19 Dissecting ARNT Expression Patterns in RCC and Association with Outcomes

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Abstract Background Hypoxia signaling is a key driver of renal cell carcinoma (RCC) and is mediated by HIF-dependent transcription. ARNT (HIF-1β) is an essential HIF binding partner, but its expression and clinical relevance in RCC are poorly defined. With ARNT inhibitors in development, characterizing ARNT expression in RCC is clinically important. Methods Next-generation DNA (592-gene/whole-exome) and RNA (whole-transcriptome) sequencing were performed on 4,062 RCC specimens. ARNT expression was measured as transcripts per million (TPM) and dichotomized as high vs low based on quartiles (Q4 vs Q1). Overall survival (OS) was measured from diagnosis to death or last follow-up, and time on treatment (ToT) of vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) was derived from claims data. Results The cohort was predominantly male (71%) and White (61%), with a median age of 64 years. Histologies included clear-cell RCC (ccRCC) (n = 1,198; 29.5%), chromophobe (n = 83; 2%), and medullary RCC (n = 15; 0.3%), with the remainder RCC-NOS. VHL alterations were present in 46% of tumors. Specimens were obtained from primary kidney tumors (44%), lymph nodes (8%), and metastatic sites (48%). ARNT expression was highest in ccRCC (ccRCC: 42.7; papillary: 40.7; medullary: 33.8; chromophobe: 18), and was otherwise comparable across racial groups (White: 41.4; Black: 40.1; Asian/Pacific: 38.0; other: 38.3), ethnic subgroups (Hispanic: 42.2; non-Hispanic: 41.3), sarcomatoid status (sarcomatoid: 43.7; non-sarcomatoid: 41.4), VHL alteration (VHL-mut: 42.5; VHL-wild: 41.7) and tumor sites (primary kidney: 41.8; lymph node: 42.7; distant metastatic sites: 40.8). High ARNT expression was associated with higher frequencies of CHEK2 (Q4: 2.1% vs Q1: 0.35%; q = 0.008) and PALB2 alterations (Q4: 0.79% vs Q1: 0%; q = 0.036), and lower frequencies of TP53 (Q4: 12% vs Q1: 18%; q = 0.003) and RB1 alterations (Q4: 0.92% vs Q1: 2.87%; q = 0.02). The alterations in PBRM1/SETD2/SMACB1 were similar. ARNT expression was not associated with OS (Q4: 81.3 vs Q1: 81.1 months, p = 0.56) or ToT of VEGF TKI (Q4: 7.6 vs Q1: 7.4 months, p = 0.49). Conclusions In this large, multi-histology RCC cohort, ARNT expression was highest in ccRCC but otherwise consistent across clinical and molecular subgroups. Although high ARNT expressions were associated with distinct genomic features, it was not associated with OS or VEGF TKI ToT. These findings provide a benchmark for ARNT-targeted therapy development.

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