Decoding Genomic Diversity to Guide Tumor Lesion-Specific Treatment of Multifocal Hepatocellular Carcinoma

IF 3.1 2区医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2025-03-27 DOI:10.1002/cam4.70814

Kenji Amemiya, Yosuke Hirotsu, Yuji Iimuro, Ryosuke Tajiri, Toshio Oyama, Shuntaro Obi, Hitoshi Mochizuki, Masao Omata

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Abstract

Background

Hepatocellular carcinoma (HCC) is a primary liver cancer often associated with chronic liver disease and characterized by multifocal tumor lesions with synchronous and metachronous lesions, which poses treatment challenges due to potential genomic heterogeneity. This study aims to assess the consistency of actionable mutation profiles across synchronous and metachronous lesions in HCC patients.

Methods

This study analyzed 68 patients with multifocal HCC, including 193 tumor lesions (82 synchronous, 111 metachronous). Genomic profiling of 72 HCC-related genes was performed using next-generation sequencing. We collected clinical and pathological data, including tumor size, grade, fibrosis, and etiology. Patients were categorized into two groups based on the consistency of actionable mutations among multifocal HCC. Statistical analyses compared clinicopathological features between these groups.

Results

A total of 252 and 445 somatic mutations were identified in synchronous and metachronous tumors, respectively. Synchronous tumors had an average of 3.1 somatic mutations and 0.7 actionable mutations per lesion. Metachronous tumors had 4.0 somatic mutations and 1.0 actionable mutations per lesion. Actionable variants were found in 12 (36.4%) of 33 patients and 20 (24.4%) of 82 nodules in the synchronous tumors, and 23 (65.7%) of 35 patients and 42 (37.8%) of 111 nodules in the metachronous tumors. Compared to synchronous tumors, metachronous tumors exhibited significantly aberrant signaling pathways including the Wnt/β-catenin (p = 0.009) and KEAP1/NRF2 (p = 0.022) pathways. There was no correlation with significant clinical differences in tumor characteristics between the consistent and divergent actionable mutation groups. Notably, divergent actionable mutations were identified in 45.6% of patients, which may be beneficial for changing potential therapies for individual tumors.

Conclusion

The study shows substantial inter-tumoral heterogeneity in multifocal HCC, indicating the necessity for comprehensive molecular profiling for tailored treatment strategies. Divergent actionable mutations across lesions suggest that a uniform treatment approach may not be effective in some patients with multifocal HCC.

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解码基因组多样性指导多灶性肝细胞癌的肿瘤病变特异性治疗

背景肝细胞癌（HCC）是一种原发性肝癌，通常与慢性肝病有关，其特点是多灶性肿瘤病变，具有同步和不同步病变，由于潜在的基因组异质性，给治疗带来了挑战。本研究旨在评估 HCC 患者同步和近同步病变中可操作突变特征的一致性。方法本研究分析了68例多灶性HCC患者，包括193个肿瘤病灶（82个同步病灶，111个近同步病灶）。采用新一代测序技术对 72 个 HCC 相关基因进行了基因组分析。我们收集了临床和病理数据，包括肿瘤大小、分级、纤维化和病因。根据多灶性HCC中可操作突变的一致性，将患者分为两组。统计分析比较了两组患者的临床病理特征。结果同步肿瘤和间变性肿瘤中分别发现了 252 个和 445 个体细胞突变。同步性肿瘤平均每个病灶有 3.1 个体细胞突变和 0.7 个可操作突变。同步肿瘤平均每个病灶有 4.0 个体细胞变异和 1.0 个可操作变异。在同步性肿瘤的 33 名患者中的 12 人（36.4%）和 82 个结节中的 20 个（24.4%）发现了可操作变异，在间变性肿瘤的 35 名患者中的 23 人（65.7%）和 111 个结节中的 42 个（37.8%）发现了可操作变异。与同步肿瘤相比，间变性肿瘤的信号通路明显异常，包括Wnt/β-catenin（p = 0.009）和KEAP1/NRF2（p = 0.022）通路。一致可作用突变组和分歧可作用突变组的肿瘤特征与显著的临床差异没有相关性。值得注意的是，在 45.6% 的患者中发现了分歧可操作突变，这可能有利于改变针对个别肿瘤的潜在疗法。结论该研究表明，多灶性 HCC 中存在严重的肿瘤间异质性，这表明有必要进行全面的分子图谱分析，以制定有针对性的治疗策略。不同病灶的可作用突变存在差异，这表明统一的治疗方法可能对某些多灶性 HCC 患者无效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.