The ubiquitin-mediated proteolysis pathway and clear cell RCC

Mutations in VHL are known to be associated with the development of clear cell renal cell carcinoma (ccRCC), and recent sequencing studies have identified several genes involved in chromatin regulation that are also frequently mutated in ccRCC (Dalgliesh et al., 2010; Varela et al., 2011 – as discussed in our previous blogs here and here). A new sequencing study by Guo et al. (2011) has now identified 12 more genes linked to ccRCC, many of which appear to be involved in the ubiquitin-mediated proteolysis pathway (UMPP).

The authors sequenced and analysed the whole exomes of 10 primary ccRCCs (with matched controls) from institutions linked to the Urinogenital Cancer Genomics Consortium in China. They also performed a screen of approximately 1,100 cancer/RCC-associated genes (from the Cancer Gene Census and the Catalogue Of Somatic Mutations In Cancer) in 88 additional samples of ccRCC, with their corresponding controls. In total, 412 non-silent somatic mutations were identified in these 98 cases of ccRCC, of which a proportion were confirmed by genotyping and Sanger sequencing.

Guo et al. then used statistical approaches to show that 23 genes were specifically mutated at elevated levels in these ccRCCs. However, 12 of these genes were not previously known to be associated with ccRCC. For example, the tumour suppressor gene TSC1 is known to be involved in tuberous sclerosis complex, but was also mutated in 3% of the ccRCCs studied. The tumour suppressor gene BAP1 was also mutated in 8% of the cases, and it encodes a component of the UMPP, a pathway which is involved in the ubiquitin-mediated degradation of proteins within cells.

Subsequent pathway analysis of the mutated genes in the whole-exome study showed that the UMPP was the most frequently altered system within these 10 tumours. Sequencing of all the genes in the UMPP in the remaining 88 samples also showed that the UMPP genes were mutated at a significantly higher frequency than background.

Since the UMPP gene VHL is known to have an important role in ccRCC tumourigenesis through its effects on HIF signalling, this particular system was analysed further. Using immunohistochemical analysis, Guo et al. noted that tumours with mutations in the UMPP had a significant overexpression of HIF1α and HIF2α. In particular, it could be seen that tumours with alterations in VHL were significantly associated with HIF1α overexpression (and not HIF2α). In contrast, tumours with alterations in non-VHLUMPP genes were significantly associated with HIF2α overexpression (and not HIF1α). Consequently, in addition to VHL, a variety of UMPP genes may be involved in the regulation HIF signalling. Furthermore, many other signalling networks could be affected by alterations in these genes in both a HIF-dependent and independent fashion.

Finally, no significant mutations were found in FLCN, which is not surprising as clear-cut cases of ccRCC are relatively uncommon in BHD syndrome. However, it would be of interest to see if these UMPP genes play a role in BHD-associated tumourigenesis, as FLCN has also been linked to HIF signalling by Preston et al. (2010).

 

  • Dalgliesh, G., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., Teague, J., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P., Forbes, S., Jia, M., Jones, D., Knott, H., Kok, C., Lau, K., Leroy, C., Lin, M., McBride, D., Maddison, M., Maguire, S., McLay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., O’Meara, S., Pleasance, E., Rajasingham, A., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P., Turrell, K., Dykema, K., Khoo, S., Petillo, D., Wondergem, B., Anema, J., Kahnoski, R., Teh, B., Stratton, M., & Futreal, P. (2010). Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes Nature, 463 (7279), 360-363. DOI:10.1038/nature08672
  • Guo G, Gui Y, Gao S, Tang A, Hu X, Huang Y, Jia W, Li Z, He M, Sun L, Song P, Sun X, Zhao X, Yang S, Liang C, Wan S, Zhou F, Chen C, Zhu J, Li X, Jian M, Zhou L, Ye R, Huang P, Chen J, Jiang T, Liu X, Wang Y, Zou J, Jiang Z, Wu R, Wu S, Fan F, Zhang Z, Liu L, Yang R, Liu X, Wu H, Yin W, Zhao X, Liu Y, Peng H, Jiang B, Feng Q, Li C, Xie J, Lu J, Kristiansen K, Li Y, Zhang X, Li S, Wang J, Yang H, Cai Z, Wang J. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet. 2011 Dec 4. doi: 10.1038/ng.1014. PMID: 22138691
  • Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, & Tee AR (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30 (10), 1159-73. PMID: 21057536
  • Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, & Futreal PA (2011). Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature, 469 (7331), 539-42. PMID: 21248752

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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