Abstract
Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated to different scoring systems, and on the genomic landscape of the tumor. In this sense, ccRCC has for a long time been known to be associated to the biallelic inactivation of Von Hippel-Lindau (VHL) gene which causes aberrant hypoxia inducible factor (HIF) accumulation. Recently, next generation-sequencing technologies have provided the bases for an in-depth molecular characterization of ccRCC, identifying additional recurrently mutated genes, such as PBRM1 (≈40–50%), SETD2 (≈12%), or BAP1 (≈10%). PBRM1, the second most common mutated gene in ccRCC after VHL, is a component of the SWI/SNF chromatin remodeling complex. Different studies have investigated the biological consequences and the potential role of PBRM1 alterations in RCC prognosis and as a drug response modulator, although some results are contradictory. In the present article, we review the current evidence on PBRM1 as potential prognostic and predictive marker in both localized and metastatic RCC.
Highlights
Kidney cancer is the 12th most frequent solid tumor worldwide with around 400,000 new cases and 175,000 deaths from renal cell carcinoma (RCC) estimated in 2018 [1]
They confirmed the prognostic role of BAP1, TP53, and PBRM1 in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors (TKI)
The results showed a significant correlation between PRBM1 status and response to anti-PD1 therapy, with a significant benefit both in progression free survival (PFS) and overall survival (OS) in those patients harboring PBRM1 mutations (HR 0.67, 95% CI, 0.47–0.96; p = 0.03, and HR 0.65, 95% CI, 0.44–0.96; p = 0.03 respectively) compared to those with PBRM1 wild type tumors
Summary
Kidney cancer is the 12th most frequent solid tumor worldwide with around 400,000 new cases and 175,000 deaths from renal cell carcinoma (RCC) estimated in 2018 [1]. Cancers 2020, 12, 16 additional genes frequently mutated in ccRCC, such as PBRM1 (≈40–50%), SETD2 (12%), BAP1 (10%), and KDM5C (5%) [9,10,11]. VHL is the initiating event in ccRCC, the acquisition of additional mutations, some in subclonal cancer cell populations, is a common characteristic during ccRCC tumor development and metastasis. In this context, multiregion sequencing-based studies have highlighted the potential relevance of PBRM1 alterations for tumor growth and metastatic capacity, which are determinant for clinical outcome [10]. In the current therapeutic context there is a need of updating the scoring systems with molecular parameters, to better personalize treatment strategies to achieve survival improvement and avoid unnecessary toxicities
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