The surveillance diagnostic approach for hepatocellular carcinoma (HCC) is fraught with challenges. Traditional surveillance methods, such as ultrasound imaging and serum biomarkers including alpha-fetoprotein (AFP), often lack adequate sensitivity and specificity, particularly in early-stage disease [
1]. This complexity is compounded by the diverse etiological factors underlying HCC, which drive distinct pathological processes within the tumor. Consequently, there is a critical demand for more reliable biomarkers that not only facilitate early detection of HCC but also elucidate its underlying causes and biological behavior [
2]. In addressing this unmet need, the study by Hong et al. [
3] utilizes a comprehensive multiomics approach, combining whole-transcriptome sequencing (WTS) and proteomics to discover and validate blood-based, etiology-specific biomarkers for HCC [
3]. This research specifically aims to distinguish between biomarkers associated with hepatitis B virus (HBV)-related HCC and those linked to non-viral causes, potentially enabling more personalized diagnostic and therapeutic strategies tailored to the specific etiology of the tumor.
The study utilized WTS to analyze gene expression in buffy coat samples and proteomics to assess protein levels in plasma. This dual approach allowed for a comprehensive profiling of molecular changes associated with HCC. Key findings from the study include the identification of distinct sets of biomarkers for HBV-associated HCC (HBV-HCC) and nonviral HCC (NV-HCC). For HBV-HCC, the biomarkers identified were predominantly related to immune response activation. Genes involved in immune cell signaling and inflammatory responses were markedly upregulated, reflecting the chronic inflammatory state induced by HBV infection which potentially drives carcinogenesis [
4]. For NV-HCC cases, the biomarkers were primarily associated with metabolic processes. This includes genes involved in metabolism regulation and oxidative stress, highlighting the metabolic alterations that occur in conditions like metabolic dysfunction associated steatotic liver diseases and alcohol associated liver disease, which can lead to cancer [
5]. The biomarkers identified were subjected to rigorous validation using independent datasets, confirming their relevance and reproducibility.
The biomarkers identified in this study have shown high diagnostic accuracy, as evidenced by robust AUC values. Early detection of HCC remains a pivotal challenge in clinical practice, with significant implications for patient survival rates. By enabling the detection of HCC at an earlier stage, these biomarkers can potentially increase the number of patients eligible for curative treatments such as surgical resection and liver transplantation. This is particularly important in regions with high rates of hepatitis B, where HBV-related HCC is prevalent. The distinction between biomarkers associated with HBV-HCC and NV-HCC allows for more tailored therapeutic strategies targeting specific molecular disruptions identified through biomarker profiling.
Once rigorously validated and widely available, the integration of these novel biomarkers into existing HCC surveillance and diagnostic protocols could greatly enhance the accuracy and timeliness of HCC detection. Current strategies primarily rely on ultrasound and serum AFP levels, which are limited by variable sensitivity and specificity, particularly in early-stage HCC [
6]. Incorporating biomarkers that are specific to HBV-HCC or NV-HCC into routine blood tests could provide a non-invasive, scalable method to augment these traditional tools, facilitating earlier and more accurate diagnosis. This could be particularly impactful in areas with high HBV prevalence, where routine blood tests could include these biomarkers as part of standard medical check-ups.
In addition, the availability of etiology-specific biomarkers enables a more stratified approach to patient management. By identifying the molecular underpinnings of a patient’s tumor, clinicians can select therapies based on the likelihood of their effectiveness, thus adopting a precision medicine approach. For HBV-HCC, for instance, biomarkers linked to immune response pathways may help identify patients who could benefit from emerging immunotherapies or targeted treatments that modulate the immune environment. Similarly, for NV-HCC, where metabolic pathways are often altered, interventions could be tailored to target specific metabolic derangements. This approach not only promises to improve treatment efficacy but also reduces the risk of adverse effects by avoiding ineffective treatments for patients unlikely to benefit from them. Furthermore, the ability to monitor these biomarkers over time could provide insights into treatment response and disease progression, allowing for dynamic adjustments to therapeutic strategies [
7].
The promising findings of the current study on etiology-specific biomarkers for HCC pave the way for several critical areas of future research. These areas are essential for transitioning from initial discovery to clinical application and for deepening our understanding of HCC pathogenesis and treatment. Future studies should focus on validating the identified biomarkers in larger and more ethnically diverse patient cohorts. This will help to establish the robustness and generalizability of the biomarkers across different populations, particularly considering the geographical and genetic diversity associated with HCC risk factors [
8]. Multicenter trials could be designed to evaluate the sensitivity, specificity, and predictive value of these biomarkers in various clinical settings, thereby solidifying their role in routine diagnostics.
There is a compelling need to explore the mechanistic pathways through which these biomarkers influence HCC development. Understanding the biological functions and pathways associated with these biomarkers can reveal crucial insights into tumor biology and the etiology-specific mechanisms that drive carcinogenesis in the liver [
9]. Such studies could involve in vitro and in vivo experiments to elucidate how these biomarkers interact with cellular processes and contribute to tumor initiation, progression, and metastasis. Identifying potential therapeutic targets based on these biomarkers is another vital research direction. For HBV-HCC, where immune response-related genes are prominent, research could explore how modulation of these immune pathways could serve as a therapeutic strategy. This could include developing or repurposing drugs that enhance antitumor immunity or block immune evasion by the tumor cells [
10]. For NV-HCC, which is associated with altered metabolic processes, studies could investigate targeted metabolic interventions that disrupt the energy supply of cancer cells, thereby inhibiting their growth and proliferation.
The study by Hong et al. demonstrates the transformative potential of a multiomics approach in the management of HCC [
3]. By integrating whole-transcriptome sequencing and proteomics, this research has identified etiology-specific biomarkers that offer not only a deeper understanding of the disease’s pathogenesis but also pave the way for advancements in early detection and personalized treatment. The ability to distinguish between biomarkers associated with HBV and non-viral causes of HCC is particularly promising, facilitating more targeted and effective therapeutic strategies.
In conclusion, the use of multiomics profiling in HCC represents a significant step forward in our fight against liver cancer. Embracing this technology and fostering collaboration across various sectors of the healthcare and scientific community will be key to translating these scientific insights into real-world benefits for patients suffering from HCC.
ACKNOWLEDGMENTS
Dr. Yang provides a consulting service for AstraZeneca, Eisai, Exact Sciences, FujiFilm Medical Sciences.
FOOTNOTES
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Authors’ contribution
Joseph C. Ahn: Drafting of the manuscript, critical revision of the manuscript for important intellectual content.
Ju Dong Yang: Editorial concept and design, critical revision of the manuscript for important intellectual content, study supervision.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
whole-transcriptome sequencing
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Citations
Citations to this article as recorded by
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