Exploration of Morphological Features of Clear Cell Renal Cell Carcinoma With PBRM1, SETD2, BAP1, or KDM5C Mutations

Abstract

The last decade has seen great advances in genomic profiling and prognosis-associated factors of clear cell renal cell carcinoma (RCC), the most common entity in kidney cancer. Following VHL, PBRM1, SETD2, BAP1, and KDM5C have been validated as the most common co-occurring gene mutations in clear cell RCC by multicenter studies. However, the morphological features of clear cell RCC with co-occurring gene mutations remain unclear. In this study, we presented 20 clear cell RCCs that underwent next-generation sequencing, of which 1 tumor was reclassified as ELOC-mutated RCC. PBRM1, SETD2, BAP1, and KDM5C were the most common mutations, following VHL. Morphologically, clear cell RCC with PBRM1 or KDM5C mutation usually displayed a low-grade pattern. Cystic changes and hyalinized stroma were often observed. The Ki67 index was <10%. These observations indicated good prognosis. However, mutated SETD2 may increase the malignancy of clear cell RCC with PBRM1 mutation. Two clear cell RCCs with mutated PBRM1 and SETD2 developed local or distant metastases. Clear cell RCC with BAP1 mutations always had high-grade patterns, and rhabdoid differentiation was also observed, indicating that BAP1 mutation was associated with poor outcomes. Papillary architecture was often a feature of BAP1 mutation, which is uncommon in clear cell RCC. PDL1 was positive in only one tumor with BAP1 mutation, and the positivity rate was limited to 5%. B7H3 was negative in all tumors. Morphologic findings in this small cohort may suggest why PBRM1 mutation does not correlate with decreased survival, whereas BAP1 mutation usually predicts poor outcomes.

Biological Biomarkers of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma

“…PBRM1 protein is a subunit of the PBAF chromatin remodeling ATP-dependent complex necessary for ligand-dependent transcriptional activation by nuclear hormone receptors; it can act either as a tumor suppressor, for example in ccRCC, or oncogene, for example in prostate cancer. It should be stressed that following VHL , PBRM1 , SETD2 , BAP1 , and KDM5C have been validated as common co-occurring gene mutations in ccRCC in multicenter studies [ 60 ]. In this latter study, results suggested that PBRM1 mutation does not correlate with decreased survival, whereas BAP1 mutation seemed to predict poor outcome.…”

Genetic and Epigenetic Characteristics in Isolated Pancreatic Metastases of Clear-Cell Renal Cell Carcinoma

“…Further frequently altered genes in ccRCC are chromatin-modifying genes: polybromo-1 (PBRM1), BRCA1 associated protein 1 (PAB1), SET domain containing 2 histone-lysine Nmethytransferase (SETD2), located on the same 3p chromosomal region [82][83][84], and less frequently, lysine demethylase 5C (KDM5C) located on the X chromosome [85] and telomerase reverse transcriptase (TERT) promoter located on chromosome 5p [86,87]. The frequency of detectable VHL defects is estimated to be up to 90% [58,86,[88][89][90]. In contrast, the incidence of the other altered driver genes is significantly lower: PBRM1 52.6-26.4%, SETD2 35-7.6%, BAP1 31-7.5%, KDM5C 16-3.8%, TERT 14-12.2% and mTor 13-5.7% [58,84,86,88,89,[91][92][93][94].…”

“…The frequency of detectable VHL defects is estimated to be up to 90% [58,86,[88][89][90]. In contrast, the incidence of the other altered driver genes is significantly lower: PBRM1 52.6-26.4%, SETD2 35-7.6%, BAP1 31-7.5%, KDM5C 16-3.8%, TERT 14-12.2% and mTor 13-5.7% [58,84,86,88,89,[91][92][93][94]. It was soon recognised that these gene alterations are associated with a different tumour biology, and thus, have an influence on the course of the disease and the outcome [90,95].…”

“…It was soon recognised that these gene alterations are associated with a different tumour biology, and thus, have an influence on the course of the disease and the outcome [90,95]. PBRM1 is the most frequently mutated gene after VHL [84,92] and mutations acquired in this gene largely do not overlap with loss of function mutations in BAP1 [58,88,90,92,96]. PBRM1 mutations are associated with improved outcome in ccRCC [95,97] and do not correlate with decreased survival [88], whereas the absence of mutations of PBRM1 resulted in worse outcome [90].…”

“…PBRM1 is the most frequently mutated gene after VHL [84,92] and mutations acquired in this gene largely do not overlap with loss of function mutations in BAP1 [58,88,90,92,96]. PBRM1 mutations are associated with improved outcome in ccRCC [95,97] and do not correlate with decreased survival [88], whereas the absence of mutations of PBRM1 resulted in worse outcome [90]. KDM5C mutations have also been associated with improved clinical outcome in clinical reports [88,94].…”