Frequent KRAS mutations in oncocytic papillary renal neoplasm with inverted nuclei

Abstract

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly documented rare tumour type. Its molecular pathological features have thus far been very little studied. There were 13 PRNRP cases including 3 The Cancer Genome Atlas (TCGA) cases and our 10 cases in this study. The 3 TCGA cases were found by a combined analysis 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 seven (77.8%) of nine 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 interprofile 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, polarised immunostaining patterns for L1CAM and EMA in the distal tubule were maintained in PRNRP. 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.