1、基于 microRNA 表达的肿瘤起源分类（英文） Andrew Fesler 刘华 郭诗翔 鞠景芳 Department of Pathology,Stony Brook University,School of Medicine 陆军军医大学第一附属医院肝胆外科 摘 要： 由于采用标准诊断方法难以识别癌变的原发部位, 诊断新发的癌症中约有 3%5%来源于原发部位不明的肿瘤。MicroRNAs (miRNAs) 近来被证实能够协助病理学家提高对原发部位不明肿瘤的诊断准确性。本文将着重讨论基于肿瘤诊断的miRNA 最新研究进展, 及该领域的未来发展方向。关键词： 微小 RNA; 诊断; 组织来
2、源不明肿瘤; 作者简介：Andrew Fesler, 1991 年生, 男, 助理研究员, 从事肿瘤研究工作。作者简介：鞠景芳, 教授, 博士, E-mail:jingfang.justongbrookmedicine.edu。收稿日期：2017-09-30基金：supported by National Institute of Health/National Cancer Institute R01CA15501904 (J.Ju) , R01CA19709801 (J.Ju) MicroRNA expression based tumor origin classificationAnd
3、rew Fesler LIU Hua GUO Shi-xiang JU Jing-fang Department of Pathology, Stony Brook University, School of Medicine; Abstract： Approximately 3 to 5% of newly diagnosed metastatic cancers are of unknown primary tissue origin due to difficulties identifying a primary tumor using standard diagnostic appr
4、oaches. MicroRNAs ( miRNAs) have recently been demonstrated to be able to assist pathologist with improved accuracy in diagnosing cancers of unknown primary origin ( CUP) . In this short commentary, we will highlight some of the recent advancements in miRNA based cancer diagnosis as well as some fut
5、ure directions for the field.Keyword： microRNA; diagnosis; tumor with unknown tissue origin; Received： 2017-09-301 IntroductionAccurate diagnosis is crucial to successful cancer treatment.Although most cancer patients present with a primary tumor, a small percentage (3%-5%) of cancer patients with m
6、etastatic disease have an unknown primary origin.In these cases, standard diagnostic approaches involving physical examinations, imaging, and pathological evaluations fail to identify a primary tissue of origin for an identified metastatic cancer.Without proper diagnosis, these patients often have a
7、 poor prognosis, as broad spectrum chemotherapy must be employed rather than targeted therapies, shown to be effective against specific cancers1-3.As a result, it is essential that new approaches are developed to enhance our ability to identify the tissue of origin and genetic finger prints as diagn
8、ostic biomarkers will be incredibly useful in helping to address this challenge.Tremendous amounts of effort have been devoted to finding diagnostic biomarkers for tumors with unknown primary origin.miRNA based diagnostic biomarkers have emerged as promising candidates for assisting pathologist in i
9、dentifying tissue of origin of metastatic cancers with unknown primary origin4.miRNAs are a class of non-coding small RNAs that post-transcriptionally, and translationally regulate mRNAs with important roles in development, differentiation, apoptosis, autophagy, and tumorigenesis5-7.Systematic evalu
10、ation of miRNA stability by our group has shown that miRNA are stable informalin fixed paraffin embedded (FFPE) specimens, making them excellent biomarkercandidates8.Additionally, miRNAs exhibit differential expression in different types of cancer9.Thus miRNA expression profiling has great potential
11、 to help in identifying tissue of origin for CUP patients.2 miRNA expression profiling for identification of tissue of origin in CUP patientsIn the past decade, there has been much interest in using miRNA expression profiling to help in identifying tissue of origin in CUP patients.Studies by Rosenfe
12、ld et al.identified a set of48 miRNA based classifiers to determine tumor tissue origins for22 tumor tissues using miRNA expression measured by microarray4.They have developed a miRNA based decision tree to guide the decision process for tumor tissue of origin determination.When used in combination
13、with the K-nearest-neighbors (KNN) classification algorithm, in an independent blinded testset, they found 86%of the cases were accurately identified.A-mong metastatic samples, the sensitivity was 85%for high-confidence classifications.This work demonstrated that primary tumor samples can be used to
14、 augment training sets if considerations are made for certain markers, which is important as availability of metastatic tissue is limited.Many of the tissue types were classified with high confidence except bladder cancer due to the small number of clinical samples used for the profiling studies4.Wi
15、th the aim of developing a standardized test for identifying tissue of origin using this approach, the microarray was replaced with qRT-PCR for analysis of miRNA expression.Even with the switch to qRT-PCR expression analysis, tissue of origin was identified with relatively high accuracy of predictio
16、n based on a large set (204) of archival FFPE tumor samples10.While these initial studies used samples that had known primary origin, in order to confirm the ability of this approach to accurately identify the tissue of origin, another study used the qRT-PCR based approach to investigate tumor sampl
17、es from CUP patients.On a set of 57 CUP patients with brain metastasis, the tissue of origin prediction based on this approach matched the diagnosis based on available clinicopathological data in 80%of the samples11.In a study that built upon on the original Rosenfeld work, again using a binary deci
18、sion tree and KNN classification, with the expression profile of 64 miRNAs and 42 tumor types, primary tissue of origin was identified with 85%accuracy in a set of 509 samples.In this study samples from CUP patients were also utilized and 88%agreement with clinicopathological based tissue of origin
19、identification was found.In cases of CUP, this type of approach can be used to supplement, other clinicopathological data, to help confirm tissue of origin.A study looking at the correlation between tissue of origin based on clinicopathological data and miRNA expression profiling found the strongest
20、 agreement (92%) between final clinical diagnosis, and prediction based on miRNA expression.The agreement with the initial clinical presentation diagnosis was 70%.This shows that miRNA profiling can help to correctly identify the primary tissue of origin, which can help to guide therapeutic interven
21、tion12.Other groups have also shown miRNA expression profiles to be effective at identifying tissue of origin.One recent study demonstrated that miRNA based classifiers provided 88%accuracy foridentifying primary tumor sites based on metastatic tumor miRNA expression data from over 200 FFPE clinical
22、 specimens representing 15 different histologies13.Another study demonstrated 86%accuracy for identification of primary origin for metastatic cases using the expression of 47 miRNAs14.A number of the miRNA biomarkers used in these studies to distinguish tissue of origin, also have functional and pro
23、gnostic significance in cancer15-20.These studies are largely retrospective in nature, and while these retrospective studies are essential to developing the approach and confirming its accuracy prospective studies are need to demonstrate its utility.A prospective study based on miRNA expression prof
24、iling demonstrated a close correlation (84%agreement) with clinical pathological diagnosis of tumors with unknown tissue origin21.This effort is highly significant in that it clearly demonstrates the clinical impact of aiding accurate diagnosis for planning proper treatment options for these patient
25、s.Tissue of origin predictions provided by miRNA profiling may be especially helpful when clinicopathological information suggests differential diagnosis.3 miRNA expression and CUP biologyBeyond the usefulness of miRNA expression profiling for identifying tissue of origin for CUP, there is also inte
26、rest in using miRNA to understand the biology of CUP.Pentheroudakis et al.investigated miRNA expression in favorable prognosis subgroups of CUP, and found no significant expression differences between CUP metastatic tumors and metastatic tumors with known primary origin22.This suggests that there is
27、 not a universal miRNA signature for CUP.Another study looked at differences in expression of miRNA in CUP tumors that are EMT positive vs.those that are EMT negative.This work found no statistically significant difference but did identify some miRNA with differential expression23.Clearly more work
28、needs to be done to understand the biology of CUP tumors and the role miRNA may play in their development.4 Summary and future perspectivemiRNA profiling has shown great promise for helping to identify tissue of origin for CUP patients.With additional efforts, approaches based on miRNA expression pr
29、ofiling of CUP may be further refined to greatly enhance our ability to identify tissue of origin and accurately diagnosis these patients.Beyond tumor tissue based diagnosis, recent studies have demonstrated promising potential of liquid (e.g.serum, plasma, urine) sample miRNA based diagnosis24.It m
30、ay be possible to identify metastatic cancer tissue origin based on miRNA expression analysis on circulating tumor cells or circulating microRNAs.Such tests will be non-invasive and may help to guide treatment decisions if tissue of primary origin can be identified.The application of such an approac
31、h will require multi-and inter-disciplinary team work and multi-center studies with large patient cohorts for discovery and validation.Hopefully miRNA expression profiling will help to improve outcomes for CUP patients.参考文献1Greco FA.Cancer of unknown primary site:evolving understanding and managemen
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