柳叶刀子刊:首个用于诊断癌症起源的表观遗传学检测问世
2016/08/30
表观遗传学是近年来的热门领域,也是多类研究的未来切入点。表观遗传学推动精准医疗的发展已被Nature等杂志证实,如今,柳叶刀子刊上的研究再次证实了它在癌症诊断上的功绩——可用于确定癌症的起源。


8月26日,巴塞罗那大学遗传学教授Manel Esteller在《The Lancet Oncology》杂志中展示了一种新发明的表观遗传学检测技术—— EPICUP,这种技术可以诊断肿瘤的起源,使医生能够根据肿瘤类型来制定更具体的治疗方案。

对于癌症患者,初级诊断往往包括检测原发肿瘤以及是否会发生转移。然而,5%-10%的人类肿瘤的诊断结果与之相反,即往往先诊断出转移的肿瘤,使用各种诊断测试后仍无法检测到原发灶,这种情况也被称为未知原发灶肿瘤(CUP)。由于肿瘤类型不为人所知,这些患者的生存率非常有限。

Manel Esteller教授是ICREA研究员、Bellvitge生物医学研究所(IDIBELL)表观遗传学与癌症生物工程(PEBC)主管,他说,“几年前,我们开始认识到,调节基因活性的化学模式(表观遗传学)因组织而异,例如它们在胰腺细胞和肺细胞中各有不同。我们已经通过一万多个人类肿瘤样本分析了每种癌症的表观遗传学特征。如今在研究原发灶未知的转移肿瘤的DNA时,我们可以通过所获取的表观基因图像来判断它属于哪个家族,如属于胰腺癌、结直肠癌、肺癌或者是乳腺癌等,换句话说,通过这种方法我们可以诊断肿瘤的起源。”

通过表观遗传学检测来确定癌症的类型,将对治疗有显著的影响。“从现在开始,患者将不用接受盲目的治疗,因为我们能够为不同类型的肿瘤提供更具体的治疗方案;事实上,我们的初步数据显示,这种方法使患者生存率翻了一番。”Esteller教授说,“需要记住的是,这不是未开发的领域,如今我们已经与Ferrer 实验室合作使这种方法的推广和应用成为了可能。”

那么,EPICUP到底是个怎样的技术?

研究人员建立了基于微阵列DNA甲基化标签(microarray DNA methylation signatures)的癌症分类方法,并将之称为EPICUP。数据源于2790个起源已知的肿瘤样本,这些样本代表了38类肿瘤,包括85个转移病例。

为了验证这种癌症分类方法,研究人员使用了另外一组包含7691个肿瘤的样本,这些肿瘤的来源与上述样本相同,包含了534个转移病例。研究人员利用自己开发的诊断方法来预测216个起源未知但特征明显的肿瘤的类型,并在尸体解剖检查、光镜、综合免疫组化分析之后对原发部位进行数月临床检测,从而对 EPICUP 方法预测肿瘤类型的准确度进行验证。

结果发现,在包含7691个肿瘤样本的试验组中,基于DNA甲基化的肿瘤分类方法表现出的特异性、敏感性、阳性预测值和阴性预测值分别为99.6%、97.7%、88.6%和99.9%。对于216个起源未知的肿瘤,DNA甲基化分析能够预测出了87%的起源。与接受经验性治疗方法的患者相比,EPICUP诊断后接受特异性治疗的患者总生存率有改善。

研究人员解释,发展基于DNA甲基化的诊断方法可显著提高未知原发灶肿瘤的诊断效率,并能更精确地指导治疗。表观遗传学分析可揭露未知原发灶患者的原发性肿瘤部位,对癌症患者的临床管理有进一步改善。

相关连接:

The first epigenetic test to diagnose tumors of unknown origin

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  • Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis

    Background Cancer of unknown primary ranks in the top ten cancer presentations and has an extremely poor prognosis. Identification of the primary tumour and development of a tailored site-specific therapy could improve the survival of these patients. We examined the feasability of using DNA methylation profiles to determine the occult original cancer in cases of cancer of unknown primary. Methods We established a classifier of cancer type based on the microarray DNA methylation signatures (EPICUP) in a training set of 2790 tumour samples of known origin representing 38 tumour types and including 85 metastases. To validate the classifier, we used an independent set of 7691 known tumour samples from the same tumour types that included 534 metastases. We applied the developed diagnostic test to predict the tumour type of 216 well-characterised cases of cancer of unknown primary. We validated the accuracy of the predictions from the EPICUP assay using autopsy examination, follow-up for subsequent clinical detection of the primary sites months after the initial presentation, light microscopy, and comprehensive immunohistochemistry profiling. Findings The tumour type classifier based on the DNA methylation profiles showed a 99·6% specificity (95% CI 99·5–99·7), 97·7% sensitivity (96·1–99·2), 88·6% positive predictive value (85·8–91·3), and 99·9% negative predictive value (99·9–100·0) in the validation set of 7691 tumours. DNA methylation profiling predicted a primary cancer of origin in 188 (87%) of 216 patients with cancer with unknown primary. Patients with EPICUP diagnoses who received a tumour type-specific therapy showed improved overall survival compared with that in patients who received empiric therapy (hazard ratio [HR] 3·24, p=0·0051 [95% CI 1·42–7·38]; log-rank p=0·0029). Interpretation We show that the development of a DNA methylation based assay can significantly improve diagnoses of cancer of unknown primary and guide more precise therapies associated with better outcomes. Epigenetic profiling could be a useful approach to unmask the original primary tumour site of cancer of unknown primary cases and a step towards the improvement of the clinical management of these patients. Funding European Research Council (ERC), Cellex Foundation, the Institute of Health Carlos III (ISCIII), Cancer Australia, Victorian Cancer Agency, Samuel Waxman Cancer Research Foundation, the Health and Science Departments of the Generalitat de Catalunya, and Ferrer.

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