Xie Qing Yan, Almudevar Anthony, Whitney-Miller Christa L, Barry Christopher T, McCall Matthew N
Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA.
Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
BMC Med Genomics. 2016 Apr 8;9:18. doi: 10.1186/s12920-016-0179-4.
Liver cancer, of which hepatocellular carcinoma (HCC) is by far the most common type, is the second most deadly cancer (746,000 deaths in 2012). Currently, the only curative treatment for HCC is surgery to remove the malignancy (resection) or to remove the entire diseased liver followed by transplantation of healthy liver tissue. Given the shortage of healthy livers, it is crucial to provide transplants to patients that have the best chance of long-term survival. Currently, transplantation is determined via the Milan criteria-patients within Milan (single tumor < 5 cm or 2-3 tumors < 3 cm with no extrahepatic spread nor intrahepatic vascular invasion) are typically eligible for transplantation. However, combining microRNA expression profiling with the Milan criteria can improve prediction of recurrence. HCC often presents with multiple distinct tumor foci arising from local spread of a primary tumor or from the oncogenic predisposition of the diseased liver. Substantial genomic heterogeneity between tumor foci within a single patient has been reported; therefore, biomarker development must account for the possibility of highly heterogeneous genomic profiles from the same individual.
MicroRNA profiling was performed on 180 HCC tumor samples from 89 patients who underwent liver transplantation at the University of Rochester Medical Center. The primary outcome was recurrence-free survival time, and patients were observed for 3 years post-transplantation.
MicroRNA expression profiles were used to develop a biomarker that distinguishes HCC patients at greater risk of recurrence post-transplantation. Unsupervised clustering uncovered two distinct subgroups with vast differences in standard transplantation selection criteria and recurrence-free survival times. These subgroups were subsequently used to identify microRNAs strongly associated with HCC recurrence. Our results show that reduced expression of five specific microRNAs is significantly associated with HCC recurrence post-transplantation.
MicroRNA profiling of distinct tumor foci, coupled with methods that address within-subject tumor heterogeneity, has the potential to significantly improve prediction of HCC recurrence post-transplantation. The development of a clinically applicable HCC biomarker would inform treatment options for patients and contribute to liver transplant selection criteria for practitioners.
肝癌中，肝细胞癌（HCC）是目前最常见的类型，是第二大致命性癌症（2012年有74.6万人死亡）。目前，HCC唯一的治愈性治疗方法是手术切除恶性肿瘤（切除术）或切除整个患病肝脏，随后移植健康肝脏组织。鉴于健康肝脏的短缺，为最有可能获得长期生存的患者提供移植至关重要。目前，移植是通过米兰标准确定的——符合米兰标准的患者（单个肿瘤<5厘米或2 - 3个肿瘤<3厘米，无肝外扩散和肝内血管侵犯）通常有资格接受移植。然而，将微小RNA表达谱分析与米兰标准相结合可以改善复发预测。HCC常表现为多个不同的肿瘤病灶，可以是原发肿瘤的局部扩散，也可以是患病肝脏的致癌易感性导致。据报道，同一患者体内肿瘤病灶之间存在显著的基因组异质性；因此，生物标志物的开发必须考虑到同一个体基因组谱高度异质性的可能性。
对来自罗切斯特大学医学中心接受肝移植的89例患者的180份HCC肿瘤样本进行了微小RNA谱分析。主要结局是无复发生存时间，对患者进行了移植后3年的观察。
微小RNA表达谱被用于开发一种生物标志物，以区分移植后复发风险更高的HCC患者。无监督聚类发现了两个不同的亚组，它们在标准移植选择标准和无复发生存时间上有巨大差异。随后，这些亚组被用于识别与HCC复发密切相关的微小RNA。我们的结果表明，五种特定微小RNA的表达降低与移植后HCC复发显著相关。
对不同肿瘤病灶进行微小RNA谱分析，结合解决个体内肿瘤异质性问题的方法，有可能显著改善移植后HCC复发的预测。开发一种临床适用的HCC生物标志物将为患者的治疗选择提供依据，并有助于从业者制定肝移植选择标准。
