Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation.
Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation.
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DOI：
10.1371/journal.pmed.1001770
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发表时间：
2014-12
期刊：
影响因子：
15.8
通讯作者：
Lee JS
中科院分区：
文献类型：
--
作者：
Kim JH;Sohn BH;Lee HS;Kim SB;Yoo JE;Park YY;Jeong W;Lee SS;Park ES;Kaseb A;Kim BH;Kim WB;Yeon JE;Byun KS;Chu IS;Kim SS;Wang XW;Thorgeirsson SS;Luk JM;Kang KJ;Heo J;Park YN;Lee JS
在这项研究中，Lee及其同事开发了一种基因组预测因子，可以识别肝细胞癌（HCC）晚期复发高风险患者，并为风险分层提供了新的生物标志物。通常在手术切除后2年观察到，晚期复发是肝细胞癌（HCC）治疗的主要挑战。我们的目标是开发一种基因组预测器，可以识别晚期复发高风险患者并评估其临床意义。对人类肝脏损伤和再生的基因表达数据进行系统分析，发现233个基因特征与HCC晚期复发显著相关。利用这一特征，我们开发了一种预后预测器，可以识别晚期复发高风险的患者，并在1990年至2011年期间在四个中心接受手术的患者（n = 396）中测试和验证了预测器的稳健性（随访时间中位数为3.7年，复发210例）。在多变量分析中，这一特征是晚期复发的最强危险因素（风险比为2.2；95%可信区间为1.3-3.7;p = 0.002）。相比之下，我们先前开发的肿瘤来源的65个基因风险评分与早期复发显著相关（p = 0.005），但与晚期复发无关（p = 0.7）。在多因素分析中，65个基因风险评分是极早期复发（手术切除后<1 y）的最强危险因素（风险比为1.7；95%可信区间为1.1-2.6;p = 0.01）。通过基因网络分析预测STAT3激活在晚期复发中的潜在意义，并随后验证。我们还从完整的233个基因预测器中开发并验证了4个和20个基因的预测器。本研究的主要局限性是我们研究中的大多数患者是乙型肝炎病毒阳性。需要进一步的研究来验证我们的预测模型是否适用于不同病因的HCC患者，如丙型肝炎病毒。两个独立开发的预测因子在分子水平上很好地反映了HCC早期和晚期复发的差异，并为风险分层提供了新的生物标志物。原发性肝癌是一种由肝细胞获得基因变化导致其生长不受控制的肿瘤，是全球癌症相关死亡的第二大原因，每年导致60多万人死亡。如果肝细胞癌（HCC；最常见的肝癌类型）在早期阶段被诊断出来，可以通过手术切除部分肝脏（切除术）、肝移植或局部消融（使用电流摧毁癌细胞）来治疗。不幸的是，肝细胞癌的症状，包括体重减轻、疲劳和黄疸（皮肤和眼睛发黄），是模糊的，很少出现，直到癌症扩散到整个肝脏。因此，HCC很少在癌症晚期和无法治疗之前被诊断出来，并且预后很差（可能的结果）-不到5%的患者在诊断后存活5年或更长时间。HCC的确切病因尚不清楚，但慢性肝损伤和炎症（例如由乙型肝炎病毒感染或酗酒引起）可促进肿瘤的发展。即使早期诊断，HCC预后也很差，因为它经常复发。接受HCC治疗的患者可经历两种不同类型的肿瘤复发。早期复发通常发生在手术后的头两年，是由于手术中留下的原发性癌细胞扩散到周围的肝脏而引起的。晚期复发，通常发生在手术后两年多，涉及到全新肿瘤的发展，似乎是慢性肝损伤的结果。由于早期和晚期复发有不同的临床病程，因此能够预测哪些患者具有哪种复发的高风险将是有用的。考虑到损伤、炎症和再生似乎为肝细胞癌的发展做好了准备，与这些条件相关的基因表达模式是否可以作为HCC晚期复发风险识别患者的预测标记？在这里，研究人员通过检测肝脏损伤和再生组织样本中的基因表达模式，开发了HCC晚期复发的基因组预测因子。通过比较肝移植或切除前后肝活检获得的基因表达数据，并记录在美国国家生物技术信息中心基因表达综合数据库中，研究人员确定了233个基因，这些基因在肝损伤（肝损伤和再生，或HIR，特征）前后在肝脏中的表达不同。统计分析表明，在三组独立的患者中，存档组织样本中HIR特征的表达与HCC晚期复发显著相关，但与早期复发无关（两个变量之间的显著关联不太可能是偶然出现的）。相比之下，研究人员先前开发的肿瘤来源的65个基因标记与早期复发显著相关，但与晚期复发无关。值得注意的是，只有来自HIR特征的四个基因足以构建HCC晚期复发的可靠预测因子。最后，研究人员报告说，HIR标记中的许多基因编码与炎症和细胞死亡有关的蛋白质，但其他基因编码与细胞生长和增殖有关的蛋白质，如STAT3，一种在肝脏再生中起着众所周知的作用的蛋白质。这些发现确定了在三组独立患者中与HCC晚期复发显著相关的基因表达特征。由于这些患者大多数感染了HBV， HIR标记预测晚期HCC发生的能力可能仅限于HBV相关的HCC，而可能无法推广到与其他原因相关的HCC。此外，HIR特征的预测能力需要在一项前瞻性研究中进行测试，该研究在基线时采集样本并进行分析，并随访患者以观察其HCC是否复发；目前的回顾性研究分析了储存的组织样本。然而，重要的是，与晚期复发相关的HIR特征和与早期复发相关的65基因特征在分子水平上为HCC晚期和早期复发之间的生物学差异提供了新的见解。了解这些差异可能会导致HCC的新治疗方法，并可能帮助临床医生为他们的患者选择最合适的治疗方法。请通过本摘要的在线版本（http://dx.doi.org/10.1371/journal.pmed.1001770）访问这些网站。美国国家癌症研究所提供了关于癌症的各个方面的信息，包括患者和专业人员关于原发性肝癌的详细信息（英语和西班牙语）。美国癌症协会也提供了关于肝癌的信息(包括支持计划和服务的信息；英国国家健康服务选择网站提供了关于原发性肝癌的信息（包括一个关于如何应对癌症的视频）英国癌症研究中心（一个非营利组织）也提供了关于原发性肝癌的详细信息（包括原发性肝癌患者的生活信息）MD安德森癌症中心提供了有关症状、诊断、治疗、MedlinePlus提供有关肝癌的更多资源的链接（英文和西班牙文）
In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification. Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications. Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3–3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1–2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus–positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus. Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary Primary liver cancer—a tumor that starts when a liver cell acquires genetic changes that allow it to grow uncontrollably—is the second-leading cause of cancer-related deaths worldwide, killing more than 600,000 people annually. If hepatocellular cancer (HCC; the most common type of liver cancer) is diagnosed in its early stages, it can be treated by surgically removing part of the liver (resection), by liver transplantation, or by local ablation, which uses an electric current to destroy the cancer cells. Unfortunately, the symptoms of HCC, which include weight loss, tiredness, and jaundice (yellowing of the skin and eyes), are vague and rarely appear until the cancer has spread throughout the liver. Consequently, HCC is rarely diagnosed before the cancer is advanced and untreatable, and has a poor prognosis (likely outcome)—fewer than 5% of patients survive for five or more years after diagnosis. The exact cause of HCC is unclear, but chronic liver (hepatic) injury and inflammation (caused, for example, by infection with hepatitis B virus [HBV] or by alcohol abuse) promote tumor development. Even when it is diagnosed early, HCC has a poor prognosis because it often recurs. Patients treated for HCC can experience two distinct types of tumor recurrence. Early recurrence, which usually happens within the first two years after surgery, arises from the spread of primary cancer cells into the surrounding liver that left behind during surgery. Late recurrence, which typically happens more than two years after surgery, involves the development of completely new tumors and seems to be the result of chronic liver damage. Because early and late recurrence have different clinical courses, it would be useful to be able to predict which patients are at high risk of which type of recurrence. Given that injury, inflammation, and regeneration seem to prime the liver for HCC development, might the gene expression patterns associated with these conditions serve as predictive markers for the identification of patients at risk of late recurrence of HCC? Here, the researchers develop a genomic predictor for the late recurrence of HCC by examining gene expression patterns in tissue samples from livers that were undergoing injury and regeneration. By comparing gene expression data obtained from liver biopsies taken before and after liver transplantation or resection and recorded in the US National Center for Biotechnology Information Gene Expression Omnibus database, the researchers identified 233 genes whose expression in liver differed before and after liver injury (the hepatic injury and regeneration, or HIR, signature). Statistical analyses indicate that the expression of the HIR signature in archived tissue samples was significantly associated with late recurrence of HCC in three independent groups of patients, but not with early recurrence (a significant association between two variables is one that is unlikely to have arisen by chance). By contrast, a tumor-derived 65-gene signature previously developed by the researchers was significantly associated with early recurrence but not with late recurrence. Notably, as few as four genes from the HIR signature were sufficient to construct a reliable predictor for late recurrence of HCC. Finally, the researchers report that many of the genes in the HIR signature encode proteins involved in inflammation and cell death, but that others encode proteins involved in cellular growth and proliferation such as STAT3, a protein with a well-known role in liver regeneration. These findings identify a gene expression signature that was significantly associated with late recurrence of HCC in three independent groups of patients. Because most of these patients were infected with HBV, the ability of the HIR signature to predict late occurrence of HCC may be limited to HBV-related HCC and may not be generalizable to HCC related to other causes. Moreover, the predictive ability of the HIR signature needs to be tested in a prospective study in which samples are taken and analyzed at baseline and patients are followed to see whether their HCC recurs; the current retrospective study analyzed stored tissue samples. Importantly, however, the HIR signature associated with late recurrence and the 65-gene signature associated with early recurrence provide new insights into the biological differences between late and early recurrence of HCC at the molecular level. Knowing about these differences may lead to new treatments for HCC and may help clinicians choose the most appropriate treatments for their patients. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001770. The US National Cancer Institute provides information about all aspects of cancer, including detailed information for patients and professionals about primary liver cancer (in English and Spanish) The American Cancer Society also provides information about liver cancer (including information on support programs and services; available in several languages) The UK National Health Service Choices website provides information about primary liver cancer (including a video about coping with cancer) Cancer Research UK (a not-for-profit organization) also provides detailed information about primary liver cancer (including information about living with primary liver cancer) MD Anderson Cancer Center provides information about symptoms, diagnosis, treatment, and prevention of primary liver cancer MedlinePlus provides links to further resources about liver cancer (in English and Spanish)
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影响因子：
9.9
作者：
通讯作者：
--
影响因子：
29.4
作者：
Davila, JA;Morgan, RO;El-Serag, HB
通讯作者：
El-Serag, HB
影响因子：
3.2
作者：
Ding, Xiangjiu;Wang, Kexin;Hu, Sanyuan
通讯作者：
Hu, Sanyuan
影响因子：
13.5
作者：
Bruix, J;Llovet, JM
通讯作者：
Llovet, JM
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR