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Genomic aberrations predicts survival in clear cell renal cell carcinoma

ABSTRACT: Detailed genetic profiling of clear cell Renal Cell Carcinoma (ccRCC) has shown that these tumors are characterized by large genetic heterogeneity with some genomic regions commonly affected by structural changes. Loss on chromosomes 3p and 14q, and gain on 5q and 7 are examples of alterations commonly reported in ccRCC. However, there is no consensus regarding the potential prognostic information carried by the identified alterations. We report on poorer outcome for patients with gain on 5q and 7, and loss on 9p, 9q and 14q. These aberrations were in addition found more frequently in metastasized tumors, suggesting that they are markers for advanced disease. Furthermore, the presence of ≥ 4 common aberrations was associated with decreased survival time. Shorter relative telomere length (RTL) has been associated with loss of chromosomal regions in ccRCC tumors, but we found no significant associations between tumor RTL and chromosomal deletions. However, significantly lower tumor-to-nontumor (T/N) RTL ratio was detected for patients with loss on 4q and 9p. Finally, we found a minimum region (MR) of genetic loss of 1.4 Mbp on chromosome 9p and this region contains only one gene, the tumor suppressor candidate 1 gene (TUSC1). TUSC1 has been implicated in lung carcinogenesis and our result further strengthens its role in tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30460 | GEO | 2014/07/01

SECONDARY ACCESSION(S): PRJNA143551

REPOSITORIES: GEO

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Genomic aberrations predicts survival in clear cell renal cell carcinoma

Project description:Detailed genetic profiling of clear cell Renal Cell Carcinoma (ccRCC) has shown that these tumors are characterized by large genetic heterogeneity with some genomic regions commonly affected by structural changes. Loss on chromosomes 3p and 14q, and gain on 5q and 7 are examples of alterations commonly reported in ccRCC. However, there is no consensus regarding the potential prognostic information carried by the identified alterations. We report on poorer outcome for patients with gain on 5q and 7, and loss on 9p, 9q and 14q. These aberrations were in addition found more frequently in metastasized tumors, suggesting that they are markers for advanced disease. Furthermore, the presence of M-bM-^IM-% 4 common aberrations was associated with decreased survival time. Shorter relative telomere length (RTL) has been associated with loss of chromosomal regions in ccRCC tumors, but we found no significant associations between tumor RTL and chromosomal deletions. However, significantly lower tumor-to-nontumor (T/N) RTL ratio was detected for patients with loss on 4q and 9p. Finally, we found a minimum region (MR) of genetic loss of 1.4 Mbp on chromosome 9p and this region contains only one gene, the tumor suppressor candidate 1 gene (TUSC1). TUSC1 has been implicated in lung carcinogenesis and our result further strengthens its role in tumorigenesis. Seventy-four ccRCC tumors and 22 paired normal kidney cortex and blood samples were genotyped on Illuminas HumanCytoSNP-12 bead chips.

2014-07-01 | E-GEOD-30460 | biostudies-arrayexpress

Patterns of gene expression and copy-number alterations in VHL disease-associated and sporadic ccRCC

Project description:Recent insights into the role of the VHL tumor suppressor gene in hereditary and sporadic clear cell carcinoma of the kidney (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of 3 genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors, and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into 2 groups: one group with genomic profiles highly dissimilar to the majority of ccRCC, and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL. Keywords: comparative genomic hybridization 90 clear cell renal cell carcinomas and 21 renal cancer cell lines were subject to 250K SNP analysis.

2010-04-10 | E-GEOD-14994 | biostudies-arrayexpress

Patterns of gene expression and copy-number alterations in VHL disease-associated and sporadic ccRCC

2009-06-02 | GSE14994 | GEO

Deregulated Expression of the 14q32 miRNA Cluster in Clear Cell Renal Cell Carcinomas

Project description:Clear cell renal cell carcinomas (ccRCC) are characterized by arm-wide chromosomal alterations. Loss at 14q is associated with disease aggressiveness in ccRCC, which responds poorly to chemotherapeutics. The 14q locus contains one of the largest miRNA clusters in the human genome; however, little is known about the contribution of these miRNAs to ccRCC pathogenesis. In this regard, we investigated the expression pattern of selected miRNAs at the 14q32 locus in TCGA kidney tumors and in ccRCC cell lines. We validated that the miRNA cluster is downregulated in ccRCC (and cell lines) as well as in papillary kidney tumors relative to normal kidney tissues and primary renal proximal tubule epithelial (RPTEC) cells. We demonstrated that agents modulating expression of DNMT1 (e.g., 5-Aza-deoxycytidine) could modulate miRNA expression in ccRCC cell lines. Lysophosphatidic acid (LPA, a Lysophospholipid mediator elevated in ccRCC) not only increased labile iron content but also modulated expression of 14q32 miRNAs. Through an overexpression approach targeting a subset of 14q32 miRNAs (specifically at subcluster A: miR-431, miR-432, miR-127, and miR-433) in 769-P cells, we uncovered changes in cellular viability and claudin-1, a tight junction marker. A global proteomic approach was implemented using these miRNA overexpressing cell lines which uncovered ATXN2 as a highly downregulated target, which has a role in chronic kidney disease pathogenesis. Collectively, these findings support a contribution of miRNAs at 14q32 in ccRCC pathogenesis.

2023-05-10 | PXD036428 | Pride

DNA Copy-Number Alterations in clear-cell Renal Cell Carcinoma (ccRCC) Tumors and Tumorgrafts for samples deficient in BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice retained >92% of mutations and exhibited similar DNA copy number alterations to corresponding primary tumors. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The genomic DNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal samples were labeled and hybridized to Affymetrix SNP arrays 6.0.

2012-06-09 | E-GEOD-25540 | biostudies-arrayexpress

Subtypes of familial breast tumors revealed by expression and copy number profiling

Project description:We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2 breast tumors by gene expression profiling and found that 74% BRCA1 tumors were basal-like, 73% of BRCA2 tumors were luminal A or B, and 52% non-BRCA1/2 tumors were luminal A. Thirty-four tumors were also analysed by single nucleotide polymorphism-comparative genomic hybridization (SNP-CGH) arrays. Copy number data could predict whether a tumor was basal-like or luminal with high accuracy, but could not predict its mutation class. Basal-like BRCA1 and basal-like non-BRCA1 tumors were very similar, and contained the highest number of chromosome aberrations. We identified regions of frequent gain containing potential driver genes in the basal (8q and 12p) and luminal A tumors (1q and 17q). Regions of homozygous loss associated with decreased expression of potential tumor suppressor genes were also detected, including in basal tumors (5q and 9p), and basal and luminal tumors (10q). This study highlights the heterogeneity of familial tumors and the clinical consequences for treatment and prognosis.

2009-12-16 | GSE19177 | GEO

Molecular Genetic Classification of clear-cell Renal Cell Carcinoma (ccRCC) based on the Gene Expression Profiling of Tumors and Tumorgrafts deficient for BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The RNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal kidney cortices were labeled and hybridized to Affymetrix Human Genome U133 Plus 2.0 arrays.

2012-06-09 | E-GEOD-36895 | biostudies-arrayexpress

DNA Copy-Number Alterations in clear-cell Renal Cell Carcinoma (ccRCC) Tumors and Tumorgrafts for samples deficient in BAP1 or PBRM1

2012-06-10 | GSE25540 | GEO

Molecular Genetic Classification of clear-cell Renal Cell Carcinoma (ccRCC) based on the Gene Expression Profiling of Tumors and Tumorgrafts deficient for BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

2012-06-10 | GSE36895 | GEO

Integrative genomic analysis of sporadic clear cell Renal Cell Carcinoma

Project description:Human clear cell renal cell carcinoma (ccRCC) is a common cancer of the kidney. We applied an integrated approach to identify important factors that influence carcinogenesis in ccRCC. 33 frozen ccRCC samples were subject to copy number analysis. The data was analyzed to identify factors affecting tumorigenesis. The samples were also stained for HIF-1alpha and HIF-2alpha expression. The tumors were subtyped based on HIF expression and investigated for differences in genetic aberrations.

2011-12-01 | E-GEOD-27852 | biostudies-arrayexpress

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