Distinct endogenous retroviruses are expressed in mutational subtypes of clear cell renal cell carcinoma and are linked to improved clinical outcomes.

Abstract

Distinct mutations in chromatin regulators and aberrant expression of transposable elements (TEs), have been associated with clinical benefit to immunotherapy (IO) in specific clear cell renal cell carcinoma (ccRCC) clinical contexts. However, the relationship between mutations in chromatin regulators and TE expression, and their effect on clinical outcomes, are incompletely understood. Here, we identified TEs expressed in distinct mutational subtypes of ccRCC, with endogenous retroviruses (ERVs) comprising the majority of TEs observed. Of these, ERVs 544 and 2014 were upregulated in PBRM1 mutant samples. Patients with high expression of these ERVs and somatic PBRM1 mutations had improved progression-free survival with IO monotherapy, but not targeted therapy, and their upregulation associated with expression of innate immune pathways. Chromatin accessibility increased at ERV 544 and 2014 loci in PBRM1-deficient ccRCC cells, and ERV 544 and 2014 were upregulated upon in vitro PBRM1 knockout in ccRCC cell line clones. Broadly, our study supports a link between PBRM1 mutations, subsequent chromatin accessibility changes, and aberrant but immunoresponsive ERVs in ccRCC.