Amemiya Kenji, Hirotsu Yosuke, Iimuro Yuji, Tajiri Ryosuke, Oyama Toshio, Obi Shuntaro, Mochizuki Hitoshi, Omata Masao
Genome Analysis Center, Yamanashi Central Hospital, Kofu, Yamanashi, Japan.
Division of Genetics and Clinical Laboratory, Yamanashi Central Hospital, Kofu, Yamanashi, Japan.
Cancer Med. 2025 Apr;14(7):e70814. doi: 10.1002/cam4.70814.
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.
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.
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.
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.
肝细胞癌（HCC）是一种原发性肝癌，常与慢性肝病相关，其特征为多灶性肿瘤病变，包括同时性和异时性病变，由于潜在的基因组异质性，这给治疗带来了挑战。本研究旨在评估HCC患者同时性和异时性病变中可操作突变谱的一致性。
本研究分析了68例多灶性HCC患者，包括193个肿瘤病灶（82个同时性病灶，111个异时性病灶）。使用下一代测序技术对72个HCC相关基因进行基因组分析。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。统计分析比较了这两组之间的临床病理特征。
在同时性和异时性肿瘤中分别鉴定出252个和445个体细胞突变。同时性肿瘤每个病灶平均有3.1个体细胞突变和0.7个可操作突变。异时性肿瘤每个病灶有4.0个体细胞突变和1.0个可操作突变。在同时性肿瘤的33例患者中有12例（36.4%）和82个结节中有20个（24.4%）发现了可操作变异，在异时性肿瘤的35例患者中有23例（65.7%）和111个结节中有42个（37.8%）发现了可操作变异。与同时性肿瘤相比，异时性肿瘤表现出明显异常的信号通路，包括Wnt/β-连环蛋白（p = 0.009）和KEAP1/NRF2（p = 0.022）通路。可操作突变一致和不一致的组之间在肿瘤特征方面没有显著的临床差异相关性。值得注意的是，45.6%的患者中发现了不一致的可操作突变，这可能有利于改变个体肿瘤的潜在治疗方案。
该研究表明多灶性HCC存在显著的肿瘤间异质性，这表明有必要进行全面的分子分析以制定个性化的治疗策略。病灶间不一致的可操作突变表明，统一的治疗方法可能对一些多灶性HCC患者无效。
