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 (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).
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.
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!
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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 |
Rearrangements
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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) [1]
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 [2]. Losses of 1p, 4p, 4q, 8p, 9p, 9q, 13q, 14q and 18q correlate with higher grade and/or stage of the tumors [3][4] [5][6] [7] and loss of 4, 9p and 14q have been reported as independent prognostic factors for survival in ccRCC[8][9][10][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)
Links
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References
- ↑ Randall JM et al. (2014). Molecular aberrations in clear cell renal cell carcinoma. Cancer Metastasis Rev (2014) 33:1109–1124 PMID:25365943
- ↑ Wolff et al.
- ↑ Zhang et al, Adv Bioinform, 2010
- ↑ Wilhelm et al, Cancer res 2002; Moore et al, Oncogenesis, 2012
- ↑ Arai et al, Clin Canc Res 2008
- ↑ Gunawan et al. Cancer Res 2001
- ↑ Monzon et al, Mod Path 2011
- ↑ Zhang 2010
- ↑ Monzon 2011
- ↑ Klatte 2009
- ↑ Arai 2008
- ↑ Alimov et al Int J Oncol 2004; Moch et al 1996