Proteomic Analysis Identifies Potential Biomarkers of ELOC-Mutated Renal Cell Carcinoma.

Abstract

ELOC-mutated renal cell carcinoma (RCC) is a rare tumor with only ∼40 cases reported to date; it shares a molecular background with clear cell RCC (ccRCC) in terms of hypoxia-inducible factor-alpha (HIF-α) protein accumulation. ELOC-mutated RCC is characterized by prominent leiomyomatous stromal growth and a more indolent clinical course compared with ccRCC. In our previous study, whole-genome sequencing of 102 ccRCC cases identified 5 cases of ELOC-mutated RCC. In the present study, we conducted proteomic and immunohistochemical analyses on up to 13 Japanese ELOC-mutated RCCs, including 8 previously reported cases, to elucidate its distinct molecular mechanisms and identify biomarkers that may be useful in distinguishing ELOC-mutated RCC from ccRCC. Proteomic profiling revealed that molecules, including cytokeratin 7, scinderin (SCIN), and sortilin 1 (SORT1), were significantly overexpressed in ELOC-mutated RCC compared with ccRCC. Notably, SCIN and SORT1 emerged as novel potential diagnostic biomarkers for distinguishing ELOC-mutated RCC from ccRCC. The analysis further suggested that ELOC-mutated RCC relies more on oxidative phosphorylation and less on glycolysis than ccRCC. This metabolic shift may be linked to the relative depletion of NAD+ due to the low expression of NAPRT and QPRT. In addition, we observed geographic variation in the disease frequency among different cohorts, with a higher frequency in Japan. Our findings provide novel insights into the pathogenesis of ELOC-mutated RCC and highlight SCIN and SORT1 as potential supportive biomarkers.