Renal Epithelioid Angiomyolipoma: Genomic Characterization and Malignant Potential

Introduction: Renal angiomyolipoma (AML) is one of the most common benign kidney tumors diagnosed. Epithelioid angiomyolipoma (eAML) is a rare variant of these kind of masses that have been classified by the World Health Organization as a potentially malignant mesenchymal neoplasm that metastasizes in one-third of cases. However, conflicting reports have brought in to question the true malignant potential of eAML. Due to eAMLs overall rarity, few studies have characterized this entity. In this study, we further define eAML by describing its genomic alterations and malignant potential by comparing it to a cohort of AML patients at a large-volume cancer center. Methods: After IRB approval, a prospectively maintained kidney cancer database was queried for all patients with eAML and AML who underwent nephrectomy between 1994 and 2008 at the Memorial Sloan Kettering Cancer Center. Patients were separated into two histologic groups, those with eAML and those with AML. Clinicopathologic features and genomic alterations were analyzed and then compared between the two cohorts. Descriptive statistics were performed using Mann-Whitney U test, and Chi-squared test, where appropriate, and reported as either median with interquartile range (IQR) or number with percentage. Genomic data was available in 6 eAML and 10 AML patients with mutational burden described as a proportion. Overall survival (OS) and recurrence-free survival (RFS) data were analyzed using Kaplan-Meier method with significance determined by log-rank tests. All statistical analyses were performed using R 3.5.2 with significance set at \u3c0.05. Results: Out of 103 patients, 44 had eAML and 59 had AML. Females in their fifth and sixth decade were more commonly diagnosed than males, Table 1. Patients with eAML had larger tumors (p\u3c0.001) and underwent radical nephrectomy more often (p=0.014). Twelve (27.3%) eAML patients metastasized, while no metastases were observed in AML patients. Median RFS for eAML patients was 131 months, and median RFS was not reached in AML patients (p\u3c0.0001), Figure 1. The most frequently mutated gene across both groups expectedly was TSC2, a mutation commonly found in AMLs. The mutational burden in eAMLs was heterogeneous compared to AMLs, with more mutations observed within TP53(43%), RB1 (14%), APC (14%), TERT (14%), ATRX (14%), TSC1 (14%), PIK3CA (14%), GNA11 (14%), and FGFR3 (14%), Figure 2. Conclusion: Patients with eAML were observed to have larger tumors and metastasized at a higher rate than patients with AML. A greater frequency of eAML patients underwent radical nephrectomy. The mutational burden across eAML was notable for a more heterogeneity, with largest mutations in TSC2 and TP53 genes. Further investigation into the impact of mutational burden on metastatic potential is warranted

Pan-urologic cancer genomic subtypes that transcend tissue of origin

AbstractUrologic cancers include cancers of the bladder, kidney, prostate, and testes, with common molecular features spanning different types. Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression). Tissue dominant effects are first removed computationally in order to define these subtypes, which reveal common processes—reflecting in part tumor microenvironmental influences—driving cellular behavior across tumor lineages. Six of the subtypes feature a mixture of represented cancer types as defined by tissue or cell of origin. Differences in patient survival and in the manifestation of specific pathways—including hypoxia, metabolism, NRF2-ARE, Hippo, and immune checkpoint—can further distinguish the subtypes. Immune checkpoint markers and molecular signatures of macrophages and T cell infiltrates are relatively high within distinct subsets of each cancer type studied. The pan-urologic cancer genomic subtypes would facilitate information sharing involving therapeutic implications between tissue-oriented domains.</jats:p

Mitochondrial DNA copy number variation across human cancers.

Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities

Plasma glycosaminoglycan scores in early stage renal cell carcinoma

Background: Previous studies have found an outstanding role in the regulation of metabolism of clear cell renal cell carcinoma (ccRCC; Gatto et al., 2014; Creighton et al., 2013). We discovered that glycosaminoglycan (GAG) biosynthesis was prominently regulated in ccRCC, and measurements of circulating GAGs could be condensed into scores that distinguished metastatic ccRCC with accuracy ranging 92.7% to 100% (Gatto et al., 2016). However, it is still unknown if GAG scores could detect cancer at earlier stages and across other histologies. Methods and Results: We measured plasma GAGs in pre-operative samples from a retrospective consecutive series of 218 patients with a radiographic finding of renal mass. A control group was formed with 19 healthy volunteers and 25 historical healthy samples. In clustering analyses, plasma GAGs distinguished the 179 RCC samples as a separate group in an unbiased fashion. The previous GAG score was updated and achieved an area-under-the-curve (AUC) equal to 0.994 (95% CI: 0.985 - 1) in the validation set with a sensitivity of 95.7%. The GAG score was not significantly associated with age or gender nor with any histopathologic features. Conclusions: Plasma GAG scores are specifically altered in RCC patients and can detect the disease irrespective of stage and histology with elevated accuracy

Genomic investigation of etiologic heterogeneity: methodologic challenges

Background: The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles. Methods: We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types. Results: The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery. Conclusions: Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology. Electronic supplementary material The online version of this article (doi:10.1186/1471-2288-14-138) contains supplementary material, which is available to authorized users

Obstructive sleep apnea and Fuhrman grade in patients with clear cell renal cell carcinoma treated surgically

PURPOSE: To assess the association between obstructive sleep apnea (OSA) and Fuhrman grade in patients with clear cell renal cell carcinoma (ccRCC). As secondary endpoints, we studied its association with tumor size, metastasis-free survival (MFS) and cancer-specific survival (CSS). METHODS: We reviewed the databases of two tertiary care centers, identifying 2579 patients who underwent partial or radical nephrectomy for ccRCC between 1991 and 2014. Descriptive statistics were used to compare pathologic variables between patients with and without OSA. Linear and logistic regression models were used to assess the association of OSA with Fuhrman grade and tumor size. A Cox proportional hazards model was used to determine OSA association with MFS and CSS. A pathway analysis was performed on a cohort with available gene expression data. RESULTS: In total, 172 patients (7 %) had self-reported OSA at diagnosis. More patients with OSA had high Fuhrman grade compared to those without OSA [51 vs. 38 %; 13 % risk difference; 95 % confidence interval (CI), 5-20 %; p = 0.003]. On multivariable analysis, the association remained significant (OR 1.41; 95 % CI 1.00-1.99; p = 0.048). OSA was not associated with tumor size (p > 0.5), MFS (p = 0.5) or CSS (p = 0.4). A trend toward vascular endothelial growth factor pathway enrichment was seen in OSA patients (p = 0.08). CONCLUSIONS: OSA is associated with high Fuhrman grade in patients undergoing surgery for ccRCC. Pending validation of this novel finding in further prospective studies, it could help shape future research to better understand etiological mechanisms associated

Plasma Glycosaminoglycans as Diagnostic and Prognostic Biomarkers in Surgically Treated Renal Cell Carcinoma

Plasma glycosaminoglycan (GAG) measurements, when aggregated into diagnostic scores, accurately distinguish metastatic clear-cell renal cell carcinoma (RCC) from healthy samples and correlate with prognosis. However, it is unknown if GAG scores can detect RCC in earlier stages or if they correlate with prognosis after surgery. Objective: To explore the sensitivity and specificity of plasma GAGs for detection of early-stage RCC and prediction of recurrence and death after RCC surgery. Design, setting, and participants: This was a retrospective case-control study consisting of a consecutive series of 175 RCC patients surgically treated between May 2011 and February 2014 and 19 healthy controls. Outcome measurements and statistical analysis: Plasma GAGs in preoperative and postoperative RCC and healthy samples were measured using capillary electrophoresis with laser-induced fluorescence in a single blinded laboratory. A discovery set was first analyzed to update the historical GAG score. The sensitivity of the new GAG score for RCC detection versus healthy subjects was validated using the remaining samples. The correlation of the new GAG score to histopathologic variables, overall survival, and recurrence-free survival was evaluated using nonparametric and log-rank tests and multivariable Cox regression analyses. Results and limitations: The RCC cohort included 94 stage I, 58 stage II–III, and 22 stage IV cases. In the first discovery set (n = 67), the new GAG score distinguished RCC from healthy samples with an area under the receiver operating characteristic curve (AUC) of 0.999. In the validation set (n = 108), the GAG score achieved an AUC of 0.991, with 93.5% sensitivity. GAG scores were elevated in RCC compared to healthy samples, irrespective of and uncorrelated to stage, grade, histology, age, or gender. The total chondroitin sulfate concentration was an independent prognostic factor for both overall and recurrence-free survival (hazard ratios 1.51 and 1.25) with high concordance when combined with variables available at pathologic diagnosis (C-index 0.926 and 0.849) or preoperatively (C-index 0.846 and 0.736). Limitations of the study include its retrospective nature and moderate variability in GAG laboratory measurements. Conclusions: Plasma GAGs are highly sensitive diagnostic and prognostic biomarkers in surgically treated RCC independent of stage, grade, or histology. Prospective validation studies on GAG scores for early detection, prediction, and surveillance for RCC recurrence are thus warranted. Patient summary: In this study, we examined if a new molecular blood test can detect renal cell carcinoma in the early stages and predict if the cancer might relapse after surgery. The trial is registered on ClinicalTrial.gov as NCT03471897. Plasma glycosaminoglycan measurements aggregated into scores had higher sensitivity for the detection of any-stage renal cell carcinoma and high concordance with survival after surgery

ClearCode34: A Prognostic Risk Predictor for Localized Clear Cell Renal Cell Carcinoma

Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer.

Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway