Frequent KRAS Mutations in Oncocytic Papillary Renal Neoplasm with Inverted Nuclei

Frequent KRAS Mutations in Oncocytic Papillary Renal Neoplasm with Inverted Nuclei:

Abstract

Aims

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly documented rare tumour type. Its molecular pathological features have thus far been studied very little.

Methods and results

Three PRNRPs were found in The Cancer Genome Atlas (TCGA) database using a combination of GATA3 mRNA expression levels and digital slides from the TCGA papillary renal cell carcinoma project. KRAS codon 12 mutations were identified in the three PRNRPs from TCGA. Of our 10 PRNRP cases, the mutations were also discovered using Sanger sequencing in 7 (77.8%) of 9 cases with available DNA, where KRAS p.G12V (n=3), p.G12D (n=2), p.G12R (n=1), and p.G12C (n=1) alterations were found. PRNRP shared similar gene expression profiles with renal distal tubules via an inter‐profile correlation analysis. Gene Set Enrichment Analysis revealed that genes involved in "KEGG aldosterone regulated sodium reabsorption" or "hallmark apical surface" were enriched in PRNRP. Moreover, identical immunostaining for CK7, EMA, GATA3, and L1CAM was found between the distal tubules and PRNRPs. Polarized immunostaining patterns for L1CAM and EMA in the distal tubule were maintained in PRNRP.

Conclusions

These results imply that the tumour potentially originates from the distal tubule, especially from the cortical collecting duct, and probably retains its cell polarity, except for nuclear inversion. We therefore propose that oncocytic papillary renal neoplasm with inverted nuclei (OPRNIN) is a better name for this tumour type. OPRNIN is a kidney site‐specific KRAS mutation neoplasm different from conventional papillary renal cell carcinoma.