Abstract 5673: Transposable element expression patterns in epigenetic mutational subtypes of clear cell renal cell carcinoma
Authors: Meli Kevin , Ricker Cora A. , Camp Sabrina Y. , Smith Christof C. , Labaki Chris , Saad Eddy , Soulati Hanna , Reardon Brendan , Park Jihye , Vokes Natalie I. , Vincent Benjamin G. , Choueiri Toni K. , Braun David A. , Van Allen Eliezer M. 
Published: March 2024

Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is characterized by mutations in epigenetic modulators and by aberrant transposable element (TE) expression, each of which have been separately associated with immunotherapy (IO) benefit in specific clinical contexts. However, the relationship between mutations in epigenetic regulators and TE expression, and the potential effect of both somatic mutations and TE expression on clinical outcomes, has not been fully investigated.
Methods: We utilized RNA sequencing from ccRCC patients’ tumors and cell lines to quantify TE subfamily expression with TEtranscripts (n=123 metastatic IO-treated; CheckMate-009, 010, 025, n=355 all stage TCGA untreated, n=8 CCLE). Locus-specific endogenous retrovirus (ERV) expression was quantified using hervQuant. Differential TE and ERV expression was determined using DESeq2. Samples were stratified by mutations in PBRM1, SETD2, BAP1 and KDM5C, four of the top five mutated genes in ccRCC. Multivariable CoxPH models and the log-rank test were used to compare overall (OS) and progression-free survival (PFS). Two validation metastatic ccRCC cohorts were employed: the everolimus arm of CheckMate-025 (n=78, CM025e) and IMmotion150 (n=146, IM150).
Results: Global TE expression (LTR, LINE, SINE and DNA transposons) did not differ significantly across mutational and clinical subtypes. However, 29 of 795 TE subfamilies were differentially expressed in &gt;1 mutational subtype across datasets, and 22 of 29 were ERVs. At locus-specific resolution, 52 of 3173 ERVs were differentially expressed in &gt;1 mutational subtype across datasets. Additionally, 6 of the 52 ERVs nominally associated with PFS, and 4 nominally associated with OS, in the IO cohort. Among them, only ERVs 544 and 2014 associated with improved PFS (multivariable CoxPH p = 0.03 and 0.02, respectively) and were expressed across all datasets. Both ERVs also exhibited increased expression in PBRM1 mutant and decreased expression in BAP1 mutant vs. wildtype samples, in discovery (IO, TCGA, CCLE) and validation (CM025e, IM150) cohorts. Lastly, PBRM1 mutant patients with high ERV 544 or 2014 expression had improved PFS in the IO (log-rank p = 0.04 and 0.03, multivariable CoxPH p = 0.008 and 0.009, respectively, HR = 0.43 both), but not in the CM025e cohort, compared to other patients regardless of PBRM1 mutations.
Conclusion: ERVs 544 and 2014 were upregulated in PBRM1 mutant and downregulated in BAP1 mutant samples. Coupled with PBRM1 inactivation, their expression served as a candidate biomarker of improved PFS in IO-treated ccRCC that may have additional biological relevance. Expanded functional and clinicogenomic studies of epigenetic mutational subtype-specific patterns of TE expression, and their relation to selective IO response, may guide additional discovery and therapeutic development strategies in ccRCC.
Citation Format: Kevin Meli, Cora A. Ricker, Sabrina Y. Camp, Christof C. Smith, Chris Labaki, Eddy Saad, Hanna Soulati, Brendan Reardon, Jihye Park, Natalie I. Vokes, Benjamin G. Vincent, Toni K. Choueiri, David A. Braun, Eliezer M. Van Allen. Transposable element expression patterns in epigenetic mutational subtypes of clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5673.