Cancer Communications最新文献

Ubiquitination, a key post-translational modification, plays an essential role in tumor biology by regulating fundamental cellular processes, such as metabolism and cell death. Additionally, it interacts with other post-translational modifications, which are closely linked to tumorigenesis, tumor progression, the tumor microenvironment, and the response to therapeutic interventions. Recent advancements in understanding the ubiquitination mechanisms have led to significant breakthroughs, offering novel perspectives and strategies for diagnosing and treating tumors. Here, we provided an overview of how ubiquitination influences tumor biology, focusing on its roles in immune regulation, metabolism, and its interactions with other modifications. We also summarized the clinical potential of targeting E3 ubiquitin ligases and deubiquitinases as therapeutic strategies in cancer treatment.

While immune checkpoint inhibitors (ICIs) are adopted as standard therapy for advanced non-small cell lung cancer (NSCLC), genetic determinants of response heterogeneity remain elusive [1]. As most hematopoietic lineages undergo dynamic changes during tumor pathogenesis and immunotherapy [2], elucidating how germline variants modulate their transcriptomes is critical. Expression quantitative trait loci (eQTL) analysis, especially integrated with single-cell RNA sequencing (scRNA-seq), enables gene regulation mapping at single-cell resolution [3, 4]. Detailed methodologies are described in the Supplementary Materials.

To investigate how germline variants shape immune gene regulation during ICI treatment, we performed single-cell-eQTL (sc-eQTL) analysis and transcriptomic network profiling. Peripheral blood mononuclear cells (PBMCs) were collected from 73 NSCLC patients treated with anti-programmed cell death protein-1 (PD-1) or programmed death-ligand 1 (PD-L1) therapy, at both baseline and 1-5 weeks post-treatment (Figure 1A, Supplementary Table S1). By integrating scRNA-seq with SNP array data, we analyzed cell-type-resolved sc-eQTLs and gene networks (Figure 1A-B).

After quality control and pseudobulk aggregation, we identified 9,147 eQTL pairs—expression-regulating SNPs (eSNPs) linked to 3,616 blood expression-regulated genes (eGenes)—across eight immune cell clusters and treatment conditions (Figure 1B-C, Supplementary Figure S1A, Supplementary Table S2). Consistent with previous studies [3, 4], eGene counts correlated with cell abundance, and eSNPs were enriched in regulatory elements (Supplementary Figure S1B-D). Multiadaptive shrinkage [5] revealed distinct cell-type- and treatment-dependent regulation, including 245 treatment-specific eQTLs (Supplementary Figure S2A-D, Supplementary Tables S3-S4). For instance, tumor necrosis factor (TNF) was regulated in monocytes post-treatment (posterior β = 1.17), while TNF receptor 1A (TNFRSF1A) was baseline-regulated in CD8⁺ T cells (β = 1.10), indicating genetic variants may shape immune gene expression during ICI therapy (Figure 1D). Additional examples include key cytotoxic mediators perforin 1 (PRF1) and granzyme B (GZMB) in baseline CD8⁺ T cells (Figure 1D, Supplementary Figure S2E).

To validate our findings, we conducted two complementary analyses. First, colocalization analyses with genome-wide association study (GWAS) loci for autoimmune and blood traits showed overlaps (PP.H4 > 0.6), suggesting possible shared regulatory mechanisms (Supplementary Figure S3, Supplementary Tables S5-S6). Second, comparison with external eQTL studies showed our study-specific eQTLs, hereafter referred to as lung cancer-specific eQTLs, were enriched in cancer- and immune response-related pathways (Figure 1E, Supplementary Figure S4A), reflecting chronic immune

Screening for colorectal cancer (CRC) is among the most effective approaches to cancer prevention, yet achieving high adherence to effective screening offers is challenging [1]. Blood-based tests that could be easily implemented in routine medical practice might be a promising approach to achieve higher adherence rates than with conventional stool-based or endoscopic screening [2, 3]. However, neoplasm detection rates of previously developed and proposed blood-based tests have not been competitive to those of modern stool-based tests [2], in particular fecal immunochemical tests (FITs) that are meanwhile widely used for CRC screening in an increasing number of countries [4]. Most recently, performance of a novel cell-free DNA (cfDNA) blood-based test for detecting colorectal neoplasms was validated in the ECLIPSE study, a large screening population undergoing screening colonoscopy [5], being the first of its kind to achieve FDA approval as a primary screening option for CRC.

Although detailed results on sensitivity and specificity were reported, the ECLIPSE study [5] did not include comparative results for screening by FIT, the best established and most widely used noninvasive CRC screening test. We aimed to compare reported measures of diagnostic performance of the cfDNA blood-based test to those of a commercially available FIT (FOB Gold, Sentinel Diagnostics, cutoff 17.0 µg hemoglobin per gram feces) in the BLITZ study, a comparable large cohort of screening colonoscopy participants recruited in the context of the German screening colonoscopy program. The complete description of the methods can be found in the Supplementary Materials and Methods.

In order to match the inclusion and exclusion criteria of the ECLIPSE study as closely as possible, analogous exclusion criteria were applied to the BLITZ sample, resulting in 5,683 participants from the BLITZ study to be included in the analysis (Supplementary Figure S1).

Supplementary Table S1 summarizes the characteristics of the ECLIPSE study, conducted in the United States with 7,861 screening colonoscopy participants, and the selected study sample from the BLITZ study. Mean age and sex distributions of participants in the ECLIPSE study (60.3 years, 53.7% women) and the BLITZ study (61.2 years, 50.4% women) were similar, as were the proportions of participants in whom CRC was detected (0.8% in both studies). Advanced precancerous lesions (APCLs) were somewhat more commonly found in the ECLIPSE study (14.2% vs. 10.3%) (Supplementary Table S1).

In the ECLIPSE study, 11.4% of participants were tested positive by the cfDNA blood test, while 9.9% tested positive by the FIT in the BLITZ study (Table 1). Applying the FIT manufacturer's recommended cutoff, the sensitivity of FIT was much higher than the cfDNA test in detecting APCL (31.5% vs. 13.2%, P < 0.001) and showed an approximately one