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. Excitingly, recent sequencing efforts identified several novel, frequent mutations of histone modifying and chromatin remodeling genes in ccRCC, including PBRM1, SETD2, BAP1 and KDM5C. Intriguingly, PBRM1, SETD2 and BAP1 are located in close proximity to VHL within a commonly lost (~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 ccRCC and matched normal tissues from a single institute. Pathologic features, baseline patient characteristics and follow-up data were recorded. Statistical Analysis The linkage between mutations and clinical and pathologic outcomes was interrogated with Fisher’s exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer specific survival). 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 3+ diseases, p=0.01 and p=0.001, respectively. Small tumors (<4cm) with PBRM1 mutations are more likely to exhibit stage 3 pathologic features (OR 6.4, p=0.001). BAP1 mutations tend to occur in Fuhrman Grade 3–4 tumors (p=0.052) and associate with worse cancer specific survival (p=0.01). Clinical outcome data is limited by the number of events. Conclusion Most mutations of chromatin modulators discovered in ccRCC are loss-of-function, which associate with advanced stage, grade, and possibly worsened cancer specific survival. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.

Loss of SETD2, but not H3K36me3, correlates with aggressive clinicopathological features of clear cell renal cell carcinoma patients

“…First of all, ccRCC exhibited a heterogeneity nature, which easily could cause sampling bias. To date, most SETD2 gene mutation status was based on multiple kinds of sequencing, which could only reflect the gene status of very circumscribed cancer lesions and potentially underestimate the mutation rates (13,(18)(19)(20)(21). In comparison, IHC could detect the protein expression of a whole block section, which is more objective.…”

“…H3K36me3 is known to be associated with transcription activation as well as elongation (9,11). It is reported that SETD2 mutations have been found to be associated with an advanced clinical stage and poor prognosis in patients with primary ccRCC (12,13), which implied that SETD2 is a tumor suppressor. However, the SETD2 protein deficiency rate, its downstream targets and the underlying mechanisms of SETD2 in ccRCC remain unclear.…”

New insights on chromatin modifiers and histone post‐translational modifications in renal cell tumours

“…Oncocytomas expressed high levels than RCC (P = 0Á027) [17] Chromatin Modifiers BAP1 NS Mutation 106 ccRCC and 176 ccRCC 8-14% of the cases had mutations, which mostly were mutually exclusive [23,28] Prognostic Mutation 185 RCC BAP1 mutations were predictors of cancer-specific survival (P = 0Á013) [22] ccRCC expressed high levels than the adjacent normal tissues (P < 0Á05).…”

The Nephrologist’s Tumor: Basic Biology and Management of Renal Cell Carcinoma

“…19 SETD2 is a tumor suppressor in proximal epithelial tubular cells. 20 Mutations in SETD2 are associated with advanced tumor stage and reduced survival as shown by The Cancer Genome Atlas (TCGA) cohort, with a median survival of 62.7 months compared with 78.2 months in patients without the mutation.…”