Identification of Genomic Alterations Associated With Metastasis and Cancer Specific Survival in Clear Cell Renal Cell Carcinoma

Sanjmyatav, Jimsgene; Junker, Kerstin; Matthes, Sophie; Muehr, Martin; Sava, Doriana; Sternal, Maria; Wessendorf, Sven; Kreuz, Markus; Gajda, Mieczysław; Wunderlich, Heiko; Schwäenen, Carsten

doi:10.1016/j.juro.2011.06.050

Cited by 30 publications

(36 citation statements)

References 22 publications

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“…4; Supplementary Table S1). Seven regions harboring key cancer-related oncogenes and tumor suppressors (Chr12, CDK4 gain; 1p, ARID1A; Chr4, SORBS2; Chr9, CDKN2A/B; 13q, RB1; 14q, NFKBIA, and Chr18, DCC deletion) were significantly associated with worse prognosis, consistent with previous reports (8,10,(13)(14)(15)(16). We further correlated miRNA let-7i in association with available overall survival in the TCGA validation set and observed significantly worse overall survival among cases with let-7i copy number gain (Fig.…”

Section: The Prognostic Significance Of Cnassupporting

confidence: 91%

“…Gain of the well-characterized 12q13.2-14.1 amplicon region containing the CDK4 oncogene and also the miR-26a oncogenic miRNA was observed. Gain of this region has been associated with metastatic ccRCCs (16). Rare gains of 11q13.3 harboring the CCND1 oncogene were identified as well.…”

Section: Genome-wide Copy Number Profiling Of Ccrccmentioning

confidence: 93%

“…Recent studies using high-resolution microarrays have identified additional copy number aberrations (CNA) at lesser frequency (7)(8)(9)(10)(11)(12). Previous reports suggested CNAs in ccRCCs to be dynamically related to clinical parameters, such as associations of 4p, 9p, and 14q deletion and 7q, 8q, 20q gains with higher stage, grade, and/or worse prognosis (8,10,(13)(14)(15)(16). In addition, 1q, 12q, and 20q gains and deletions of 9p have been associated with metastatic risk (16).…”

Section: Introductionmentioning

confidence: 99%

“…Previous reports suggested CNAs in ccRCCs to be dynamically related to clinical parameters, such as associations of 4p, 9p, and 14q deletion and 7q, 8q, 20q gains with higher stage, grade, and/or worse prognosis (8,10,(13)(14)(15)(16). In addition, 1q, 12q, and 20q gains and deletions of 9p have been associated with metastatic risk (16). Moreover, ccRCC molecular subtypes have been recently proposed on the basis of gene expression profiles (6,17,18).…”

Section: Introductionmentioning

confidence: 99%

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Multilevel Whole-Genome Analysis Reveals Candidate Biomarkers in Clear Cell Renal Cell Carcinoma

et al. 2012

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Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. We conducted an integrated analysis of copy number, gene expression (mRNA and miRNA), protein expression, and methylation changes in clear cell renal cell carcinoma (ccRCC). We used a stepwise approach to identify the most significant copy number aberrations (CNA) and identified regions of peak and broad copy number gain and loss, including peak gains (3q21, 5q32, 5q34-q35, 7p11, 7q21, 8q24, 11q13, and 12q14) and deletions (1p36, 2q34-q37, 3p25, 4q33-q35, 6q23-q27, and 9p21). These regions harbor novel tumor-related genes and miRNAs not previously reported in renal carcinoma. Integration of genome-wide expression data and gene set enrichment analysis revealed 75 gene sets significantly altered in tumors with CNAs compared with tumors without aberration. We also identified genes located in peak CNAs with concordant methylation changes (hypomethylated in copy number gains such as STC2 and CCND1 and hypermethylated in deletions such as CLCNKB, VHL, and CDKN2A/2B). For other genes, such as CA9, expression represents the net outcome of opposing forces (deletion and hypomethylation) that also significantly influences patient survival. We also validated the prognostic value of miRNA let-7i in RCCs. miR-138, located in chromosome 3p deletion, was also found to have suppressive effects on tumor proliferation and migration abilities. Our findings provide a significant advance in the delineation of the ccRCC genome by better defining the impact of CNAs in conjunction with methylation changes on the expression of cancer-related genes, miRNAs, and proteins and their influence on patient survival. Cancer Res; 72(20); 5273-84. Ó2012 AACR.

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Section: The Prognostic Significance Of Cnassupporting

confidence: 91%

Section: Genome-wide Copy Number Profiling Of Ccrccmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Multilevel Whole-Genome Analysis Reveals Candidate Biomarkers in Clear Cell Renal Cell Carcinoma

et al. 2012

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“…Sanjmyatav et al used single cell suspension extracted from fresh frozen tumour tissue and 10 from normal kidney tissues as negative control to set threshold for deletion [38]. …”

Section: Resultsmentioning

confidence: 99%

Significance of Chromosome 9p Status in Renal Cell Carcinoma: A Systematic Review and Quality of the Reported Studies

El‐Mokadem

Fitzpatrick

Prasad

et al. 2014

BioMed Research International

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Defining the prognosis of renal cell carcinoma (RCC) using genetic tests is an evolving area. The prognostic significance of 9p status in RCC, although described in the literature, remains underutilised in clinical practice. The study explored the causes of this translational gap. A systematic review on the significance of 9p status in RCC was performed to assess its clinical applicability and impact on clinical decision-making. Medline, Embase, and other electronic searches were made for studies reporting on 9p status in RCC. We collected data on: genetic techniques, pathological parameters, clinical outcomes, and completeness of follow-up assessment. Eleven studies reporting on 1,431 patients using different genetic techniques were included. The most commonly used genetic technique for the assessment of 9p status in RCC was fluorescence in situ hybridization. Combined genomic hybridisation (CGH), microsatellite analysis, karyotyping, and sequencing were other reported techniques. Various thresholds and cut-off values were used for the diagnosis of 9p deletion in different studies. Standardization, interobserver agreement, and consensus on the interpretation of test remained poor. The studies lacked validation and had high risk of bias and poor clinical applicability as assessed by two independent reviewers using a modified quality assessment tool. Further protocol driven studies with standardised methodology including use of appropriate positive and negative controls, assessment of interobserver variations, and evidenced based follow-up protocols are needed to clarify the role of 9p status in predicting oncological outcomes in renal cell cancer.

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Downregulation of NDUFB6 due to 9p24.1‐p13.3 loss is implicated in metastatic clear cell renal cell carcinoma

et al. 2014

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This study was conducted to clarify the genomic profiles of metastatic clear cell renal cell carcinomas (ccRCCs) and identify the genes responsible for development of metastasis. We analyzed the genomic profiles of 20 cases of primary ccRCC and their corresponding metastases using array-based comparative genomic hybridization, and identified 32 chromosomal regions in which gene copy number alterations were detected more frequently in metastases than in the primary tumors. Among these 32 regions, 9p24.1-p13.3 loss was the most statistically significant alteration. Furthermore, we found that patients with 9p24.1-p13.3 loss in primary tumors exhibited significantly lower rates of recurrence-free and cancer-specific survival, suggesting that 9p loss in the primary tumor is a potential biomarker predicting early recurrence of metastasis. Interestingly, the genomic profiles of primary tumors with 9p loss resembled those of their corresponding metastases, though 9p loss was accumulated in the metastases derived from the primary tumors without 9p loss. Comparison of the mRNA expression levels revealed that 2 of 58 genes located at 9p24.1-p13.3 were downregulated due to gene copy number loss in ccRCCs. An overexpression study of these two genes in ccRCC cell lines revealed that downregulation of NDUFB6 due to loss at 9p24.1-p13.3 may confer a growth advantage on metastatic ccRCC cells. These results were confirmed by analyzing the data of 405 cases of ccRCC obtained from The Cancer Genome Atlas (TCGA). On the basis of our present data, we propose that NDUFB6 is a possible tumor suppressor of metastatic ccRCCs.

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Identification of Genomic Alterations Associated With Metastasis and Cancer Specific Survival in Clear Cell Renal Cell Carcinoma

Cited by 30 publications

References 22 publications

Multilevel Whole-Genome Analysis Reveals Candidate Biomarkers in Clear Cell Renal Cell Carcinoma

Multilevel Whole-Genome Analysis Reveals Candidate Biomarkers in Clear Cell Renal Cell Carcinoma

Significance of Chromosome 9p Status in Renal Cell Carcinoma: A Systematic Review and Quality of the Reported Studies

Downregulation of NDUFB6 due to 9p24.1‐p13.3 loss is implicated in metastatic clear cell renal cell carcinoma

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