Abstract 2806: Inactivation of PBRM1, a gene frequently mutated in clear cell renal carcinoma, suppresses tumor growth

Abstract The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell renal carcinoma (ccRCC), the commonest histological subtype. However, our previous work has demonstrated that VHL loss alone is insufficient for ccRCC tumourigenesis arguing the need for additional genetic events. Recently, we have sequenced of the protein coding exome in 257 cases of primary renal carcinoma (RCC) and reported the identification of the SWI/SNF chromatin remodeling complex gene Polybromo 1 (PBRM1) as a second major RCC cancer gene with truncating mutations in 41% (85/257) of cases. In particular, all 9 cases with a SETD2 mutation have a mutation in either PBRM1 or VHL, with 7 of 9 cases having mutations in all three genes. The concomitant VHL, PBRM1 and SETD2 mutations, with all three genes mapping to chromosome 3p, suggest that the mutations are non-redundant functionally. To obtain further evidence that PBRM1 can act as a cancer gene, transcriptional profiling before and after PBRM1 knockdown was performed using gene expression microarrays. The results showed that PBRM1 activity regulates pathways associated with chromosomal instability and cellular proliferation. Consistently, knockdown of PBRM1 RNA resulted in a significant increase in proliferation 4/5 RCC lines. No effect was seen, however, in A704 cell, which carries a homozygous truncating PBRM1 mutation, confirming the specificity of the assay. Further, knockdown of PBRM1 resulted in significantly increased colony formation in soft-agar and increased cell migration indicative of an increase in transformed phenotype. Taken together, these data support PBRM1 having a tumor suppressor role in ccRCC. Therefore, understanding the contribution of PBRM1 mutation to clinical disease progression and outcome as well the potential for exploiting SWI/SNF complex abrogation therapeutically are important future areas of renal cancer research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2011-2806</jats:p

Abstract 2805: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene <i>PBRM1</i> in renal carcinoma

Abstract 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 ∼3500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (KDM6A), JARID1C (KDM5C) and SETD2. 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 remodeling complex gene PBRM1 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2805. doi:10.1158/1538-7445.AM2011-2805</jats:p

Exome sequencing of liver flukeg-associated cholangiocarcinoma

10.1038/ng.2273Nature Genetics446690-693NGEN

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

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