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. 2019 Feb;21(2):247-256.
doi: 10.1016/j.neo.2018.12.006. Epub 2019 Jan 16.

Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma

Svenja Bihr  1 , Riuko Ohashi  2 , Ariane L Moore  3 , Jan H Rüschoff  4 , Christian Beisel  3 , Thomas Hermanns  5 , Axel Mischo  1 , Claudia Corrò  4 , Jörg Beyer  1 , Niko Beerenwinkel  3 , Holger Moch  4 , Peter Schraml  6
Affiliations

Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma

Svenja Bihr et al. Neoplasia. 2019 Feb.

Abstract

Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples. In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each). By assigning the protein expression patterns to evolutionary subtypes, we revealed similar clinical phenotypes as suggested by TRACERx Renal. Given their important contribution to tumor suppression, we conclude that combined functional inactivation of PBRM1, BAP1, SETD2 and pVHL is critical for ccRCC progression.

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Figures

Figure 1
Figure 1
Schematic illustration of the cell microarray (CMA) with different RCC and kidney cell lines (top). Immunohistochemical staining of PBRM1, BAP1 and H3K36me3 with representative examples of nuclear positive (circled red) and negative (circled blue) stained cell lines (20- and 60-fold magnification). Core diameter: 0.6 mm.
Figure 2
Figure 2
Representative images of immunohistochemically stained tissue samples: strong nuclear PBRM1 expression in normal kidney (a) and one ccRCC (b); strong nuclear BAP1 expression in one pRCC and strong nuclear H3K36me3 expression in one pccRCC (20- and 60-fold magnification; core diameter: 0.6 mm).
Figure 3
Figure 3
Relationships between BAP1, PBRM1 and H3K36me3 expression patterns in ccRCC. 0, 1, 2 refers to negative, weak and strong nuclear expression.
Figure 4
Figure 4
Correlation of PBRM1, SETD2, and BAP1 mutation and protein expression.
Figure 5
Figure 5
A. ccRCC grouped by evolutionary subtypes: BAP1 driven (only BAP1 negative), PBRM1- > SCNA and PBRM1- > PI3K (only PBRM1 negative), Multiple clonal drivers (≥2 BAP1, SETD2 or PBRM1 negative), VHL monodriver/wildtype and other (PBRM1, BAP1 and SETD2 positive as well as only SETD2 negative). PBRM1 and SETD2 negative tumors were assigned to both multiple clonal drivers and PBRM1- > SETD2 subtype (gray arrow). B. Distribution of tumor grade, tumor stage and overall survival per subtype.
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