Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

By I. Varela, P. Tarpey, K. Raine, Dachuan Huang, C. Ong, P. Stephens, Helen R. Davies, David Jones, Meng‐Lay Lin, J. Teague and 34 more. Nature, 2011

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The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/7c84507d717e36b1563dfb180f43bc2ea2893869

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Citations in the corpus

Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics (2015, background): “BAF180 is mutated or deleted in more than 50% of clear cell renal cell carcinoma (ccRCC) (92).”
Epigenetic Determinants of Cancer. (2016, background): “Continued Process Gene Function Tumor type Alteration BRG1 (SMARCA4) ATPase of BAF Lung, rhabdoid, medulloblastoma Mutation, low expression (Wilson and Roberts 2011) BRM (SMARCA2) ATPase of BAF Prostate, basal cell carcinoma Mutation, low expression (Sun et al. 2007; de Zwaan and Haass 2010) ARID1A ”
A survey of tools for variant analysis of next-generation genome sequencing data (2013, background): “For example, the usage of NGS has led to the identification of driver mutations for specific types of cancer [18, 19], which”
Pan-Cancer Network Analysis Identifies Combinations of Rare Somatic Mutations across Pathways and Protein Complexes (2014, positive): “In addition, we find that well-characterized mutations in a single gene in one cancer type (e.g. inactivating mutations BAP1 in KIRC) are replaced in other cancer types by rare mutations in other members of the same complex (e.g. inactivating mutations in ASXL1, ASXL2, FOXK2, KDM1B).”
The Somatic Genomic Landscape of Glioblastoma (2013, background): “, 2010) and renal carcinoma (Varela et al., 2011), is suggested.”