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Development and validation of a PBRM1-associated immune prognostic model for clear cell renal cell carcinoma.

ABSTRACT: Alteration in the polybromo-1 (PBRM1) protein encoding gene PBRM1 is the second most frequent mutation in clear cell renal cell carcinoma (ccRCC). It causes a series of changes in the tumorigenesis, progression, prognosis, and immune response of ccRCC patients. This study explored the PBRM1-associated immunological features and identified the immune-related genes (IRGs) linked to PBRM1 mutation using bioinformatics methods. A total of 37 survival IRGs associated with PBRM1 mutation in ccRCC patients were identified. To further explore the role of these IRGs in ccRCC and their association with immune status, eight IRGs with remarkable potential as individual targets were selected. An immune model that was constructed showed good performance in stratifying patients into different subgroups, showing clinical application potential compared to traditional clinical factors. Patients in the high-risk group were inclined to have more advanced stage and higher grade tumors with node metastasis, distant metastasis, and poorer prognosis. Furthermore, these patients had high percentages of regulatory T cells, follicular helper T cells, and M0 macrophages and exhibited high expression levels of immune checkpoints proteins, such as CTLA-4, PD-1, LAG-3, TIGIT, and CD47. Finally, a nomogram integrating the model and clinical factors for clinical application showed a more robust predictive performance for prognosis. The prediction model associated with PBRM1 mutation status and immunity can serve as a promising tool to stratify patients depending upon their immune status, thus facilitating immunotherapy in the future.

SUBMITTER: Chen J

PROVIDER: S-EPMC8495284 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Loss of PBRM1 and BAP1 expression is less common in non-clear cell renal cell carcinoma than in clear cell renal cell carcinoma.

Project description:BackgroundRecurrent mutations in polybromo-1 (PBRM1, ~40%) and BRCA1-associated protein-1 (BAP1, ~10%) occur in clear cell renal cell carcinoma (ccRCC), but their prevalence in non-ccRCC or renal oncocytoma (RO) is unknown. We evaluated loss of PBRM1 and BAP1 staining in ccRCC, papillary RCC (pRCC), chromophobe RCC (chRCC), and RO tumors using an immunohistochemistry assay in which negative staining was associated with loss-of-function mutations.MethodsWe identified 458 patients treated surgically for ccRCC, pRCC, chRCC, and RO between 2004 and 2012. We performed immunohistochemistry assays to evaluate PBRM1 and BAP1 protein expression to classify tumors as PBRM1 or BAP1 negative. We compared loss of staining of these 2 proteins in ccRCC and non-ccRCC using the Fisher exact test.ResultsFor the total cohort of 458 patients, we successfully stained both PBRM1 and BAP1 in 408 tumor samples. Consistent with the mutation rate, loss of PBRM1 and BAP1 staining occurred in 43% (80/187) and 10% (18/187) of ccRCC cases, respectively. However, loss of PBRM1 staining occurred in only 3% (2/59), 6% (1/17), and 0% (0/34) of pRCC, chRCC, and RO tumors, respectively (P<0.0001). BAP1 loss was not observed in any of the pRCC (n = 61), chRCC (n = 17), or RO (n = 34) tumors, (P = 0.00021).ConclusionOur data suggest that biallelic inactivation of PBRM1 or BAP1 is less common in non-ccRCC when compared with ccRCC tumors. These findings suggest that loss of PBRM1 or BAP1 are key events in ccRCC, whereas other pathways may support tumorigenesis in non-ccRCC subtypes.

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