Division of Gastroenterology, AOU Modena, Modena, Italy.
Institute of Radiology, AOU Modena, Modena, Italy.
Gut. 2016 May;65(5):861-9. doi: 10.1136/gutjnl-2014-308483. Epub 2015 Feb 9.
The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC.
Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model.
Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54-82 days (n=20), 83-110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001).
The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC.
ClinicalTrials.gov Identifier: NCT01657695.
肝细胞癌（HCC）的生物学异质性使得预后困难。我们将全基因组高通量分析的结果转化为一种工具，该工具可以准确预测 HCC 患者就诊时肿瘤的生长和生存情况。
超声监测在 78 例（训练集）和 54 例（验证集）连续肝硬化患者中发现 HCC。患者接受两次 CT 扫描（中间无治疗），以确定肿瘤体积（V0 和 V1）并计算 HCC 倍增时间。还获得了基线配对的 HCC 和周围组织活检，用于微阵列研究（Agilent Whole Human Genome Oligo Microarrays）。通过多变量 Cox 模型评估生存预测因子。
计算的肿瘤倍增时间范围为 30 至 621 天（平均值为 107±91 天；中位数为 83 天），并分为四分位组：≤53 天（n=19），54-82 天（n=20），83-110 天（n=20）和≥111 天（n=19）。根据倍增时间，第一四分位数的中位生存期明显低于其他三分位数（11 与 41 个月，42 和 47 个月，分别）（p<0.0001）。发现包括血管生成素-2（ANGPT2）、Delta 样配体 4（DLL4）、神经纤毛蛋白（NRP）/Tolloid（TLL）样 2（NETO2）、内皮细胞特异性分子-1（ESM1）和核受体亚家族 4，组 A，成员 1（NR4A1）的转录组肝标志可以准确识别第一四分位数中快速生长的 HCC（ROC AUC：0.961；95%CI 0.919 至 1.000；p<0.0001），并且是死亡的独立因素（HR：3.987；95%CI 1.941 至 8.193，p<0.0001）。
肝五基因标志能够预测个体患者 HCC 的生长及其随后的死亡风险。这意味着该分子工具在未来 HCC 患者的治疗管理中可能发挥作用。
ClinicalTrials.gov 标识符：NCT01657695。
