Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network

Abstract

Purpose: To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer-specific survival (CSS) of 609 patients with clear cell renal cell carcinoma (ccRCC) from 2 distinct cohorts.

Experimental design: Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was conducted to interrogate the genotype-phenotype associations. These findings were compared with analyses of the genomic and clinical dataset from our nonoverlapping The Cancer Genome Atlas (TCGA) cohort of 421 patients with primary ccRCC.

Results: 3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts [MSKCC, P = 0.002; HR 7.71; 95% confidence interval (CI)2.08-28.6; TCGA, P = 0.002; HR 2.21; 95% CI 1.35-3.63]. SETD2 are associated with worse CSS in the TCGA cohort (P = 0.036; HR 1.68; 95% CI 1.04-2.73). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS.

Conclusion: The chromosome 3p21 locus harbors 3 frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6%-12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30%-34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic, and molecular interrogation of this novel class of tumor suppressors.

Figure 1

A: Chromosome 3 map showing geographic proximity of the frequently mutated 3p tumor suppressors, and GISTIC copy number plot demonstrating heterozygous loss of a large segment of 3p in ~90% of the TCGA cohort. Blue color denotes copy number loss, and red –denotes copy number gain. B: Mutation heat map of MSKCC and TCGA cohorts highlights similar mutation frequencies and co-occurrences of the 3p tumors suppressors in both cohorts. C: Mutation percentages by type shows similar patterns in both cohorts (truncating = frameshift, nonsense, or essential splice site).

Figure 2

Competing risk cumulative incidence curves for the MSKCC cohort (n=188) DOD = death of disease.

Figure 3

Competing risk cumulative incidence curves for the TCGA cohort (n=421) DOD = death of disease.

Figure 4

A: Box plots demonstrate the statistically significant incremental increase of purported tumor suppressor genes (TSG) as defined by mutations occurring in the setting of copy number loss across the ccRCC genome. Values in parentheses represent median TSG mutation counts. B: Percentage of TCGA tumors with 3p TSG’s mutated as defined by increasing tumor size, nuclear grade, and AJCC stage. C: Fold change in mutation (%) frequency for 3p TSGs. Note the marked increase in BAP1 mutations with both advanced tumor grade and stage, and the trend in SETD2 mutations for advanced stage.