Transcriptomic Profiling Identifies a Subset of Renal Tumours with Overlapping Features of Clear Cell Papillary Renal Cell Tumour and Renal Cell Carcinoma with Fibromyomatous Stroma

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Background: Renal cell carcinomas (RCC) represent neoplasms with variable biological behaviour. Some remain difficult to classify within the current diagnostic framework. Clear cell papillary renal cell tumour (CCPRCT) is now recognized as an indolent entity, whereas renal cell carcinoma with fibromyomatous stroma (RCCFMS) remains a provisional subtype with partially overlapping morphological features. Methods: We analysed a multifocal RCC with clear cell morphology and prominent fibromyomatous stroma using whole-genome and RNA sequencing. The molecular profile was compared with the Cancer Genome Atlas (TCGA) pan-cancer dataset including 885 RCC cases. Histological re-evaluation of 10 identified similar cases was performed. Transcriptional data was mined for potential markers which were validated in an independent cohort. Results: The ten TCGA cases with similar transcriptomic features were characterized by diploid genomes, absence of recurrent chromosomal alterations and lack of VHL gene mutations. Reduced VHL mRNA expression was observed, with increased methylation at selected CpG sites consistent with possible epigenetic down-regulation. Histological re-evaluation by three urological pathologists identified diagnostic variability. Differential expression analysis highlighted cytokeratin 17 (KRT17) and collagen 17A1 (COL17A1) as candidate markers. Immunohistochemical evaluation in a small (n = 6) independent cohort of CCPRCT demonstrated expression of both markers, whereas tissue microarrays of 257 clear cell and 68 papillary RCC cases were found to be negative. Conclusions: These findings suggest that a subset of renal tumours with overlapping morphological features of CCPRCT and RCCFMS may share common molecular characteristics. These observations are exploratory and hypothesis-generating, and further studies in larger, well characterized cohorts are required to clarify the biological and diagnostic significance of this subgroup.

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