Differentially expressed miRs were identified and analyzed in 113 specimens (Normal kidney: 59; tumor: 54). In the discovery phase, miRNA-profiling was initially performed in matched normal and tumor specimens from 8 patients, followed by validation in 16 additional specimens. Seven miRs that were significantly aberrantly expressed in miRs in both discovery phases were analyzed by qPCR and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in a TCGA dataset of 241 RCC specimens. Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150 and miR-155 as significantly upregulated (2-4-fold) and miR-192, miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (&amp;lt; 4 cm) from benign oncocytomas. miR-142-5p levels were significantly up-regulated in patients with lymph node positive disease and metastasis (P=0.0002). A 3-miR combination, miR-21+142-5p+194 significantly but negatively correlated with metastasis (P=0.0017; OR: 0.53) and disease-specific mortality (P=0.018; OR: 0.37). The signature had high sensitivity (86.7 - 93.3%) and specificity (82 - 87%) to predict metastasis and disease-specific mortality. In the TCGA dataset, the 3-miR signature significantly and negatively associated with metastasis (P=0.019; OR: 0.54) and overall survival (P=0.0919; OR: 0.37). Conclusion: The interconnected discovery-validation approach identified a novel signature of 3 aberrantly expressed miRs as a potential prognostic indicator for disease outcome among RCC patients. Early detection of metastasis using the validated qPCR assay for the 3-miR signature may allow early intervention for improving patient prognosis. Citation Format: Soum D. Lokeshwar, Andre R. Jordan, Sarrah S. Lahorewala, Vinata B. Lokeshwar. Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2658.

Molecular Characterization of Renal Cell Carcinoma: A Potential Three-MicroRNA Prognostic Signature

Background: Aberrantly expressed miRNAs promote renal cell carcinoma (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, a consensus clinically significant miRNA signature has not been identified. To identify an miRNA signature for predicting clinical outcome in RCC patients, we used a four-pronged interconnected approach.Methods: Differentially expressed miRNAs were identified and analyzed in 113 specimens (normal kidney: 59; tumor: 54). miRNA profiling was performed in matched normal and tumor specimens from 8 patients and extended to 32 specimens. Seven aberrantly expressed miRNAs were analyzed by qPCR, and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in The Cancer Genome Atlas RCC dataset (n = 241).Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150, and miR-155 as significantly upregulated (2-4-fold) and miR-192 and miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (<4 cm) from benign oncocytomas. In univariate and multivariate analyses, miRNA combinations (miR-21+194; miR-21+142-5p+194) significantly predicted metastasis and/or disease-specific mortality; miR-21+142-5p+194 (for metastasis): P = 0.0017; OR, 0.53; 95% confidence interval (CI), 0.75-0.33; 86.7% sensitivity; 82% specificity. In the TCGA dataset, combined biomarkers associated with metastasis and overall survival (miR-21+142-5p+194: P < 0.0001; OR, 0.37; 95% CI, 0.58-0.23).Conclusions: The interconnected discovery-validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients.Impact: With 10% survival at 5 years, metastatic disease presents poor prognosis for RCC patients. The three-miRNA signature discovered and validated may potentially at an early stage detect and predict metastasis, to allow early intervention for improving patient prognosis. Cancer Epidemiol Biomarkers Prev; 27(4); 464-72. ©2018 AACR.

Novel imaging in renal cell carcinoma.

Renal cell carcinoma is a heterogeneous disease with a spectrum of subtypes and clinical behavior. Quantitative and qualitative imaging biomarkers are sought to correlate with genetic and histologic features and complement pathologic analysis. Texture analysis, radiogenomics, and modality-specific advancements have yielded an array of renal cell carcinoma imaging biomarkers in the research domain. Although many techniques are promising, standardization and validation of these procedures are needed prior to implementation into clinical practice. We introduce novel imaging techniques and analytic methods which have been shown to contribute to characterization of renal cell carcinoma and its subtypes, aggressiveness, and responsiveness to therapy, including associated advantages and limitations.

Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations

BackgroundThe genomic features underpinning renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) are not well understood, and at present, there are no specific or effective therapies for sRCC. ObjectiveTo identify genomic alterations in patients with sRCC. Design, setting, and participantsWe conducted genomic profiling on paired epithelial and sarcomatoid areas of three sRCC cases. Genomic profiling was performed on another 23 sRCC patients harboring diverse epithelial components (total of 26 cases). Genomic profiling was conducted using a hybrid capture DNA next-generation sequencing assay of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC (ccRCC) devoid of a sarcomatoid component, and with clear cell, papillary, and chromophobe renal cell carcinoma datasets from The Cancer Genome Atlas. Four additional ccRCC cases underwent whole exome sequencing. Outcome measurements and statistical analysisGenomic alterations in patients with sRCC and ccRCC were described, and their frequencies were compared using the Fisher exact test. Results and limitationsTwo of three patients with sRCC who underwent genomic profiling of both their epithelial and sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 26 sRCCs, TP53 (42.3%), VHL (34.6%), CDKN2A (26.9%), and NF2 (19.2%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Limitations include the small sample size. ConclusionsWe found that sRCC contains different driver mutations than ccRCC. The epithelial and sarcomatoid components of sRCC largely contain the same genomic features. On the basis of harboring either TP53 or NF2 mutations, sRCC can be divided into two groups. These findings may have implications for understanding the oncogenesis of sarcomatoid renal tumors and for defining systemic treatment options. Patient summaryNext-generation sequencing of tumors from patients with sarcomatoid kidney cancer reveals mutations that differ from those in nonsarcomatoid patients. These findings have implications in understanding the pathobiology of sarcomatoid kidney cancer and indicate the need for a different treatment approach in these patients.

Strain elastography in the characterization of renal cell carcinoma and angiomyolipoma.

We evaluate the diagnostic performance of strain elastography to differentiate renal cell carcinoma (RCC) from angiomyolipoma (AML). Strain elastography was performed in 65 patients (mean age 55.5 years; range: 32-81) who had renal lesions (24 AMLs and 41 RCCs) prospectively. Lesions were classified according to lesion size and histological subtypes. The strain ratios of the RCCs and AMLs were evaluated by a radiologist. The area under the curve and the cut-off point were used to assess diagnostic performance. Sensitivity, specificity, and positive and negative predictive values were obtained. In assessing the mean strain ratio, we divided the groups in 3 according to size: (1) <20-mm lesions; (2) 20- to 40-mm lesions; and (3) >40-mm lesions; the respective mean strain ratios were: 1.5 ± 0.5 (range: 0.06-5.92), 2.8 ± 0.4 (range: 0.17-9.92), 2.7 ± 0.3 (range: 0.08-6.15). When RCCs and AMLs were compared, there was a statistically significant difference in the strain ratio among the 3 groups divided per lesion size (p < 0.01). For the strain ratio, the mean ± standard deviation was 1.1 ± 0.1 for AMLs and 3.4 ± 0.3 for RCCs (p < 0.01). When lesion subtypes were compared, there was a statistically significant difference in the strain ratio between the AML and clear cell RCC (p < 0.01). For assessing renal lesions, strain elastography and strain ratio values may be useful in differentiating RCCs from AMLs.

Characterization of renal cell carcinoma, oncocytoma, and lipid-poor angiomyolipoma by unenhanced, nephrographic, and delayed phase contrast-enhanced computed tomography

The purpose of this study was to assess the characterization of renal cell carcinoma (RCC) and benign renal tumors by unenhanced, nephrographic, and delayed phase computed tomography (CT). The study group consisted of 129 renal tumors including 79 clear cell RCCs, 17 papillary RCCs, 6 chromophobe RCCs, 21 oncocytoma, and 6 lipid-poor angiomyolipomas (AMLs). CT studies were retrospectively reviewed. Our results suggested that it was possible to discriminate clear cell RCC from papillary RCC, chromophobe RCC, and lipid-poor AML. CT findings of oncocytoma overlapped with both clear cell and non-clear cell RCCs, although oncocytoma more commonly became homogeneous in the delayed phase.

Combining differential expression, chromosomal and pathway analyses for the molecular characterization of renal cell carcinoma

Using high-throughput gene-expression profiling technology, we can now gain a better understanding of the complex biology that is taking place in cancer cells. This complexity is largely dictated by the abnormal genetic makeup of the cancer cells. This abnormal genetic makeup can have profound effects on cellular activities such as cell growth, cell survival and other regulatory processes. Based on the pattern of gene expression, or molecular signatures of the tumours, we can distinguish or subclassify different types of cancers according to their cell of origin, behaviour, and the way they respond to therapeutic agents and radiation. These approaches will lead to better molecular subclassification of tumours, the basis of personalized medicine. We have, to date, done whole-genome microarray gene-expression profiling on several hundreds of kidney tumours. We adopt a combined bioinformatic approach, based on an integrative analysis of the gene-expression data. These data are used to identify both cytogenetic abnormalities and molecular pathways that are deregulated in renal cell carcinoma (RCC). For example, we have identified the deregulation of the VHL-hypoxia pathway in clear-cell RCC, as previously known, and the c-Myc pathway in aggressive papillary RCC. Besides the more common clear-cell, papillary and chromophobe RCCs, we are currently characterizing the molecular signatures of rarer forms of renal neoplasia such as carcinoma of the collecting ducts, mixed epithelial and stromal tumours, chromosome Xp11 translocations associated with papillary RCC, renal medullary carcinoma, mucinous tubular and spindle-cell carcinoma, and a group of unclassified tumours. Continued development and improvement in the field of molecular profiling will better characterize cancer and provide more accurate diagnosis, prognosis and prediction of drug response.