Two new RCC subtypes were defined by distinct epigenetic and metabolic pathway expression patterns, the hypermethylated CpG island methylator phenotype-associated (CIMP) RCCs and metabolically divergent chRCCs, and new biomarkers of poor patient outcome were identified, including PBRM1 mutation in type 1 pRCC and CDKN2A loss in chRCC.
As an application of this resource, we discovered RCC GCN edges and modules that were associated with genetic lesions in known RCC driver genes, including VHL, a common initiating clear cell RCC (ccRCC) genetic lesion, and PBRM1 and BAP1 which are early genetic lesions in the Braided Cancer River Model (BCRM).
Recurrent secondary molecular alterations in clear cell RCC (BAP1, SETD2, PBRM1, and TP53) and papillary RCC (CDKN2A) may be associated with poor prognosis; however, intratumoral genomic heterogeneity may limit the clinical utility of these molecular biomarkers in renal mass biopsies.
Renal cell carcinomas (RCCs) are a diverse set of malignancies that have recently been shown to harbour mutations in a number of chromatin modifier genes - including PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2 - through high-throughput sequencing efforts.
While in clear cell renal cell carcinoma, BAP1 mutation was mutually exclusive with PBRM1 mutations, and BAP1-mutant clear cell renal cell carcinomas also showed significantly worse prognosis than PBRM1-mutant clear cell renal cell carcinomas ( p = 0.001).
PBRM1 was expressed at high levels in RCC ACHN cells and lentivirus-mediated PBRM1 knockdown in these cells caused an increase in the proportion of cells in S phase of the cell cycle and promoted in vitro proliferation and migration.
Compared to patients with PBRM1+ BAP1+ tumors those with PBRM1- BAP1+ lesions were more likely to die of renal cell carcinoma (HR 1.39, p = 0.035), followed by those with PBRM1+ BAP1- and PBRM1- BAP1- tumors (HR 3.25 and 5.2, respectively, each p <0.001).
The four most commonly mutated genes in RCC of clear-cell type (the most common type) are two-hit tumor suppressor genes, and they cluster in a 43-Mb region on chromosome 3p that is deleted in approximately 90% of tumors: VHL (mutated in ∼80%), PBRM1 (∼50%), BAP1 (∼15%), and SETD2 (∼15%).
Data from RNA interference (RNAi) assays suggest that loss of function of PBRM1 drives proliferation and growth of ccRCC, but the clinical relevance of this is unclear and restoring the function of these genes for therapeutic purposes is likely to be challenging.