As mentioned in the blog last week, high-throughput DNA sequencing is helping to identify novel mutations related to a number of different genetic disorders. A recent example of this can be seen in a study by Varela et al. (2011), in which exome sequencing was used to identify truncating mutations in the PBRM1 gene in 41% (92/227) of the clear cell renal cell carcinoma (ccRCC) samples examined.
PBRM1 is found on chromosome 3 and is a component of the SWI/SNF chromatin-remodelling complex. It is known to contain domains which mediate binding to acetylated histones, protein-protein interactions and DNA-binding. Additionally, mutations in this gene have been implicated in breast cancer (Xia et al., 2008), and are also observed by Varela et al. in pancreatic, lung, gall bladder and renal cancer cell lines, as well as a mouse pancreatic cancer model.
The authors showed that knocking down PBRM1 expression with small interfering RNAs in four different RCC cell lines led to increased cell proliferation, increased colony formation in soft agar and increased cell migration – which suggests PBRM1 may play a tumour suppressor role in RCC.
The SWI/SNF chromatin-remodelling complex is involved in DNA replication, DNA repair and transcription (Tang et al., 2010), as well as cellular responses to hypoxia (Kenneth et al., 2009) and cell proliferation and differentiation (Reisman et al., 2009). Consequently, mutations in PBRM1 may interfere with these processes, and Varela et al. used gene expression microarrays to show that the knock-down of PBRM1 affected pathways associated with chromosomal instability and cellular proliferation.
In the ccRCC samples used in this paper, mutations in ARID1A (another component of the SWI/SNF complex) and the related ARID5B gene were also observed. However, the extent to which they contribute to ccRCC is unknown and would necessitate a large-scale follow-up screen. Additionally, VHL was often mutated, and it is hypothesised that the loss of VHL is insufficient for the development of ccRCC – consequently, additional events may be necessary for renal tumourigenesis, such as the loss of PBRM1. Furthermore, could PBRM1 mutations also be found in BHD patients with RCC?
Ultimately, the role of chromatin regulation in RCC is becoming better understood, which will help in the development both of diagnostic tests and appropriate therapies for kidney cancer.
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Kenneth NS, Mudie S, van Uden P, Rocha S. (2009) SWI/SNF regulates the cellular response to hypoxia. J Biol Chem. Feb 13; 284(7): 4123-31.
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Reisman D, Glaros S, Thompson EA. (2009) The SWI/SNF complex and cancer. Oncogene. Apr 9; 28(14): 1653-68.
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Tang L, Nogales E, Ciferri C. (2010) Structure and function of SWI/SNF chromatin remodeling complexes and mechanistic implications for transcription. Prog Biophys Mol Biol. Jun-Jul; 102(2-3): 122-8.
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Varela I, Tarpey P, Raine K et al. (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. Jan 27; 469(7331): 539-42.
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Xia W, Nagase S, Montia AG et al. (2008) BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer. Cancer Res. Mar 15; 68(6): 1667-74.
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