Fristrup, N. | bioRxiv Science

bioRxiv2026

Preoperative thymic output and T cell repertoire diversity are associated with recurrence after nephrectomy for localized renal cell carcinoma

Radiographic thymic health and peripheral T-cell repertoire features have been linked to outcomes in renal cell carcinoma (RCC), but their prognostic value after curative-intent surgery is unclear. We quantified preoperative blood signal-joint T-cell receptor excision circles (sjTRECs), a marker of thymic output, in 218 patients with localized RCC undergoing nephrectomy and characterized T-cell receptor {beta} (TCR{beta}) repertoires in 201 patients. We assessed overall survival (OS) and recurrence-free survival (RFS) using Kaplan-Meier and Cox models adjusted for age, sex, and Leibovich risk group. High sjTREC levels were associated with longer RFS after adjustment for age, sex, and Leibovich risk group (hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.29-0.87; p=0.015), with a concordant OS estimate (HR 0.62; 95% CI, 0.38-1.02; p=0.058). sjTREC provided additional prognostic information beyond Leibovich risk stratification for recurrence overall and among intermediate/high-risk patients (likelihood-ratio test, p=0.024 and p=0.034, respectively). Higher TCR{beta} diversity was associated with longer RFS overall (HR 0.76; 95% CI, 0.60-0.96; p=0.024) and among intermediate/high-risk patients with longer RFS (HR 0.71; 95% CI, 0.55-0.92; p=0.009) and OS (HR 0.80; 95% CI, 0.65-0.98; p=0.031). Preoperative sjTREC provided prognostic information beyond clinicopathological risk, with higher TCR{beta} diversity associated with favorable outcomes.

cancer biology↗

bioRxiv2020

Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

Circular RNAs (circRNAs) are stable, often highly expressed RNA transcripts with potential to modulate other regulatory RNAs. A few circRNAs have been shown to bind RNA binding proteins (RBPs), however, little is known about the prevalence and strength of these interactions in different biological contexts. Here, we comprehensively evaluate the interplay between circRNAs and RBPs in the ENCODE cell lines, HepG2 and K562, by profiling the expression of circRNAs in fractionated total RNA-sequencing samples and analyzing binding sites of 150 RBPs in large eCLIP data sets. We show that KHSRP binding sites are enriched in flanking introns of circRNAs in both HepG2 and K562 cells, and that KHSRP depletion affects circRNA biogenesis. Additionally, we show that exons forming circRNAs are generally enriched with RBP binding sites compared to non-circularizing exons. To detect individual circRNAs with regulatory potency, we computationally identify circRNAs that are highly covered by RBP binding sites and experimentally validate circRNA-RBP interactions by RNA immunoprecipitations. We characterize circCDYL, a highly expressed circRNA with clinical and functional implications in bladder cancer, which is covered with GRWD1 binding sites. We confirm that circCDYL binds GRWD1 in vivo and functionally characterizes the effect of circCDYL-GRWD1 interactions on target genes in HepG2. Furthermore, we confirm interactions between circCDYL and RBPs in bladder cancer cells and demonstrate that circCDYL depletion affects hallmarks of cancer and perturbs the expression of key cancer genes, e.g. TP53 and MYC. Finally, we show that elevated levels of highly RBP-covered circRNAs, including circCDYL, are associated with overall survival of bladder cancer patients. Our study demonstrates transcriptome-wide and cell-type-specific circRNA-RBP interactions that could play important regulatory roles in tumorigenesis.

genomics↗