Abstract：
Hepatocellular adenoma (HCA) represents a rare benign hepatic neoplasm with potential for malignant transformation into hepatocellular carcinoma (HCC), yet the underlying mechanism remains elusive. In this study, we investigated the genomic landscape of this process to identify therapeutic strategies for blocking malignant transformation. Using micro-detection techniques, we obtained specimens of adenoma, cancerous neoplasm and adjacent normal liver from three patients undergoing hepatic resection surgery. Whole-exome sequencing (WES) was performed, and genomic interactions between HCA and HCC components within the same tumour were evaluated using somatic variant calling, copy number variation (CNV) analysis, clonality evaluation and mutational signature analysis. Our results revealed genomic heterogeneity among patient cases, yet within each sample, HCA and HCC tissues exhibited a similar mutational landscape, suggesting a high degree of homology. Using nonnegative matrix factorization and phylogenetic trees, we identified shared and distinct mutational characteristics and uncovering necessary pathways associated with HCA-HCC malignant transformation. Remarkably, we found that HCA and HCC shared a common monoclonal origin while displaying significant genetic diversity within HCA-HCC tumours, indicating fundamental genetic connections or evolutionary pathways between the two. Moreover, elevated immune therapy-related markers in these patients suggested heightened sensitivity to immune therapy, providing novel avenues for the treatment of hepatic malignancies. This study sheds light on the genetic mechanisms underlying HCA-HCC progression, offering potential targets for therapeutic intervention and highlighting the promise of immune-based therapies in managing hepatic malignancies.
摘要：
肝细胞腺瘤（HCA）代表一种罕见的良性肝肿瘤，有可能恶性转化为肝细胞癌（HCC），然而，潜在的机制仍然难以捉摸。在这项研究中,我们调查了该过程的基因组景观,以确定阻断恶性转化的治疗策略.使用微检测技术，我们得到了腺瘤的标本,3例接受肝切除手术的患者的癌性肿瘤和邻近的正常肝脏。进行全外显子组测序（WES），和基因组之间的相互作用在同一肿瘤内的HCA和HCC成分进行评估使用体细胞变异调用，拷贝数变异(CNV)分析，克隆性评估和突变特征分析。我们的结果揭示了患者病例之间的基因组异质性，然而在每个样本中，HCA和HCC组织表现出相似的突变景观，表明高度的同源性。使用非负矩阵分解和系统发育树，我们确定了共同和独特的突变特征,并发现了与HCA-HCC恶性转化相关的必要途径.值得注意的是,我们发现HCA和HCC具有共同的单克隆起源，同时在HCA-HCC肿瘤中显示出显著的遗传多样性，表明两者之间的基本遗传联系或进化途径。此外，这些患者的免疫治疗相关标志物升高表明对免疫治疗的敏感性增强，为肝脏恶性肿瘤的治疗提供了新的途径。本研究揭示了HCA-HCC进展的遗传机制，为治疗干预提供潜在的目标，并强调免疫疗法在管理肝脏恶性肿瘤方面的前景。
