Joung Je-Gun, Ha Sang Yun, Bae Joon Seol, Nam Jae-Yong, Gwak Geum-Youn, Lee Hae-Ock, Son Dae-Soon, Park Cheol-Keun, Park Woong-Yang
Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Departments of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Oncotarget. 2017 Jan 10;8(2):2076-2082. doi: 10.18632/oncotarget.10502.
Dysplastic nodules are premalignant neoplastic nodules found in explanted livers with cirrhosis. Genetic signatures of premalignant dysplastic nodules (DNs) with concurrent hepatocellular carcinoma (HCC) may provide an insight in the molecular evolution of hepatocellular carcinogenesis. We analyzed four patients with multifocal nodular lesions and cirrhotic background by whole-exome sequencing (WES). The genomic profiles of somatic single nucleotide variations (SNV) and copy number variations (CNV) in DNs were compared to those of HCCs. The number and variant allele frequency of somatic SNVs of DNs and HCCs in each patient was identical along the progression of pathological grade. The somatic SNVs in DNs showed little conservation in HCC. Additionally, CNVs showed no conservation. Phylogenetic analysis based on SNVs and copy number profiles indicated a nonlinear segregation pattern, implying independent development of DNs and HCC in each patient. Thus, somatic mutations in DNs may be developed separately from other malignant nodules in the same liver, suggesting a nonlinear model for hepatocarcinogenesis from DNs to HCC.
发育异常结节是在肝硬化的移植肝脏中发现的癌前肿瘤结节。伴有肝细胞癌（HCC）的癌前发育异常结节（DNs）的基因特征可能有助于深入了解肝细胞癌发生的分子演变。我们通过全外显子组测序（WES）分析了4例具有多灶性结节病变和肝硬化背景的患者。将DNs中体细胞单核苷酸变异（SNV）和拷贝数变异（CNV）的基因组图谱与HCCs的进行比较。在每个患者中，随着病理分级的进展，DNs和HCCs的体细胞SNVs数量和变异等位基因频率是相同的。DNs中的体细胞SNVs在HCC中几乎没有保守性。此外，CNVs也没有保守性。基于SNVs和拷贝数图谱的系统发育分析表明存在非线性分离模式，这意味着每个患者的DNs和HCC是独立发展的。因此，DNs中的体细胞突变可能与同一肝脏中的其他恶性结节分开发生，提示从DNs到HCC的肝癌发生呈非线性模式。
