Following on from the blog last week, which described the identification of PBRM1 mutations in clear-cell RCC (ccRCC), other sequencing studies are also finding new genes that are mutated in ccRCC. For example, Dalgliesh et al. (2010) have identified mutations in histone modifying enzymes and DNA repair enzymes.
In this study, 3,544 protein-coding genes were sequenced in 101 cases of ccRCC. As expected, a large proportion (56%) had mutations in VHL. It has been hypothesised that VHL mutations alone are insufficient for the development of ccRCC, and that further mutations in additional genes are also required. This study identifies some of these possible additional genes.
Mutations were found in the histone modifying genes SETD2 and JARID1C. SETD2 is a histone H3 lysine 36 methyltransferase and JARID1C is a histone H3 lysine 4 demethylase. These observations, in tandem with a previous study that identified mutations in the histone H3 lysine 27 demethylase gene UTX (van Haaften et al., 2009), and the PBRM1 results discussed last week, support the idea of a link between dysfunctional chromatin modification and ccRCC.
The authors also found mutations in several genes involved in DNA repair. Three different mutations were identified in the DNA mismatch-repair gene PMS1, as well as mutations in WRN and NBN, which are both involved in DNA double-strand break repair. These results suggest that mutations in DNA repair enzymes may play a role in the development of ccRCC. This is of interest for BHD syndrome since, as previously discussed, FNIP2 is believed to be involved in apoptosis induced by DNA mis-pairings (Komori et al., 2009).
The 3,544 genes sequenced in this study included FLCN; however no mutations were identified in the 101 ccRCC samples tested. This may be because clear-cell histologies are rare in BHD syndrome.
This study has highlighted the heterogeneity that exists in cancers. Although ccRCC is largely characterised by VHL mutations, many other genes are also mutated. Additional sequencing studies are required to further understand the cancer genome.
- 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
- Komori, K., Takagi, Y., Sanada, M., Lim, T., Nakatsu, Y., Tsuzuki, T., Sekiguchi, M., & Hidaka, M. (2009). A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA Oncogene, 28 (8), 1142-1150 DOI: 10.1038/onc.2008.462
- van Haaften, G., Dalgliesh, G., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., O’Meara, S., Teague, J., Butler, A., Hinton, J., Latimer, C., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P., Cole, J., Forbes, S., Jia, M., Jones, D., Kok, C., Leroy, C., Lin, M., McBride, D., Maddison, M., Maquire, S., McLay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., Pleasance, E., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P., Turner, R., Turrell, K., Varian, J., West, S., Widaa, S., Wray, P., Collins, V., Ichimura, K., Law, S., Wong, J., Yuen, S., Leung, S., Tonon, G., DePinho, R., Tai, Y., Anderson, K., Kahnoski, R., Massie, A., Khoo, S., Teh, B., Stratton, M., & Futreal, P. (2009). Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer Nature Genetics, 41 (5), 521-523 DOI: 10.1038/ng.349