Letter to the Editor: Origin recognition complex subunit 1 as a biomarker in hepatitis B virus-related hepatocellular carcinoma: Promises and pitfalls

Abstract

This commentary discusses the recent study by Feng et al published in World Journal of Gastroenterology. Serum origin recognition complex subunit 1 (ORC1) was identified as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma (HCC). The study reported improved diagnostic accuracy when ORC1 was combined with extra spindle pole bodies-like 1 and alpha-fetoprotein, providing an opportunity to contextualize ORC1 within existing multi-marker biomarker strategies for hepatitis B virus-related HCC surveillance. These observations, along with the limitations of the study, are briefly discussed. Several suggestions have also been made regarding prospective validation and the incorporation of ORC1 into broader multi-marker surveillance strategies.

Key Words: Hepatocellular carcinoma; Hepatitis B virus; Origin recognition complex subunit 1; Diagnostic biomarker; Alpha-fetoprotein-negative

Core Tip: Serum origin recognition complex subunit 1 has emerged as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma, which improves diagnostic accuracy when combined with extra spindle pole bodies-like 1 and alpha-fetoprotein. These indicators may eventually be integrated into a unified surveillance model to enhance early detection. Large, multicenter prospective studies and standardized assay development are essential to confirm its applicability across diverse clinical settings.

TO THE EDITOR

We read with great interest the study by Feng et al[1] published in World Journal of Gastroenterology, which evaluated the diagnostic performance of serum origin recognition complex subunit 1 (ORC1) as a biomarker for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Their findings provide an opportunity to contextualize serum ORC1 within existing multi-marker biomarker strategies for HBV-related HCC surveillance.

HCC ranks as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide[2], underscoring the importance of effective surveillance for early detection. Current surveillance strategies rely primarily on semiannual liver ultrasonography, and the use of serum alpha-fetoprotein (AFP) remains controversial across international guidelines[3]. Imaging-based surveillance, even when combined with AFP, remains insufficient for the reliable early detection of HCC[4]. Individuals with HBV infection represent one of the populations at highest risk for developing HCC. In China, HBV infection remains the leading etiologic factor underlying HCC. As reported by Feng et al[1], recurrent HBV integration near the ORC1 locus was observed in a large proportion of HBV-related HCC cases, and serum ORC1 concentrations were markedly higher in patients with HBV-related HCC compared with non-HCC controls. It should be noted that ORC1 overexpression may not be exclusively driven by HBV integration, and alternative mechanisms, such as transcriptional dysregulation or influences from the inflammatory tumor microenvironment, may also contribute to its elevated expression. ORC1 levels were also elevated in AFP-negative HCC, identifying 64.8% of these otherwise difficult-to-detect cases. Given that ORC1 functions as a DNA replication licensing factor whose dysregulation may drive aberrant cell-cycle progression[5], its overexpression provides biologic plausibility as a tumor-associated marker. Therefore, ORC1 represents a promising complement to AFP, particularly considering that approximately 30%-40% of early-stage HCCs are AFP-negative and may evade detection by conventional surveillance methods[6,7].

We commend the authors for quantifying serum ORC1 and examining its diagnostic performance in combination with extra spindle pole bodies-like 1 (ESPL1), another biomarker linked to HBV integration. In their cohort, ORC1 alone demonstrated modest discriminative ability (area under the curve [AUC] = 0.587); however, the addition of ESPL1 and AFP substantially increased the diagnostic accuracy, yielding a combined AUC of 0.887. While this level of discrimination is encouraging, its clinical relevance should be interpreted in the context of real-world surveillance, where improvements in AUC do not necessarily translate directly into meaningful clinical benefit. In surveillance settings, outcomes such as negative predictive value, false-positive burden, downstream diagnostic testing, and cost-effectiveness may be more consequential than AUC alone. Consistent with prior biomarker studies, multi-marker strategies have shown advantages over single-marker approaches. Previous studies have shown that combining AFP with other biomarkers, such as protein induced by vitamin K absence or antagonist-II or multi-marker panels, improves HCC detection compared with single markers, particularly for early-stage and AFP-negative disease. Collectively, these findings support the potential value of integrating ORC1 into broader multi-marker diagnostic strategies[6,8]. Moreover, prospective validation is required to determine whether these statistical gains translate into meaningful improvements in surveillance outcomes.

Despite these encouraging findings, several important limitations warrant consideration. First, the study cohort was relatively homogeneous in both ethnicity and disease etiology, consisting exclusively of Chinese patients with HBV-related HCC. Such uniformity may limit the generalizability of the findings to broader clinical populations. Variations in HBV genotypes, underlying liver diseases, and ethnic or genetic backgrounds could potentially influence circulating ORC1 levels, as has been observed with other HCC biomarkers. To address these uncertainties, future investigations incorporating larger, more diverse cohorts and spatially resolved tumor sampling would be valuable. Such efforts could help confirm whether ORC1 represents a genuine HBV integration hotspot and determine whether its overexpression is consistently driven by viral integration rather than alternative mechanisms such as epigenetic regulation or microenvironmental changes.

In addition, Feng et al[1] acknowledge that their study was retrospective and conducted at a single center, with a relatively small subset of patients exhibiting HBV S-gene integration. Indeed, only 20 integration-positive cases were identified among nearly 500 participants. Such limited sample sizes, combined with the absence of an external validation cohort, pose substantial methodological challenges. It is well recognized that small cohorts and the lack of independent validation can result in overestimation of diagnostic performance and restrict reproducibility[9]. The clinical value of ORC1 as a single diagnostic marker is limited, given its modest AUC (0.587). Although the combined panel achieved improved discrimination (AUC = 0.887), the incremental value provided specifically by ORC1 remains uncertain. From a clinical perspective, incremental improvements are considered meaningful only when they translate into tangible gains in patient classification, such as improved sensitivity or specificity at clinically relevant thresholds, meaningful reclassification, or demonstrable benefits in downstream clinical decision-making. Formal metrics, including net reclassification improvement and decision curve analysis, would be appropriate tools to rigorously evaluate the incremental clinical value of ORC1. Moreover, the receiver operating characteristic analysis was generated using the entire dataset without a separate testing set, which increases the risk of selection bias and inflation of diagnostic accuracy. Notably, inadequate sample size remains one of the principal reasons that many promising biomarker candidates ultimately fail to achieve clinical translation[9].

We also recognize several practical challenges that may affect the clinical implementation of ORC1 testing. The study cohort spans more than two decades, from 2002 to 2024, raising the possibility that variations in sample handling and storage could introduce unavoidable heterogeneity. Such temporal variability may also affect the stability and consistency of serum ORC1 measurements, potentially influencing biomarker levels across different collection periods. In addition, routine measurement of ORC1 would require the development and regulatory approval of a standardized enzyme-linked immunosorbent assay or comparable assay, which is not yet available. Important clinical considerations also remain unresolved, including how ORC1 levels behave in non-HBV-related HCC, in other chronic liver diseases, and what diagnostic thresholds would be appropriate across different patient populations. The authors appropriately emphasize the need for prospective, multicenter validation. Experiences in HCC surveillance have shown that many biomarkers appear promising in retrospective analyses but require prospective validation[10].

In summary, Feng et al[1] highlighted ORC1 as a compelling biomarker potentially linked to HBV-related hepatocarcinogenesis, and their combined ORC1-ESPL1-AFP panel demonstrated impressive diagnostic performance within their cohort. While this multi-marker approach merits further investigation, the study’s methodological constraints inevitably temper the overall enthusiasm. Importantly, these findings should be interpreted within the phase of biomarker discovery, and ORC1 appears more suitable as a complementary component within multi-marker panels rather than a replacement for established surveillance tools such as AFP. Successful clinical translation will depend on validation in larger, prospective, and ethnically diverse populations, along with independent replication and formal evaluation of cost-effectiveness. Future research should aim to incorporate ORC1 into established surveillance frameworks and compare its performance directly with other emerging biomarkers to more clearly define its clinical value.