Difference between revisions of "Clear cell renal cell carcinoma"
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| + | [[Category:Recently Added Pages]] | ||
| + | [[Category:Kidney]] | ||
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__TOC__ | __TOC__ | ||
== Contributors == | == Contributors == | ||
| − | Daynna Wolff PhD FACMG | + | Daynna Wolff, PhD FACMG |
| + | <br> | ||
| + | Yajuan Liu, PhD | ||
| + | <br> | ||
| + | Rajyasree Emmadi, MD | ||
| + | <br> | ||
| + | Banumathy Gowrishankar, PhD | ||
| + | <br> | ||
| + | Jane Houldsworth, PhD | ||
== Tumor Type == | == Tumor Type == | ||
| Line 10: | Line 21: | ||
== Tumor Classification == | == Tumor Classification == | ||
| − | ''Clear Cell RCC'' | + | '''Clear Cell RCC''' |
| − | This tumor type accounts for 70 | + | |
| + | This tumor type accounts for ~70% of all renal cell carcinoma cases.<ref name=eble>Eble JN, Sauter G, Epstein JI, Sesterhenn IA. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press; 2004.</ref> | ||
== Description == | == Description == | ||
| − | + | Malignant epithelial cells with clear cytoplasm and a compact-alveolar (nested) or acinar growth pattern interspersed with intricate, arborizing vasculature. A variable proportion of cells with granular eosinophilic cytoplasm may be present. Infrequently, clear cell renal cell carcinoma has a distinct tubular pattern and rarely a pseudopapillary architecture is focally present. | |
| + | |||
| + | Also see https://en.wikipedia.org/wiki/Renal_cell_carcinoma | ||
== IHC Markers == | == IHC Markers == | ||
| − | + | Positive: [[vimentin]], [[CD10]], [[RCC]], [[PAX2]], [[PAX8]], [[CA-IX]], [[EMA]] | |
| + | |||
| + | Negative: [[CK7]], [[CD117]], [[AMACR]], [[E-cadherin]] | ||
== Genomic Gain/Loss/LOH == | == Genomic Gain/Loss/LOH == | ||
| − | + | <imagemap> | |
| + | Image:TCGA.RCC.png | 1000px | ||
| + | default [[KRCC interactive copy number|Explore the data interactively!]] | ||
| − | |||
| − | + | </imagemap> | |
| + | |||
| + | The image shows the cumulative copy number of 528 RCC samples from the TCGA (reference needed). | ||
| + | Click the image for an interactive version of the data. | ||
| + | |||
| + | {| class="wikitable sortable" | ||
| + | |- | ||
| + | ! Chromosome !! Gain/Loss/Amp !! Region | ||
| + | |- | ||
| + | | 1 || Loss || 1p | ||
| + | |- | ||
| + | |3 || Loss || 3p (3p21, 3p25 and/or 3p13-p14) | ||
| + | |- | ||
| + | |4 || Loss || 4q | ||
| + | |- | ||
| + | |5 || Gain || 5q | ||
| + | |- | ||
| + | |8 || Loss || 8p | ||
| + | |- | ||
| + | |9 || Loss || 9p, 9q | ||
| + | |- | ||
| + | |14 ||Loss || 14q | ||
| + | |||
| + | |} | ||
== Mutations (SNV/INDEL) == | == Mutations (SNV/INDEL) == | ||
| − | + | === Mutated in >20% === | |
| + | |||
| + | [[VHL]] (43%), [[PBRM1]] (30%) | ||
| − | |||
=== Mutated in 10-20% === | === Mutated in 10-20% === | ||
| − | === Mutated in 5-10% === | + | |
| + | [[BAP1]] (11%), [[SETD2]] (11%) | ||
| + | |||
| + | === Mutated in 5-10% === | ||
| + | |||
| + | [[KDMC5]] (6%), [[TP53]] (5%) | ||
| + | |||
=== Mutated in 2-5% === | === Mutated in 2-5% === | ||
| − | |||
| − | + | [[PTEN]], [[KMT2C]], [[AKAP9]], [[KMT2D]], [[TERT]], [[RANBP2]], [[PIK3CA]], [[ATM]], [[ARID1A]], [[CDKN2A]], [[SRGAP3]], [[SMARCA4]], [[MLLT4]], [[TCF12]] | |
| + | |||
| + | Note that additional rare gene mutations are listed by Randall et al (2014) <ref>Randall JM et al. (2014). | ||
| + | |||
| + | Molecular aberrations in clear cell renal cell carcinoma. | ||
| + | |||
| + | Cancer Metastasis Rev (2014) 33:1109–1124 PMID:[http://www.ncbi.nlm.nih.gov/pubmed/?term=25365943 25365943]</ref> | ||
| − | + | === mtDNA === | |
| − | == | + | == Epigenomics (methylation) == |
| − | |||
| − | + | subset of ccRCC have DNA hypermethylation patterns associated with poor patient outcome | |
| − | + | == Main Pathways Involved == | |
| + | 1) Loss of VHL function results in an uncoupling of an oxygen-sensing pathway, which results in stabilization and activation of the HIF transcription factors, leading to overexpression of a number of factors that promote proliferation, cell survival, angiogenesis, and metabolic changes, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF). 2) histone acetyltranferases/components of the SWI/SNF complex; mutations in chromosome 3p chromatin modifiers PBRM1, SETD2 and BAP1 associated with widspread alterations in transcription or methylation MAP kinase pathway phosphoprotein signature PI3K/AKT and mTOR pathways elevated; high expression of several genes representing targets for immunotherapy including PDCD1, CD247, PDCD1LG2, CTLA4, TNFRSF9, TNFRSF4 | ||
== Diagnosis == | == Diagnosis == | ||
| − | + | Deletion of 3p (bands) or LOH for 3p | |
== Prognosis == | == Prognosis == | ||
| − | + | Loss of 14, loss of 9p, loss of 18q and highly complex genotype are associated with high risk histological features and adverse clinical outcome, also significantly associated with high risk histologic features: loss of 1p, 4p, 9q, 15q, 16q, 17p, 18p, 21q, 22q and gains of 3q, 5p, 7p, 7q, 17q.<ref>Wolff, Nicholas C, Andrea Pavía-Jiménez, Vanina T Tcheuyap, Shane Alexander, Mridula Vishwanath, Alana Christie, Xian-Jin Xie, Noelle S Williams, Payal Kapur, Bruce Posner, Renée M Mckay, and James Brugarolas. "High-throughput Simultaneous Screen and Counterscreen Identifies Homoharringtonine as Synthetic Lethal with Von Hippel-Lindau Loss in Renal Cell Carcinoma." Oncotarget 6.19 (2015): 16951-62.</ref> Losses of 1p, 4p, 4q, 8p, 9p, 9q, 13q, 14q and 18q correlate with higher grade and/or stage of the tumors <ref name=zhang>Zhang, Zhongfa, Bill Wondergem, and Karl Dykema. "A Comprehensive Study of Progressive Cytogenetic Alterations in Clear Cell Renal Cell Carcinoma and a New Model for CcRCC Tumorigenesis and Progression." Advances in Bioinformatics 2010 (2010): 14.</ref><ref>Wilhelm, Mónica, Joris A Veltman, Adam B Olshen, Ajay N Jain, Dan H Moore, Joe C Presti, Gyula Kovacs, and Frederic M Waldman. "Array-based Comparative Genomic Hybridization for the Differential Diagnosis of Renal Cell Cancer." Cancer Research 62.4 (2002): 957-60.</ref><ref>Moore LE, Jaeger E, Nickerson ML, Brennan P, De Vries S, Roy R, et al. Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation. Oncogenesis. 2012;1 doi: 10.1038/oncsis.2012.14.</ref><ref name=arai>Arai, Eri, Saori Ushijima, Hitoshi Tsuda, Hiroyuki Fujimoto, Fumie Hosoda, Tatsuhiro Shibata, Tadashi Kondo, Issei Imoto, Johji Inazawa, Setsuo Hirohashi, and Yae Kanai. "Genetic Clustering of Clear Cell Renal Cell Carcinoma Based on Array-comparative Genomic Hybridization: Its Association with DNA Methylation Alteration and Patient Outcome." Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 14.17 (2008): 5531-9.</ref><ref>Gunawan, Huber, Holtrup, Von Heydebreck, Efferth, Poustka, Ringert, Jakse, and Füzesi. "Prognostic Impacts of Cytogenetic Findings in Clear Cell Renal Cell Carcinoma: Gain of 5q31-qter Predicts a Distinct Clinical Phenotype with Favorable Prognosis." Cancer Research 61.21 (2001): 7731-8.</ref><ref name=monzon>Monzon, Federico A, Karla Alvarez, Lief Peterson, Luan Truong, Robert J Amato, Joan Hernandez-Mcclain, Nizar Tannir, Anil V Parwani, and Eric Jonasch. "Chromosome 14q Loss Defines a Molecular Subtype of Clear-cell Renal Cell Carcinoma Associated with Poor Prognosis." Modern Pathology : An Official Journal of the United States and Canadian Academy of Pathology, Inc 24.11 (2011): 1470-9.</ref> and loss of 4, 9p and 14q have been reported as independent prognostic factors for survival in ccRCC.<ref name=zhang></ref><ref name=monzon></ref><ref>Klatte, Tobias, Allan J Pantuck, Jonathan W Said, David B Seligson, Nagesh P Rao, Jeffrey C Larochelle, Brian Shuch, Amnon Zisman, Fairooz F Kabbinavar, and Arie S Belldegrun. "Cytogenetic and Molecular Tumor Profiling for Type 1 and Type 2 Papillary Renal Cell Carcinoma." Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 15.4 (2009): 1162-9.</ref><ref name=arai></ref><ref>Andrei Alimov, Maria Kost-Alimova, Jian Liu, Chunde Li, Ulf Bergerheim, Stefan Imreh, George Klein, and Eugene R Zabarovsky. "Combined LOH/CGH Analysis Proves the Existence of Interstitial 3p Deletions in Renal Cell Carcinoma." Oncogene 19.11 (2000): 1392.</ref><ref>Moch, H., J C Presti, G. Sauter, N. Buchholz, P. Jordan, M J Mihatsch, and F M Waldman. "Genetic Aberrations Detected by Comparative Genomic Hybridization Are Associated with Clinical Outcome in Renal Cell Carcinoma." Cancer Research 56.1 (1996): 27-30.</ref> | |
== Therapeutics == | == Therapeutics == | ||
| − | + | Metastatic disease: loss of 21q, 22q | |
== Familial Forms == | == Familial Forms == | ||
| − | + | [[von Hippel-Lindau disease]] ([[VHL]]; 3p25) | |
| + | |||
| + | Hereditary clear cell RCC ( [[DIRC1]], [[DIRC2]], [[DIRC3]], [[FHIT]], [[RNF139]]) | ||
| + | |||
| + | [[Birt-Hogg-Dube syndrome]] ([[FLCN]] 17p11.2) | ||
| + | |||
==References== | ==References== | ||
{{Reflist}} | {{Reflist}} | ||
Latest revision as of 16:48, 19 August 2016
Contributors
Daynna Wolff, PhD FACMG
Yajuan Liu, PhD
Rajyasree Emmadi, MD
Banumathy Gowrishankar, PhD
Jane Houldsworth, PhD
Tumor Type
Renal Cell Carcinoma
Tumor Classification
Clear Cell RCC
This tumor type accounts for ~70% of all renal cell carcinoma cases.[1]
Description
Malignant epithelial cells with clear cytoplasm and a compact-alveolar (nested) or acinar growth pattern interspersed with intricate, arborizing vasculature. A variable proportion of cells with granular eosinophilic cytoplasm may be present. Infrequently, clear cell renal cell carcinoma has a distinct tubular pattern and rarely a pseudopapillary architecture is focally present.
Also see https://en.wikipedia.org/wiki/Renal_cell_carcinoma
IHC Markers
Positive: vimentin, CD10, RCC, PAX2, PAX8, CA-IX, EMA
Negative: CK7, CD117, AMACR, E-cadherin
Genomic Gain/Loss/LOH
<imagemap> Image:TCGA.RCC.png | 1000px default Explore the data interactively!
</imagemap>
The image shows the cumulative copy number of 528 RCC samples from the TCGA (reference needed). Click the image for an interactive version of the data.
| Chromosome | Gain/Loss/Amp | Region |
|---|---|---|
| 1 | Loss | 1p |
| 3 | Loss | 3p (3p21, 3p25 and/or 3p13-p14) |
| 4 | Loss | 4q |
| 5 | Gain | 5q |
| 8 | Loss | 8p |
| 9 | Loss | 9p, 9q |
| 14 | Loss | 14q |
Mutations (SNV/INDEL)
Mutated in >20%
Mutated in 10-20%
Mutated in 5-10%
Mutated in 2-5%
PTEN, KMT2C, AKAP9, KMT2D, TERT, RANBP2, PIK3CA, ATM, ARID1A, CDKN2A, SRGAP3, SMARCA4, MLLT4, TCF12
Note that additional rare gene mutations are listed by Randall et al (2014) [2]
mtDNA
Epigenomics (methylation)
subset of ccRCC have DNA hypermethylation patterns associated with poor patient outcome
Main Pathways Involved
1) Loss of VHL function results in an uncoupling of an oxygen-sensing pathway, which results in stabilization and activation of the HIF transcription factors, leading to overexpression of a number of factors that promote proliferation, cell survival, angiogenesis, and metabolic changes, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF). 2) histone acetyltranferases/components of the SWI/SNF complex; mutations in chromosome 3p chromatin modifiers PBRM1, SETD2 and BAP1 associated with widspread alterations in transcription or methylation MAP kinase pathway phosphoprotein signature PI3K/AKT and mTOR pathways elevated; high expression of several genes representing targets for immunotherapy including PDCD1, CD247, PDCD1LG2, CTLA4, TNFRSF9, TNFRSF4
Diagnosis
Deletion of 3p (bands) or LOH for 3p
Prognosis
Loss of 14, loss of 9p, loss of 18q and highly complex genotype are associated with high risk histological features and adverse clinical outcome, also significantly associated with high risk histologic features: loss of 1p, 4p, 9q, 15q, 16q, 17p, 18p, 21q, 22q and gains of 3q, 5p, 7p, 7q, 17q.[3] Losses of 1p, 4p, 4q, 8p, 9p, 9q, 13q, 14q and 18q correlate with higher grade and/or stage of the tumors [4][5][6][7][8][9] and loss of 4, 9p and 14q have been reported as independent prognostic factors for survival in ccRCC.[4][9][10][7][11][12]
Therapeutics
Metastatic disease: loss of 21q, 22q
Familial Forms
von Hippel-Lindau disease (VHL; 3p25)
Hereditary clear cell RCC ( DIRC1, DIRC2, DIRC3, FHIT, RNF139)
Birt-Hogg-Dube syndrome (FLCN 17p11.2)
References
- ↑ Eble JN, Sauter G, Epstein JI, Sesterhenn IA. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press; 2004.
- ↑ Randall JM et al. (2014). Molecular aberrations in clear cell renal cell carcinoma. Cancer Metastasis Rev (2014) 33:1109–1124 PMID:25365943
- ↑ Wolff, Nicholas C, Andrea Pavía-Jiménez, Vanina T Tcheuyap, Shane Alexander, Mridula Vishwanath, Alana Christie, Xian-Jin Xie, Noelle S Williams, Payal Kapur, Bruce Posner, Renée M Mckay, and James Brugarolas. "High-throughput Simultaneous Screen and Counterscreen Identifies Homoharringtonine as Synthetic Lethal with Von Hippel-Lindau Loss in Renal Cell Carcinoma." Oncotarget 6.19 (2015): 16951-62.
- ↑ 4.0 4.1 Zhang, Zhongfa, Bill Wondergem, and Karl Dykema. "A Comprehensive Study of Progressive Cytogenetic Alterations in Clear Cell Renal Cell Carcinoma and a New Model for CcRCC Tumorigenesis and Progression." Advances in Bioinformatics 2010 (2010): 14.
- ↑ Wilhelm, Mónica, Joris A Veltman, Adam B Olshen, Ajay N Jain, Dan H Moore, Joe C Presti, Gyula Kovacs, and Frederic M Waldman. "Array-based Comparative Genomic Hybridization for the Differential Diagnosis of Renal Cell Cancer." Cancer Research 62.4 (2002): 957-60.
- ↑ Moore LE, Jaeger E, Nickerson ML, Brennan P, De Vries S, Roy R, et al. Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation. Oncogenesis. 2012;1 doi: 10.1038/oncsis.2012.14.
- ↑ 7.0 7.1 Arai, Eri, Saori Ushijima, Hitoshi Tsuda, Hiroyuki Fujimoto, Fumie Hosoda, Tatsuhiro Shibata, Tadashi Kondo, Issei Imoto, Johji Inazawa, Setsuo Hirohashi, and Yae Kanai. "Genetic Clustering of Clear Cell Renal Cell Carcinoma Based on Array-comparative Genomic Hybridization: Its Association with DNA Methylation Alteration and Patient Outcome." Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 14.17 (2008): 5531-9.
- ↑ Gunawan, Huber, Holtrup, Von Heydebreck, Efferth, Poustka, Ringert, Jakse, and Füzesi. "Prognostic Impacts of Cytogenetic Findings in Clear Cell Renal Cell Carcinoma: Gain of 5q31-qter Predicts a Distinct Clinical Phenotype with Favorable Prognosis." Cancer Research 61.21 (2001): 7731-8.
- ↑ 9.0 9.1 Monzon, Federico A, Karla Alvarez, Lief Peterson, Luan Truong, Robert J Amato, Joan Hernandez-Mcclain, Nizar Tannir, Anil V Parwani, and Eric Jonasch. "Chromosome 14q Loss Defines a Molecular Subtype of Clear-cell Renal Cell Carcinoma Associated with Poor Prognosis." Modern Pathology : An Official Journal of the United States and Canadian Academy of Pathology, Inc 24.11 (2011): 1470-9.
- ↑ Klatte, Tobias, Allan J Pantuck, Jonathan W Said, David B Seligson, Nagesh P Rao, Jeffrey C Larochelle, Brian Shuch, Amnon Zisman, Fairooz F Kabbinavar, and Arie S Belldegrun. "Cytogenetic and Molecular Tumor Profiling for Type 1 and Type 2 Papillary Renal Cell Carcinoma." Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 15.4 (2009): 1162-9.
- ↑ Andrei Alimov, Maria Kost-Alimova, Jian Liu, Chunde Li, Ulf Bergerheim, Stefan Imreh, George Klein, and Eugene R Zabarovsky. "Combined LOH/CGH Analysis Proves the Existence of Interstitial 3p Deletions in Renal Cell Carcinoma." Oncogene 19.11 (2000): 1392.
- ↑ Moch, H., J C Presti, G. Sauter, N. Buchholz, P. Jordan, M J Mihatsch, and F M Waldman. "Genetic Aberrations Detected by Comparative Genomic Hybridization Are Associated with Clinical Outcome in Renal Cell Carcinoma." Cancer Research 56.1 (1996): 27-30.