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Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma.

ABSTRACT: Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively.

SUBMITTER: Arseneault M

PROVIDER: S-EPMC5362952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Epigenetic alterations of chromosome 3 revealed by NotI-microarrays in clear cell renal cell carcinoma.

Project description:This study aimed to clarify epigenetic and genetic alterations that occur during renal carcinogenesis. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI-clones associated with 188 genes for hybridization with 23 paired normal/tumor DNA samples of primary clear cell renal cell carcinomas (ccRCC). Twenty-two genes showed methylation and/or deletion in 17-57% of tumors. These genes include tumor suppressors or candidates (VHL, CTDSPL, LRRC3B, ALDH1L1, and EPHB1) and genes that were not previously considered as cancer-associated (e.g., LRRN1, GORASP1, FGD5, and PLCL2). Bisulfite sequencing analysis confirmed methylation as a frequent event in ccRCC. A set of six markers (NKIRAS1/RPL15, LRRN1, LRRC3B, CTDSPL, GORASP1/TTC21A, and VHL) was suggested for ccRCC detection in renal biopsies. The mRNA level decrease was shown for 6 NotI-associated genes in ccRCC using quantitative PCR: LRRN1, GORASP1, FOXP1, FGD5, PLCL2, and ALDH1L1. The majority of examined genes showed distinct expression profiles in ccRCC and papillary RCC. The strongest extent and frequency of downregulation were shown for ALDH1L1 gene both in ccRCC and papillary RCC. Moreover, the extent of ALDH1L1 mRNA level decrease was more pronounced in both histological types of RCC stage III compared with stages I and II (P = 0.03). The same was observed for FGD5 gene in ccRCC (P < 0.06). Dedicated to thememory of Eugene R. Zabarovsky.

| S-EPMC4054851 | biostudies-literature

Loss of RANBP3L leads to transformation of renal epithelial cells towards a renal clear cell carcinoma like phenotype.

Project description:BackgroundRenal cell carcinomas (RCC) are characterized by the deregulation of several hundred hyperosmolality-responsive genes. High expression of a subset of these genes including the Ran binding protein 3 like (RANBP3L) is linked to a favorable prognostic outcome in RCC. However, the cellular function of RANBP3L remains largely unknown.MethodsWe used CRISPR/Cas9-mediated gene editing to generate functional deletions of the Ranbp3l and nuclear factor of activated T cells 5 (Nfat5) gene loci in a murine renal cell line. The NFAT5-KO cells were used to assess the regulation of Ranbp3l by NFAT5 using immunofluorescence, RNA-Seq and promoter assays. RANBP3L-deficient cells were analyzed for changes in cell morphology, proliferation, migration and colony-forming capacity using immunofluorescence and live cell imaging. RANPB3L-dependent changes in gene expression were identified by RNA-Seq.ResultsWe show that NFAT5 directly regulates Ranpb3l under hyperosmotic conditions by binding its promoter. Functional analysis of RANBP3L-deficient cells revealed a loss of epithelial structure, an increased cell migration behavior and colony forming capacity, accompanied by massive alterations in gene expression, all of which are hallmarks for tumor cells. Strikingly, a RANBP3L dependent signature of 60 genes separated samples with clear cell carcinoma (KIRC) from papillary (KIRP), chromophobe renal carcinoma (KICH) and healthy tissue.ConclusionsLoss of RANBP3L induces a tumor like phenotype resembles RCC, especially KIRC, on the morphological and gene expression level and might promote tumor development and progression. Therapeutic reconstitution or elevation of osmoregulated RANBP3L expression might represent a novel treatment strategy for RCC or KIRC.

| S-EPMC8265145 | biostudies-literature

Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis.

Project description:Loss of chromosome 14 has been associated with poor outcomes in clear-cell renal cell carcinoma. Expression of HIFα isoforms has been linked to distinct molecular phenotypes of clear-cell renal cell carcinoma. We hypothesized that chromosome 14 loss could lead to a decrease in HIF1α levels, as its gene (HIF1A) resides in this chromosome. We analyzed 112 archival clear-cell renal cell carcinoma tumor specimens with 250K SNP microarrays. We also evaluated expression of HIFα isoforms by qPCR and immunohistochemistry in a subset of 30 patients. Loss of chromosome 14q was associated with high stage (III-IV, P=0.001), high risk for recurrence (P=0.002, RR 2.78 (1.506-5.153)) and with decreased overall survival (P=0.030) in non-metastatic clear-cell renal cell carcinoma. HIF1α mRNA and protein expression was reduced in specimens with loss of 14q (P=0.014) whereas HIF2α was not. Gain of 8q was associated with decreased overall survival (P<0.0001). Our studies confirm an association between 14q loss and clinical outcome in non-metastatic clear-cell renal cell carcinoma patients and that 8q gain is a candidate prognostic marker for decreased overall survival and appears to further decrease survival in patients with 14q loss. We have also identified that differential expression of HIF1α is associated with 14q loss. Further exploration of 8q gain, 14q loss, MYC, HIF1A and EPAS1 (HIF2α) as molecular markers of tumor behavior and prognosis could aid in personalizing medicine for patients with clear-cell renal cell carcinoma.

| S-EPMC4639322 | biostudies-literature

Epigenetic signature predicts overall survival clear cell renal cell carcinoma.

Project description:BackgroundRecently, increasing study have found that DNA methylation plays an important role in tumor, including clear cell renal cell carcinoma (ccRCC).MethodsWe used the DNA methylation dataset of The Cancer Genome Atlas (TCGA) database to construct a 31-CpG-based signature which could accurately predict the overall survival of ccRCC. Meanwhile, we constructed a nomogram to predict the prognosis of patients with ccRCC.ResultThrough LASSO Cox regression analysis, we obtained the 31-CpG-based epigenetic signature which were significantly related to the prognosis of ccRCC. According to the epigenetic signature, patients were divided into two groups with high and low risk, and the predictive value of the epigenetic signature was verified by other two sets. In the training set, hazard ratio (HR)?=?13.0, 95% confidence interval (CI) 8.0-21.2, P?<?0.0001; testing set: HR?=?4.1, CI 2.2-7.7, P?<?0.0001; entire set: HR?=?7.2, CI 4.9-10.6, P?<?0.0001, Moreover, combined with clinical indicators, the prediction of 5-year survival of ccRCC reached an AUC of 0.871.ConclusionsOur study constructed a 31-CpG-based epigenetic signature that could accurately predicted overall survival of ccRCC and staging progression of ccRCC. At the same time, we constructed a nomogram, which may facilitate the prediction of prognosis for patients with ccRCC.

| S-EPMC7686748 | biostudies-literature

Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma.

Project description:Several common oncogenic pathways have been implicated in the emergence of renowned metabolic features in cancer, which in turn are deemed essential for cancer proliferation and survival. However, the extent to which different cancers coordinate their metabolism to meet these requirements is largely unexplored. Here we show that even in the heterogeneity of metabolic regulation a distinct signature encompassed most cancers. On the other hand, clear cell renal cell carcinoma (ccRCC) strongly deviated in terms of metabolic gene expression changes, showing widespread down-regulation. We observed a metabolic shift that associates differential regulation of enzymes in one-carbon metabolism with high tumor stage and poor clinical outcome. A significant yet limited set of metabolic genes that explained the partial divergence of ccRCC metabolism correlated with loss of von Hippel-Lindau tumor suppressor (VHL) and a potential activation of signal transducer and activator of transcription 1. Further network-dependent analyses revealed unique defects in nucleotide, one-carbon, and glycerophospholipid metabolism at the transcript and protein level, which contrasts findings in other tumors. Notably, this behavior is recapitulated by recurrent loss of heterozygosity in multiple metabolic genes adjacent to VHL. This study therefore shows how loss of heterozygosity, hallmarked by VHL deletion in ccRCC, may uniquely shape tumor metabolism.

| S-EPMC3948310 | biostudies-literature

Identification of DNA Methylation-Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma.

Project description:Alterations in chromatin accessibility independent of DNA methylation can affect cancer-related gene expression, but are often overlooked in conventional epigenomic profiling approaches. In this study, we describe a cost-effective and computationally simple assay called AcceSssIble to simultaneously interrogate DNA methylation and chromatin accessibility alterations in primary human clear cell renal cell carcinomas (ccRCC). Our study revealed significant perturbations to the ccRCC epigenome and identified gene expression changes that were specifically attributed to the chromatin accessibility status whether or not DNA methylation was involved. Compared with commonly mutated genes in ccRCC, such as the von Hippel-Lindau (VHL) tumor suppressor, the genes identified by AcceSssIble comprised distinct pathways and more frequently underwent epigenetic changes, suggesting that genetic and epigenetic alterations could be independent events in ccRCC. Specifically, we found unique DNA methylation-independent promoter accessibility alterations in pathways mimicking VHL deficiency. Overall, this study provides a novel approach for identifying new epigenetic-based therapeutic targets, previously undetectable by DNA methylation studies alone, that may complement current genetic-based treatment strategies. Cancer Res; 76(7); 1954-64. ©2016 AACR.

| S-EPMC4873378 | biostudies-literature

Loss of PBRM1 and BAP1 expression is less common in non-clear cell renal cell carcinoma than in clear cell renal cell carcinoma.

Project description:BACKGROUND:Recurrent mutations in polybromo-1 (PBRM1, ~40%) and BRCA1-associated protein-1 (BAP1, ~10%) occur in clear cell renal cell carcinoma (ccRCC), but their prevalence in non-ccRCC or renal oncocytoma (RO) is unknown. We evaluated loss of PBRM1 and BAP1 staining in ccRCC, papillary RCC (pRCC), chromophobe RCC (chRCC), and RO tumors using an immunohistochemistry assay in which negative staining was associated with loss-of-function mutations. METHODS:We identified 458 patients treated surgically for ccRCC, pRCC, chRCC, and RO between 2004 and 2012. We performed immunohistochemistry assays to evaluate PBRM1 and BAP1 protein expression to classify tumors as PBRM1 or BAP1 negative. We compared loss of staining of these 2 proteins in ccRCC and non-ccRCC using the Fisher exact test. RESULTS:For the total cohort of 458 patients, we successfully stained both PBRM1 and BAP1 in 408 tumor samples. Consistent with the mutation rate, loss of PBRM1 and BAP1 staining occurred in 43% (80/187) and 10% (18/187) of ccRCC cases, respectively. However, loss of PBRM1 staining occurred in only 3% (2/59), 6% (1/17), and 0% (0/34) of pRCC, chRCC, and RO tumors, respectively (P<0.0001). BAP1 loss was not observed in any of the pRCC (n = 61), chRCC (n = 17), or RO (n = 34) tumors, (P = 0.00021). CONCLUSION:Our data suggest that biallelic inactivation of PBRM1 or BAP1 is less common in non-ccRCC when compared with ccRCC tumors. These findings suggest that loss of PBRM1 or BAP1 are key events in ccRCC, whereas other pathways may support tumorigenesis in non-ccRCC subtypes.

| S-EPMC4274200 | biostudies-literature

VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2.

Project description:The von Hippel-Lindau (VHL) is deficient in ?70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. Here we show that VHL-deficient ccRCC cells present enhanced cytotoxicity of anthracyclines in a hypoxia-inducible factor-independent manner. By subtractive proteomic analysis coupling with RNAi or overexpression verification, aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in ccRCC cells. Furthermore, VHL regulates ALDH2 expression by directly binding the promoter of -130?bp to -160?bp to activate the transcription of hepatocyte nuclear factor 4 alpha (HNF-4?). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4? and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients.

| S-EPMC5481740 | biostudies-literature

Down-regulation of BCL2L13 renders poor prognosis in clear cell and papillary renal cell carcinoma.

Project description:BackgroundBCL2L13 belongs to the BCL2 super family, with its protein product exhibits capacity of apoptosis-mediating in diversified cell lines. Previous studies have shown that BCL2L13 has functional consequence in several tumor types, including ALL and GBM, however, its function in kidney cancer remains as yet unclearly.MethodsMultiple web-based portals were employed to analyze the effect of BCL2L13 in kidney cancer using the data from TCGA database. Functional enrichment analysis and hubs of BCL2L13 co-expressed genes in clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) were carried out on Cytoscape. Evaluation of BCL2L13 protein level was accomplished through immunohistochemistry on paraffin embedded renal cancer tissue sections. Western blotting and flow cytometry were implemented to further analyze the pro-apoptotic function of BCL2L13 in ccRCC cell line 786-0.ResultsBCL2L13 expression is significantly decreased in ccRCC and pRCC patients, however, mutations and copy number alterations are rarely observed. The poor prognosis of ccRCC that derived from down-regulated BCL2L13 is independent of patients' gender or tumor grade. Furthermore, BCL2L13 only weakly correlates with the genes that mutated in kidney cancer or the genes that associated with inherited kidney cancer predisposing syndrome, while actively correlates with SLC25A4. As a downstream effector of BCL2L13 in its pro-apoptotic pathway, SLC25A4 is found as one of the hub genes that involved in the physiological function of BCL2L13 in kidney cancer tissues.ConclusionsDown-regulation of BCL2L13 renders poor prognosis in ccRCC and pRCC. This disadvantageous factor is independent of any well-known kidney cancer related genes, so BCL2L13 can be used as an effective indicator for prognostic evaluation of renal cell carcinoma.

| S-EPMC8247248 | biostudies-literature

Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery.

Project description:Wider clinical applications of 9p status in clear cell renal cell carcinoma (ccRCC) are limited owing to the lack of validation and consensus for interphase fluorescent in situ hybridisation (I-FISH) scoring technique. The aim of this study was to analytically validate the applicability of I-FISH in assessing 9p deletion in ccRCC and to clinically assess its long-term prognostic impact following surgical excision of ccRCC.Tissue microarrays were constructed from 108 renal cell carcinoma (RCC) tumour paraffin blocks. Interphase fluorescent in situ hybridisation analysis was undertaken based on preset criteria by two independent observers to assess interobserver variability. 9p status in ccRCC tumours was determined and correlated to clinicopathological variables, recurrence-free survival and disease-specific survival.There were 80 ccRCCs with valid 9p scoring and a median follow-up of 95 months. Kappa statistic for interobserver variability was 0.71 (good agreement). 9p deletion was detected in 44% of ccRCCs. 9p loss was associated with higher stage, larger tumours, necrosis, microvascular and renal vein invasion, and higher SSIGN (stage, size, grade and necrosis) score. Patients with 9p-deleted ccRCC were at a higher risk of recurrence (P=0.008) and RCC-specific mortality (P=0.001). On multivariate analysis, 9p deletion was an independent predictor of recurrence (hazard ratio 4.323; P=0.021) and RCC-specific mortality (hazard ratio 4.603; P=0.007). The predictive accuracy of SSIGN score improved from 87.7% to 93.1% by integrating 9p status to the model (P=0.001).Loss of 9p is associated with aggressive ccRCC and worse prognosis in patients following surgery. Our findings independently confirm the findings of previous reports relying on I-FISH to detect 9p (CDKN2A) deletion.

| S-EPMC4183850 | biostudies-other

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