{"doi":"10.1002/ctm2.70465","title":"Unravelling the distinct effects of VHL mutations and chromosome 3p loss in clear cell renal cell carcinoma: Implications for prognosis and treatment","abstract":"Dear Editor, In this study, we delineated the distinct transcriptomic effects of VHL mutation and chromosome 3p (chr3p) loss, revealing that chr3p loss is specifically associated with immune suppression in clear cell renal cell carcinoma (ccRCC). Furthermore, we developed driver genomic aberration (DGA) gene signatures that demonstrate superior performance in predicting both patient prognosis and treatment response compared to traditional mutation-based approaches. Renal cell carcinoma (RCC) accounts for 80%–85% of all primary kidney cancers, with ccRCC being the most common subtype (∼75%).1 In 2023, ∼82 000 new RCC cases and ∼15 000 deaths were reported in the U.S. Despite surgery being curative for localised disease, ∼33% of patients relapse, and those with metastatic disease (∼15%) have a poor prognosis.1 Despite treatment advances, significant variability in outcomes highlights the need for reliable molecular biomarkers to guide the treatment. Large-scale genomic studies such as the Cancer Genome Atlas (TCGA) have shown that the VHL gene is frequently inactivated in ccRCC through mutation or chr3p deletion.2 However, the prognostic and therapeutic relevance of VHL mutations and chr3p loss remains controversial. We examined the most frequently mutated genes in the TCGA KIRC dataset.2 The VHL gene exhibited the highest mutation rate (52%), followed by PBRM1 (31%), SETD2 (11%) and BAP1 (5%) (Figure 1A). Copy number analysis revealed that chr3p loss occurred in 27% of patients, and most loss events, interestingly, encompassed these four genes. (Figure 1B). This genomic configuration is largely unique to ccRCC among TCGA cancer types (Figure S1A). Mutation rates of these genes were consistent across tumour stages, indicating early tumourigenic roles (Figure S1B). To investigate the transcriptomic effects of VHL mutation and chr3p loss, we stratified TCGA-KIRC data by these aberrations and identified differentially expressed genes. In VHL-WT tumours, chr3p loss led to 1719 differentially expressed genes (DEGs; FDR < .05, |log2FC| > 1.5), while in tumours with intact chr3p, VHL mutation resulted in 1577 DEGs. However, in the presence of VHL mutation, chr3p loss still induced 442 DEGs, whereas VHL mutation had no significant transcriptomic impact in chr3p-loss tumours, indicating that chr3p loss exerts a dominant regulatory effect (Figure 1C). Notably, immune-related genes were significantly enriched in genes that were downregulated in chr3p-loss tumours (Figure 1D), and GSEA analysis confirmed the suppression of immune pathways (Figure S2). Given that immune gene suppression associated with chr3p loss, we explored its impact on the tumour immune microenvironment (TIME). Using previously reported data,3 we discovered that leukocyte and lymphocyte infiltration levels in TCGA-KIRC were significantly lower in chr3p-loss versus chr3p-WT tumours (p < .01), whereas VHL mutation had no significant impact on immune infiltration metrics (Figures 2A,B). Using the TIMER algorithm,4 we estimated immune cell infiltration levels and observed that chr3p-loss tumours had significantly reduced infiltration of B cells, CD8+ and CD4+ T cells, macrophages, dendritic cells and neutrophils (Figure 2C). We also quantified BCR and TCR richness from RNA-seq reads and found both significantly diminished in chr3p-loss tumours, consistent with the immune suppression phenotype (Figures 2D,E). We next performed unsupervised clustering using expression of immune cell marker genes (Table S1) to classify tumours into immune “hot” and “cold” clusters. Chr3p-loss tumours were significantly enriched in the immune-cold cluster (79% vs. 41% in chr3p-WT; p = 9e-12, Fisher's exact test), while VHL-mutant tumours were evenly distributed, indicating that chr3p loss, not VHL, drives immune suppression (Figures 2F,G). To better understand this, we did stratified analysis, and chr3p loss alone showed reduced immune infiltration, which is not observed in VHL mutation only sam","journal":"Clinical and Translational Medicine","year":2025,"id":554243,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":236198,"name":"Jiànróng Lǐ","orcid":"0000-0002-7130-1084","position":1,"is_corresponding":false},{"id":1452076,"name":"Naail Raed Chowdhury","orcid":null,"position":2,"is_corresponding":false},{"id":240062,"name":"Lang Wu","orcid":"0000-0001-9938-3627","position":3,"is_corresponding":false},{"id":363,"name":"Chao Cheng","orcid":"0000-0002-5002-3417","position":4,"is_corresponding":false},{"id":1136749,"name":"Xiang Wang","orcid":"0000-0001-5056-8014","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:54:50.112989Z","pmid":"40999577","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}