BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies

Abstract

Several novel recurrent mutations of histone modifying and chromatin remodeling genes have been identified in renal cell carcinoma. These mutations cause loss of function of several genes located in close proximity to VHL and include PBRM1, BAP1 and SETD2. PBRM1 encodes for BAF180, a component of the SWI/SNF chromatin remodeling complex, and is inactivated in, on average, 36% of clear cell renal cell carcinoma (ccRCC). Mutations of BAP1 encode for the histone deubiquitinase BRCA1 associated protein-1, and are present in 10% of ccRCCs. They are largely mutually exclusive with PBRM1 mutations. Mutations to SETD2, a histone methyltransferase, occur in 10% of ccRCC. BAP1- or SETD2-mutated ccRCCs have been associated with poor overall survival, while PBRM1 mutations seem to identify a favorable group of ccRCC tumors. This review describes the roles of PBRM1, BAP1 and SETD2 in the development and progression of ccRCC and their potential for future personalized approaches.

Keywords:

• BRCA1-associated protein-1
• clear cell renal cell carcinoma
• molecular diagnostics
• Polybromo-1
• personalized therapies
• SETD2

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Mutations to BAP1, PBRM1 and SETD2, in close proximity to VHL gene, are frequent in ccRCC patients.

• In the mouse, VHL is on a different chromosome than BAP1, PBRM1 or SETD2, thus explaining why VHL heterozygous humans, but not mice, develop.

• The inactivation of PBRM1 and BAP1 is less common in papillary, chromophobe RCC and oncocytoma than in ccRCC.

• BAP1 mutation may be predictive of the sensitivity to mTOR inhibitors and radiotherapy.

• Patients with BAP1- or SETD2-mutant ccRCC have been associated with poor overall survival, while PBRM1 mutations seem to identify a favorable group of ccRCC tumors.

• Potential biomarkers, such as BAP1, PBRM1 and SETD2, and others will be all the more important in order to personalize therapies for ccRCC patients.

• The roles of these genes as therapeutic targets in ccRCC patients have not been elucidated yet.

• Research should be also focused on the potential correlation between the risk of relapsing after partial or complete nephrectomy and BAP1, PBRM1 and SETD2 mutations.