Association of genomic driver mutation, histologic subtype, and mTORC1 biomarker expression in mTOR pathway-altered renal tumors.

A widening spectrum of renal tumors is driven by alterations in mTOR pathway genes. We examined the relationship between the specific underlying genomic driver mutation, mTOR signaling activation and tumor histologic subtype among mTOR pathway-altered tumors. mTOR pathway activation was assessed by quantifying expression of GPNMB in 16 cases of eosinophilic vacuolated tumor (EVT), 13 cases of low grade oncocytic tumor (LOT), 10 cases of eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), and 1 case of xanthomatous giant cell renal cell carcinoma (XGC-RCC), all with previous sequencing. p-S6 expression was additionally quantified in the LOT and EVT cases. A literature review of 217 previously reported mTOR pathway-altered renal tumors identified the frequency of driver alterations by histologic subtype. GPNMB and p-S6 expression were correlated with one another (r = 0.51, p = 0.007) and GPNMB expression was higher among tumors with underlying TSC1/2 alterations compared to MTOR/PIK3CA alterations (p = 0.02) with a nonsignificant trend for p-S6 (p = 0.15). There was no significant association of GPNMB or pS6 with tumor histologic subtype in this series. In the literature, TSC1/2 alterations predominated in ESC-RCC (84%), though were less common in LOT (24%) where MTOR or other mTOR pathway mutations (PIK3CA, PTEN, RHEB, RICTOR, NF1/2) were frequent (55%). In EVT, RCC-FMS and renal hemangioblastoma, TSC1/2 and MTOR mutations occurred with similar frequency, with a slight predominance of the former. GPNMB expression is associated with p-S6 activation and is higher in renal tumors driven by TSC1/2 compared to MTOR/PIK3CA alterations, suggesting that it may be most useful in ESC-RCC.