{"doi":"10.1002/ctm2.405","title":"Genomewide transcriptomic profiling identifies a gene signature for predicting recurrence in early‐stage hepatocellular carcinoma","abstract":"Dear Editor, A majority of patients with hepatocellular carcinoma (HCC) suffer from tumor recurrence even after curative treatments. Such events can be categorized as either the early phase (within 2 years of treatment) or the late phase recurrence (after 2 years).1 The prognosis for patients with early phase recurrence (EPR) is generally much worse than the other group.2-4 As per the AJCC guidelines (7th edition) and the BCLC recommendations, an early-stage HCC with an AJCC-TNM stage-I and BCLC stage-0/A is defined by the following features: a solitary tumor, 5 cm or smaller in size, and a cancer without pathological vascular invasion. Accordingly, perhaps ∼25% of the early-stage HCCs is likely at risk for developing EPR following curative treatment.5 Unfortunately, currently this is lack of availability of clinically useful biomarkers for predicting EPR in patients with early-stage HCCs.4, 6 In the present study, we for the first time undertook a systematic and comprehensive biomarker discovery and validation approach to unravel a novel gene expression signature for detecting an EPR in early-stage HCC patients. Our study design included multiple biomarker discovery and validation phases (Figure S1). We first analyzed TCGA RNA-Seq cohort comprising 59 early-stage HCC patients with (n = 21) and without EPR (n = 38). Among the 20,502 transcripts, 342 genes were differentially expressed. Following exclusion of highly correlated genes, the association of each gene with recurrence-free survival was assessed using Cox's proportional hazards (CoxPH) regression model and LASSO regression analysis, which resulted in a panel of eight-candidate genes (Figure 1A), which were not correlated with each other (Figure 1B). We next plotted the receiver operating characteristic (ROC) curves in TCGA cohort. This eight-gene panel accurately predicted EPR (the area under the curves [AUC] = 0.88; Figure 1C); which was subsequently validated in the GSE76427 cohort comprising 26 early-stage HCC patients with (n = 15) and without EPR (n = 11; AUC = 0.81; Figure 1D). Patients who were categorized as high-risk exhibited higher cumulative recurrence rates compared to the low-risk group in both TCGA and GSE76437 cohorts (p < 0.0001 and p = 0.0030, respectively; Figures 1E and 1F). Next, we interrogated the performance of the eight-gene panel in two independent clinical cohorts of 130 HCC patients (Table 1). In cohort-1 (n = 54), 13 cases (24.1%) experienced EPR, while EPR occurred in 27 of 76 cases (35.5%) in the cohort-2. We excluded the TSSK1B gene from further analysis due to low expression in FFPE tissues. We evaluated the expression of the remaining seven genes in the clinical cohorts using qRT-PCR (Table S1). These experiments revealed that three genes (SNX24, C1QTNF8, and HERC5) were commonly expressed in both clinical cohorts (Figure S2) and hence were selected for further analysis. We thereafter confirmed the predictive accuracy of the three-gene panel in TCGA and GSE76427 cohorts (Figure S3). We assessed the predictive potential of this three-gene panel in the clinical training cohort (cohort-1). Using a partial likelihood in CoxPH model, we obtained a risk scoring formula for the three-gene panel as follows: (0.8777 x NSX24) + (0.2245 x HERC5) + (0.00483 x C1QTNF8). In this formula, we used -ΔCT values for determining the expression of each gene. The three-gene panel demonstrated a significant predictive power in detecting EPR in early-stage HCC patients (AUC = 0.82; Figure 2A, left panel). The waterfall plot with the risk scores and heatmap of gene expression for each patient is shown in Figure 2B (left panel). Cumulative recurrence rate analysis revealed that the high-risk patients, categorized based upon our three-gene panel, were associated with significantly higher recurrence rate in the clinical training cohort (p = 0.0004; Figure 2C, left panel). In univariate CoxPH regression analyses, our three-gene panel emerged as the only significan","journal":"Clinical and Translational Medicine","year":2021,"id":211136,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":800035,"name":"Moto Fukai","orcid":"0000-0002-8593-2258","position":1,"is_corresponding":false},{"id":295099,"name":"Jasjit K. Banwait","orcid":"0000-0002-1643-3375","position":2,"is_corresponding":false},{"id":800036,"name":"Toshiya Kamiyama","orcid":"0000-0002-9157-7811","position":3,"is_corresponding":false},{"id":800037,"name":"Tatsuya Orimo","orcid":"0000-0003-4398-0697","position":4,"is_corresponding":false},{"id":800038,"name":"Tomoko Mitsuhashi","orcid":"0000-0001-8155-0685","position":5,"is_corresponding":false},{"id":325308,"name":"Kensuke Yamamura","orcid":"0000-0003-0506-6394","position":6,"is_corresponding":false},{"id":800039,"name":"Takeo Toshima","orcid":"0000-0003-4019-8288","position":7,"is_corresponding":false},{"id":456443,"name":"Hideo Baba","orcid":"0000-0002-3474-2550","position":8,"is_corresponding":false},{"id":800040,"name":"Akinobu Taketomi","orcid":"0000-0002-5238-3678","position":9,"is_corresponding":false},{"id":243020,"name":"Ajay Goel","orcid":"0000-0003-1396-6341","position":10,"is_corresponding":false},{"id":800034,"name":"Tatsuhiko Kakisaka","orcid":"0000-0002-8556-5945","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-18T23:52:16.049481Z","pmid":"34185415","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":[]}