來自北京市腫瘤防治研究所，北京大學腫瘤醫(yī)院病因研究室的研究人員在之前研究的基礎(chǔ)上,，展開了胃癌發(fā)生發(fā)展相關(guān)DNA甲基化組掃描,，進行了所獲90余個基因的DHPLC大規(guī)模研究，在中日韓三國驗證隊列中證明了了GFRA1的去甲基化激活,，SRF和ZNF382的甲基化失活可用作胃癌等惡性腫瘤的轉(zhuǎn)移標志物,。就此研究進展，研究人員在《科學通報》上發(fā)表了相關(guān)評述性文章,。
文章的通訊作者是北京大學腫瘤醫(yī)院鄧大君教授,，鄧教授曾證明人胃內(nèi)能夠合成亞硝酰胺類致癌物N-甲基亞硝基脲，得到國際同行驗證認可,，并且創(chuàng)建靈敏的DHPLC定性和定量檢測DNA甲基化方法,，已在國內(nèi)外推廣應(yīng)用，還發(fā)現(xiàn)了一組早期預(yù)測胃癌轉(zhuǎn)移的DNA甲基化標志物等,。
一直以來,，科學家們都認為表觀遺傳學與遺傳學是作為兩個獨立的機制，參與癌變過程,。癌癥研究領(lǐng)域的科學家們一面忙著尋找致癌基因,，分析癌癥發(fā)生的遺傳學，一面又在表觀遺傳調(diào)控方面進行深入分析,，希望了解環(huán)境等因素對于癌癥發(fā)生發(fā)展的影響,，卻沒有想過把這兩方面聯(lián)系起來。然而近期關(guān)于人類癌癥,，上千個癌細胞外顯子測序結(jié)果的研究卻令人驚訝的發(fā)現(xiàn)了許多調(diào)控表觀遺傳的基因休眠突變,，由此癌癥表觀遺傳學成為了研究熱點。
癌前病變進展和腫瘤侵襲,、轉(zhuǎn)移,、治療敏感性和耐藥性等均為癌細胞的生物學特征, 理論上有用表觀遺傳等生物學手段進行識別的可能。在這篇文章中,，研究人員利用甲基化 CpG 島擴增與芯片組合分析(methylated CpG island amplification, MCAM),，和甲基化敏感酶切基因組掃描技術(shù), 分別測定了4對轉(zhuǎn)移性胃癌和 4 對配對的非轉(zhuǎn)移性胃癌及其切緣非癌組織CpG 島的甲基化信號。對所篩選出的90余個轉(zhuǎn)移和發(fā)生相關(guān)候選基因 CpG島開展了DHPLC驗證研究。
研究人員分別為這90余個基因轉(zhuǎn)錄起始點附近CpG 島的甲基化狀態(tài)建立了DHPLC測定方法, 結(jié)果發(fā)現(xiàn)在胃癌與切緣(及非癌對照)之間, 15 個基因(BMP3, BNIP3, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, p16, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, ZNF382)存在有統(tǒng)計學顯著性的甲基化明顯差別, 提示這些基因甲基化變異與胃癌發(fā)生相關(guān),。
其中, GFRA1 的去甲基化激活和SRF 以及 ZNF382 的甲基化失活均與胃癌的轉(zhuǎn)移和患者總生存時間存在明顯相關(guān)性, 并且在中,、日、韓三國胃癌患者驗證隊列中反復(fù)得到驗證,。事實上, 它們在結(jié)腸癌和肝癌上也有相似的作用,。這些病例對照研究結(jié)果說明, 這3個基因在早期測定胃癌等惡性腫瘤轉(zhuǎn)移狀態(tài)方面可能有重要應(yīng)用價值, 以前未見類似報道。
下一步研究人員將通過在手術(shù)時未見轉(zhuǎn)移的胃癌患者中開展前瞻隊列研究, 來確證這些轉(zhuǎn)移標志物在預(yù)測腫瘤轉(zhuǎn)移復(fù)發(fā)上的價值,。此外, 研究人員還發(fā)現(xiàn)了9個 miR CpG 島(miR-9-1, miR-9-3, miR- 34b/c, miR-137, miR-193b/365a, miR-200b/200c/429, miR-210, miR-375, miR-663)的甲基化變化與胃癌發(fā)展生存在明顯的相關(guān)性,，這提示血漿miR-221等含量的進行性升高可能是胃癌發(fā)生的預(yù)警信號。(生物谷Bioon.com)
10.1007/s11434-012-5578-0
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PMID:
Differentiation and adaptation epigenetic networks: Translational research in gastric carcinogenesis
DaJun Deng, ZheMing Lu
There are several kinds of epigenetic networks in the human body including the cell differentiation epigenetic network (DiEN) and the host adaptation epigenetic network (AdEN). DiEN networks are static and cell/tissue-specific. AdEN networks are variable and dependent upon environmental factors. DiEN and AdEN alterations can respectively serve as biomarkers for different kinds of diseases. Cancer is a consequence of accumulated pathophysiological adaptations of tissue stem cells to exposure of environmental carcinogens. Cancer cells are de-differentiated cells that obtain the capacity of unrestricted proliferation, local invasion, and distant migration/metastasis. Both DiEN and AdEN changes can be observed in cancer tissues. Alterations of DNA methylation are the most stable epigenetic modifications and can be sensitively detected in a small cell population. These advantages make DNA methylation the optimal biomarkers for detection of initiated cells in precancerous lesions and metastasis stem cells in cancer tissues. It has been proven that p16 methylation can be used as a diagnostic biomarker to determine malignant potential of epithelium dysplasia in many organs including the stomach. In a large-scale validation study on the DNA methylome of gastric carcinomas (GC), the methylation status of more than 90 CpG islands has been analyzed by DHPLC. Furthermore, GFRA1 demethylation and methylation of SRF and ZNF382 are frequent events during gastric carcinogenesis and consistently correlate to GC metastasis and overall survival of GC patients from China, Japan, and Korea, respectively. In a population study, it has been demonstrated that gradual increasing of plasma miR-211 and other miRNA levels may be an early risk predictor for GC development.
