The somatic genomic landscape of chromophobe renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Davis CF
PROVIDER: S-EPMC4160352 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
Publications
The somatic genomic landscape of chromophobe renal cell carcinoma.
Davis Caleb F CF Ricketts Christopher J CJ Wang Min M Yang Lixing L Cherniack Andrew D AD Shen Hui H Buhay Christian C Kang Hyojin H Kim Sang Cheol SC Fahey Catherine C CC Hacker Kathryn E KE Bhanot Gyan G Gordenin Dmitry A DA Chu Andy A Gunaratne Preethi H PH Biehl Michael M Seth Sahil S Kaipparettu Benny A BA Bristow Christopher A CA Donehower Lawrence A LA Wallen Eric M EM Smith Angela B AB Tickoo Satish K SK Tamboli Pheroze P Reuter Victor V Schmidt Laura S LS Hsieh James J JJ Choueiri Toni K TK Hakimi A Ari AA Chin Lynda L Meyerson Matthew M Kucherlapati Raju R Park Woong-Yang WY Robertson A Gordon AG Laird Peter W PW Henske Elizabeth P EP Kwiatkowski David J DJ Park Peter J PJ Morgan Margaret M Shuch Brian B Muzny Donna D Wheeler David A DA Linehan W Marston WM Gibbs Richard A RA Rathmell W Kimryn WK Creighton Chad J CJ
Cancer cell 20140821 3
We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting a ...[more]
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Project description:Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%-10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ? 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.
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Project description:Chromophobe renal cell carcinoma (ChRCC) represents 5% of all RCC cases and frequently demonstrates multiple chromosomal losses and an indolent pattern of local growth, but can demonstrate aggressive features and resistance to treatment in a metastatic setting. Cell line models are an important tool for the investigation of tumor biology and therapeutic drug efficacy. Currently, there are few ChRCC-derived cell lines and none is well characterized. This study characterizes a novel ChRCC-derived cell line model, UOK276. A large ChRCC tumor with regions of sarcomatoid differentiation was used to establish a spontaneously immortal cell line, UOK276. UOK276 was evaluated for chromosomal, mutational, and metabolic aberrations. The UOK276 cell line is hyperdiploid with a modal number of 49 chromosomes per cell, and evidence of copy-neutral loss of heterozygosity, as opposed to the classic pattern of ChRCC chromosomal losses. UOK276 demonstrated a TP53 missense mutation, expressed mutant TP53 protein, and responded to treatment with a small-molecule therapeutic agent, NSC319726, designed to reactivate mutated TP53. Xenograft tumors grew in nude mice and provide an in vivo animal model for the investigation of potential therapeutic regimes. The xenograft pathology and genetic analysis suggested that UOK276 was derived from the sarcomatoid region of the original tumor. In summary, UOK276 represents a novel in vitro and in vivo cell line model for aggressive, sarcomatoid-differentiated, TP53 mutant ChRCC. This preclinical model system could be used to investigate the novel biology of aggressive, sarcomatoid ChRCC and evaluate the new therapeutic regimes.
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Project description:BACKGROUND: Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, oncocytoma is usually regarded as a benign entity. The overlapping characteristics are best explained by a common cellular origin, and the biologic differences between chRCC and oncocytoma are therefore of considerable interest in terms of carcinogenesis, diagnosis and clinical management. Previous studies have been relatively limited in terms of examining the differences between oncocytoma and chromophobe RCC. METHODS: Gene expression profiling using the Affymetrix HGU133Plus2 platform was applied on chRCC (n = 15) and oncocytoma specimens (n = 15). Supervised analysis was applied to identify a discriminatory gene signature, as well as differentially expressed genes. High throughput single-nucleotide polymorphism (SNP) genotyping was performed on independent samples (n = 14) using Affymetrix GeneChip Mapping 100 K arrays to assess correlation between expression and gene copy number. Immunohistochemical validation was performed in an independent set of tumors. RESULTS: A novel 14 probe-set signature was developed to classify the tumors internally with 93% accuracy, and this was successfully validated on an external data-set with 94% accuracy. Pathway analysis highlighted clinically relevant dysregulated pathways of c-erbB2 and mammalian target of rapamycin (mTOR) signaling in chRCC, but no significant differences in p-AKT or extracellular HER2 expression was identified on immunohistochemistry. Loss of chromosome 1p, reflected in both cytogenetic and expression analysis, is common to both entities, implying this may be an early event in histogenesis. Multiple regional areas of cytogenetic alterations and corresponding expression biases differentiating the two entities were identified. Parafibromin, aquaporin 6, and synaptogyrin 3 were novel immunohistochemical markers effectively discriminating the two pathologic entities. CONCLUSIONS: Gene expression profiles, high-throughput SNP genotyping, and pathway analysis effectively distinguish chRCC from oncocytoma. We have generated a novel transcript predictor that is able to discriminate between the two entities accurately, and which has been validated both in an internal and an independent data-set, implying generalizability. A cytogenetic alteration, loss of chromosome 1p, common to renal oncocytoma and chRCC has been identified, providing the opportunities for identifying novel tumor suppressor genes and we have identified a series of immunohistochemical markers that are clinically useful in discriminating chRCC and oncocytoma.
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Project description:Past research on pathogenesis of a complex disease suggests that differentially expressed message RNAs (mRNAs) can be noted as biomarkers of a disease. However, significant miRNA-mediated regulation change might also be more deep underlying cause of a disease. In this study, a miRNA-mediated regulation module is defined based on GO terms (Gene Ontology terms) from which dysfunctional modules are identified as the suspected cause of a disease. A miRNA-mediated regulation module contains mRNAs annotated to a GO term and MicroRNAs (miRNAs) which regulate the mRNAs. Based on the miRNA-mediated regulation coefficients estimated from the expression profiles of the mRNA and the miRNAs, a SW (single regulation-weight) value is then designed to evaluate the miRNA-mediated regulation change of an mRNA, and the modules with significantly differential SW values are thus identified as dysfunctional modules. The approach is applied to Chromophobe renal cell carcinoma and it identifies 70 dysfunctional miRNA-mediated regulation modules from initial 4381 modules. The identified dysfunctional modules are detected to be comprehensive reflection of chromophobe renal cell carcinoma. The proposed approach suggests that accumulated alteration in miRNA-mediated regulation might cause functional alterations, which further cause a disease. Moreover, this approach can also be used to identify diffentially miRNA-mediated regulated mRNAs showing more comprehensive underlying association with a disease than differentially expressed mRNAs.
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Project description:In this study, we investigated CNAs of 4 tumor samples from 2 patients, including conventioanl chromophobe renal cell carcinoma(ChRCC), ChRCC with neuroendocrine differentiation and no-tumor region by 44k oligonucleotide-based array comparative genomic hybridization (array CGH).
2015-01-21 | GSE52641 | GEO
Project description:Background:The various pathogenesis between Clear cell renal carcinoma (CCRCC) and Chromophobe renal carcinoma (CHRCC) contributes to the different tumor growth rate and metastasis. In this study, we explored the distinct proteomic profiles between these two cancers and found different expression of glycogen phosphorylases in two cancers. Methods:We explored novel targets by proteomics. Five CCRCC cases and five CHRCC cases were selected for tandem mass tag-labeling liquid chromatography-mass spectroscopy (LC-MS). Gene ontology and KEGG pathway were applied for bioinformatic analysis. Glycogen phosphorylases were detected by Western blotting. Results:CHRCC were younger, more commonly female, and had larger tumors compared to those with CCRCC. 101 differentially expressed proteins (DEPs) in CCRCC and 235 DEPs in CHRCC were detected by LC-MS. It was found that disruption of metabolic pathways, epithelial cell differentiation, and cell response were the common characters for two tumor types. Activation of cell-cell adhesion and oxidation-reduction process stimulate CCRCC growth and epithelial cell differentiation and transferrin transport was involved in CHRCC growth, We also found that oxidative phosphorylation is activated in CHRCC and inhibited in CCRCC. More importantly, we found and confirmed that upregulation of glycogen phosphorylase liver type in CCRCC and glycogen phosphorylase brain type in CHRCC mediated differential glycogenolysis in the two tumor types, which could serve as potential therapeutic targets. Conclusion:We found different expression of glycogen phosphorylases in CCRCC and CHRCC by quantitative proteomics, which provides potential therapeutic targets in the future.
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Project description:Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). The genomic landscape in Chinese ccRCC needs to be elucidated. Herein, we investigated the molecular features of Chinese ccRCC patients. Genomic profiling of DNA was performed through next-generation sequencing (NGS) in Chinese patients with ccRCC between January 2017 and March 2020. Clinical information including age, gender, and tumor histology was collected. Immunohistochemistry (IHC) staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using R 3.6.1. A total of 880 Chinese ccRCC patients who have undergone NGS were included in this study. The most common somatic alterations were detected in VHL (59.7%), PBRM1 (18.0%), SETD2 (12.2%), BAP1 (10.2%), and TP53 (9.4%). Compared with The Cancer Genome Atlas (TCGA) database, a higher mutation frequency of VHL (59.7% vs. 50.0%, p < 0.001) and TP53 (9.4% vs. 3.5%, p < 0.001) and a lower mutation frequency of PBRM1 (18.0% vs. 31.0%, p < 0.001) were found in the Chinese cohort. Of the 460 patients who were evaluated for PD-L1 expression, 139 (30.2%) had positive PD-L1 expression. The median tumor mutational burden (TMB) value was 4.5 muts/Mb (range, 0-46.0). Five (0.7%) patients were identified as microsatellite instability-high (MSI-H). Furthermore, 52 (5.9%) patients were identified to carry pathogenic or likely pathogenic germline mutations in 22 cancer predisposition genes. This is the first large-scale comprehensive genomic analysis for Chinese ccRCC patients, and these results might provide a better understanding of molecular features in Chinese ccRCC patients, which can lead to an improvement in the personalized treatment for these patients.
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Project description:IntroductionChromophobe renal cell carcinoma, a distinct subtype of renal cell carcinoma (RCC) with characteristic light microscopic, histochemical, and ultrastructural features, typically has a favorable clinical course.Presentation of caseA 45-year-old femele presented with abdominal pain. A physical examination found a palpable mass in the left upper quadrant of the abdomen. A CT scan of the abdomen showed a heterogeneously enhancing mass, with necrosis and calcifications contents betwen the liver and the right kidney. she underwent surgical resection. Partial nephrectomy was performed. Pathological diagnosis was Chromophobe renal cell carcinoma.Discussion and conclusionChromophobe RCC is a rare variety of kidney neoplasm that has recently been better characterized from a molecular and genetic perspective. Overall, it is considered to have a better prognosis, and is associated with earlier stage tumors and longer overall survival compared with clear cell RCC.
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Project description:Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.
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