Clinical and Pathologic Impact of Select Chromatin-modulating Tumor Suppressors in Clear Cell Renal Cell Carcinoma

Abstract Background Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1 , SETD2 , BAP1 , and KDM5C. PBRM1 , SETD2 , and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown. Objective To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC. Design, setting, and participants Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded. Outcome measurements and statistical analysis The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]). Results and limitations PBRM1 , BAP1 , SETD2 , and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1 , SETD2 , or KDM5C (19%) are more likely to present with stage III disease or higher ( p = 0.01 and p = 0.001, respectively). Small tumors (