The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 ...genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent ...somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic ...mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Background Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations ...of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors. Objective The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations. Design, setting, and participants Eight seminomas and matched normal samples were surgically obtained from eight patients. Intervention DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations. Outcome measurements and statistical analysis The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality. Results and limitations The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS , were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic. Conclusions Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy. Patient summary We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.
Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype ...classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach.
Objective To compare the prevalence of proteinuria in the urology clinic with other outpatient settings. Chronic kidney disease is classified according to cause, glomerular filtration rate, and ...proteinuria. Proteinuria may be more prevalent in patients with known chronic kidney disease, renal disorders (benign or malignant), or after urologic surgery. Methods A cross-sectional study of 3 populations undergoing urinalysis (UA) testing was carried out: general outpatients (n = 20,334), urology outpatients (n = 5023), and kidney cancer patients (n = 1016). Proteinuria was classified under Kidney Disease: Improving Global Outcomes guidelines: A1 (<30 mg), A2 (30-300 mg), and A3 (>300 mg). Results Proteinuria was detected throughout a community-based health system in 8.6% of UA (8.2%: A2; 0.4%: A3). In comparison, 18.6% of urology office-performed UA had proteinuria (16.0%: A2, 2.5%: A3) ( P < .0001 vs non-urology). Kidney cancer patients were more likely to have proteinuria (17.9%: A2, 3.8%: A3). The proportion with A3 was significantly higher in urology and kidney cancer patients when compared with other outpatients (each P < .0001), and in the kidney cancer subgroup compared with all urology patients ( P < .0001). Additional abnormalities were frequently present on microscopic analysis of UA in the urology clinic, including hematuria (20.9%), pyuria (21.8%), and bacteriuria (3.1%). Conclusion The value of UA in the urology clinic as a screening test for proteinuria and other conditions appears high, with >56% having at least 1 abnormality. The population risk of proteinuria in the urology clinic is 18.5%, which is higher than that observed in non-urology clinics. Patients with kidney cancer appear more likely to have proteinuria than the average urology patient. We recommend evaluation of urology patients with UA to identify proteinuria.
Abstract Objective To investigate whether a combination of variables from each nephrometry system improves performance. There are 3 first-generation systems that quantify tumor complexity: R.E.N.A.L. ...nephrometry score (RNS), preoperative aspects and dimensions used for an anatomical (PADUA) classification (PC), and centrality index (CI). Although each has been subjected to validation and comparative analysis, to our knowledge, no work has been done to combine variables from each method to optimize their performance. Patients and methods Scores were assigned to each of 276 patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN). Individual components of all 3 systems were evaluated in multivariable logistic regression analysis of surgery type (PN vs. RN) and combined into a “second-generation model.” Results In multivariable analysis, each scoring system was a significant predictor of PN vs. RN ( P <0.0001). Of the first-generation systems, CI was most highly correlated with surgery type (area under the curve AUC = 0.91), followed by RNS (AUC = 0.90) and PC (AUC = 0.88). Each individual component of these scoring systems was also a predictor of surgery type ( P <0.0001). In a multivariable model incorporating each component individually, 4 were independent predictors of surgery type (each P <0.005): tumor size (RNS and PC), nearness to the collecting system (RNS), location along the lateral rim (PC), and centrality (CI). A novel model in which these 4 variables were rescaled outperformed each first-generation system (AUC = 0.91). Conclusions Optimization of first-generation models of renal tumor complexity results in a novel scoring system, which strongly predicts surgery type. This second-generation model should aid comprehension, but future work is still needed to establish the most clinically useful model.
Purpose The strongest predictors of renal function after partial nephrectomy are the preoperative glomerular filtration rate and the amount of preserved parenchyma. Measuring volume preservation by ...3-dimensional imaging is accurate but time-consuming. Percent functional volume preservation was designed to replace surgeon assessment of volume preservation with a less labor intensive, objective assessment. We compared volume preservation with 3-dimensional imaging, percent functional volume preservation and surgeon assessment of volume preservation as predictors of renal function after partial nephrectomy. Materials and Methods We calculated volume preservation with 3-dimensional imaging, percent functional volume preservation and surgeon assessment of volume preservation in 41 patients with preoperative and postoperative cross-sectional imaging available. Surgeon assessment was validated internally in another 75 patients. Short-term and long-term renal function was assessed with univariate and multivariate linear regression models. Results Median parenchymal preservation was 85% (range 37% to 105%) by 3-dimensional imaging, 91% (range 51% to 114%) by percent functional preservation and 88% (range 45% to 99%) by surgeon assessment. Each method strongly correlated with nadir glomerular filtration rate (r2 = 0.75, 0.65 and 0.78) and latest glomerular filtration rate (r2 = 0.65, 0.66 and 0.67, respectively, each p <0.0001). Univariate analysis revealed that age, preoperative glomerular filtration rate, renal nephrometry score and each assessment were significant predictors of renal function (p <0.05). On multivariate analysis parenchymal preservation was the strongest predictor (p <0.0001). Models using volume preservation with 3-dimensional imaging, percent functional volume preservation and surgeon assessment of volume preservation were statistically similar in the ability to predict the nadir and latest glomerular filtration rates. In an additional validation cohort surgeon assessment remained strongly correlated with nadir glomerular filtration rate (r2 = 0.74) and latest glomerular filtration rate (r2 = 0.73, each p <0.0001). Conclusions Surgeon assessment of volume preservation provides a reliable estimate of renal functional preservation with characteristics comparable to those of more time intensive alternatives. We propose that surgeon assessment of volume preservation should be routinely reported to facilitate analysis of partial nephrectomy outcomes.
Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic ...markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.
Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval CI 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.
This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose Partial nephrectomy has become a reference standard for tumors amenable to a kidney sparing approach but reported utilization rates vary widely. The R.E.N.A.L. (radius, exophytic/endophytic, ...nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines and hilar tumor touching main renal artery or vein) nephrometry score was developed to standardize the reporting of tumor complexity with applicability in academic and community based settings. We hypothesized that tumor and surgeon factors account for variable use of partial nephrectomy. Materials and Methods Clinical and R.E.N.A.L. nephrometry score data were analyzed on 1,433 cases performed between 2004 and 2011 by a total of 19 surgeons with varying partial nephrectomy utilization rates (0% to 100%) who practiced at a total of 2 academic centers and 1 community based health system. Results Partial nephrectomy use increased during the study period from 36% before 2007 to 73% for 2010 to 2012 (p <0.0001). Increasing proportions of intermediate and high R.E.N.A.L. nephrometry score tumors were treated with partial nephrectomy during this time (35% to 86% and 11% to 36%, respectively, p <0.0001). Partial nephrectomy use was stable for low complexity tumors at 91% overall. Individual surgeons performed partial nephrectomy for 0% to 100% of intermediate complexity and 0% to 45% of high complexity tumors. On multivariable analysis surgery year, tumor size, each R.E.N.A.L. nephrometry score component, surgeon and annual surgeon volume predicted partial vs radical nephrectomy (each p <0.05). On multivariable analysis several surgeon factors, including surgeon volume, setting, fellowship training, and proportional use of minimally invasive and robotic partial nephrectomy, were associated with higher partial nephrectomy use (each p <0.002). Conclusions Surgeon and tumor factors contribute significantly to the choice of partial nephrectomy. The significant variation in partial nephrectomy use by individual surgeons appears to be caused by differential treatment for intermediate and high complexity tumors. This may be due to surgical volume, training, setting and the use of minimally invasive techniques.
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