據(jù)physorg網(wǎng)站2007年11月4日報道，一個國際科學(xué)家研究小組4日宣布,，通過共同努力他們繪制了肺癌遺傳變異圖,。肺癌是世界上導(dǎo)致癌癥病人死亡的頭號殺手?！蹲匀弧冯s志在線版本于11月4日刊登了這一研究成果,。研究對肺癌細(xì)胞的非正常遺傳進(jìn)行了全面觀察，發(fā)現(xiàn)在人肺腫瘤中有五十多個基因組區(qū)域頻率地出現(xiàn)或消失,。
雖然我們已經(jīng)知道這些區(qū)域中包含的基因有三分之一在導(dǎo)致肺癌的過程中扮演著重要角色,，但是通過此次研究我們發(fā)現(xiàn)了大量存在的新基因?？茖W(xué)家們在研究中發(fā)現(xiàn)了一個重要的基因變異,，以前我們并沒有將他們與任何癌癥聯(lián)系在一起。該基因變異是肺癌的重要一部分,。這一研究發(fā)現(xiàn)為了解肺癌疾病的生物學(xué)起因和找到治療潛在的新目標(biāo)帶來了光明,。
麻省理工和哈佛大學(xué)Broad研究院資深準(zhǔn)成員和Dana-Farber癌癥研究院與哈佛醫(yī)學(xué)院副教授馬太.米爾森是該論文的作者之一,。他說，“肺癌基因組的新研究發(fā)現(xiàn)不論是其寬度和深度都是空前絕后,。它為我們樹立根基,，為我們指明了控制肺細(xì)胞生長的重要基因。這一研究發(fā)現(xiàn)對于肺癌的生物學(xué)研究至關(guān)重要,，將幫助我們制定新的癌癥診斷和治療的新策略,。”
麻省理工學(xué)院和哈佛大學(xué)Broad研究院創(chuàng)始董事埃里克.藍(lán)德爾是本論文的作者之一。他說,，“肺癌遺傳圖為我們提供了一幅肺癌這種可怕疾病的系統(tǒng)體系圖,，確定了我們所知道的東西，但是同時也為我們解答了一直令我們迷惑不解的存在許多缺失部分的原因,。這一研究成果具有更加廣泛的應(yīng)用范疇,，我們可以和應(yīng)當(dāng)把這一研究成果用于分析各種類型的癌癥。當(dāng)然,，當(dāng)初該研究就被定義為一個引導(dǎo)項(xiàng)目,，用于指引科學(xué)家更加全面的找到引發(fā)癌癥的遺傳原因。”
肺癌是世界上導(dǎo)致癌癥病人死亡的頭號殺手,，每年都有100多萬人死于肺癌,，其中美國有15萬多人。新肺癌治療方法依賴于對刺激癌細(xì)胞錯誤生長的更深入了解,。經(jīng)過數(shù)十年的研究,，我們已經(jīng)很清楚，肺癌像大多數(shù)其它癌癥一樣主要源于脫氧核糖核酸變異,。脫氧核糖核酸變異相伴人的一生,。但是這些自然脫氧核糖核酸變異和他們的生物學(xué)原理的大部分我們?nèi)詿o法了解。為了創(chuàng)建一個肺癌細(xì)胞遺傳差異基因組目錄,，科學(xué)家最近發(fā)起了一個大型研究項(xiàng)目,，以研究肺腺癌。這一項(xiàng)目被命名為腫瘤排序計(jì)劃（TSP）,，癌癥研究領(lǐng)域的科學(xué)家和臨床醫(yī)生共同參與這一研究項(xiàng)目,。
腫瘤排序項(xiàng)目研究人員對肺癌病人的五百多腫瘤樣品進(jìn)行了研究。通過大量收集高質(zhì)量的樣品,，使確定不同病人共同具有的遺傳變異成為可能,。這種遺傳變異能夠幫助確定導(dǎo)致癌細(xì)胞生長的重要基因。米爾森說,，“該研究項(xiàng)目盡可能地吸納腫瘤學(xué)家、病理學(xué)家和外科醫(yī)生參與,，因?yàn)樗麄兌嗄暌詠硪恢眻?jiān)持不懈地從事防止肺癌病人組織免受損害的研究,。”
為了分析每個肺腫瘤中的脫氧核糖核酸,，科學(xué)家們依靠最近的基因組技術(shù)，對人體中數(shù)百萬個遺傳標(biāo)記進(jìn)行了掃描,，即單核苷酸多態(tài)性,。獲得的高分辨率圖像幫助確定了腫瘤中基因組過多出現(xiàn)或缺失部分。然后利用包括GISTIC計(jì)算機(jī)分析方法和肉眼觀察單核苷酸多態(tài)性數(shù)據(jù)方法在內(nèi)的新分析工具對基因組失常區(qū)域進(jìn)行分析,。加迪.格茲,、芭芭拉.威爾、拉米恩.伯洛克西姆和杰姆.羅賓遜共同發(fā)明了以上兩種分析方法,。
在此項(xiàng)研究中,，研究人員發(fā)現(xiàn)了頻率出現(xiàn)在肺癌病人體內(nèi)的57%的遺傳變異。這部分遺傳變異中僅有約15%是我們以前所知道的與肺癌存在關(guān)系的,。此次研究所取得的最突出成果在于確定了14號染色體區(qū)域有兩個已知基因環(huán)繞,，以前我們并未將這種基因與癌癥聯(lián)系在一起。通過對癌癥細(xì)胞的進(jìn)一步研究,，休.安烏和其它Dana-Farber研究院的研究人員一道發(fā)現(xiàn)了一外名為NKX2.1的基因,，該基因可以影響癌癥細(xì)胞的生長。NKX2.1基因通常在肺內(nèi)部微小氣囊（氣泡）特殊細(xì)胞群中扮演“規(guī)則主管”的角色,，控制其它關(guān)鍵基因的活動,。這一研究發(fā)現(xiàn)是一個特定細(xì)胞群的基因而不是所有細(xì)胞基因都能夠促使癌癥生長。該研究發(fā)現(xiàn)將幫助我們研制新的分子靶向癌癥藥物,。
腫瘤排序項(xiàng)目的第二階段研究目前正在進(jìn)行之中,，將對第一階段分析所用的肺腫瘤樣品進(jìn)行檢查。第二階段研究可能會獲得甚至更加詳細(xì)的遺傳變異圖,。使用高產(chǎn)脫氧核糖核酸排序法,，科學(xué)家將確定數(shù)百個基因中遺傳代碼的微小變化。這一排序法已經(jīng)應(yīng)用于其它癌癥或更為普通常見的細(xì)胞生長研究中,。 （中國科技信息網(wǎng)Chinainfo）
英文原文鏈接參見：http://www.physorg.com/news113410062.html
原始出處:
Nature advance online publication 4 November 2007 | doi:10.1038/nature06358; Received 12 April 2007; Accepted 10 October 2007; Published online 4 November 2007
Characterizing the cancer genome in lung adenocarcinoma
Barbara A. Weir1,2,27, Michele S. Woo1,27, Gad Getz2,27, Sven Perner3,4, Li Ding5, Rameen Beroukhim1,2, William M. Lin1,2, Michael A. Province6, Aldi Kraja6, Laura A. Johnson3, Kinjal Shah1,2, Mitsuo Sato8, Roman K. Thomas1,2,9,10, Justine A. Barletta3, Ingrid B. Borecki6, Stephen Broderick11,12, Andrew C. Chang14, Derek Y. Chiang1,2, Lucian R. Chirieac3,16, Jeonghee Cho1, Yoshitaka Fujii18, Adi F. Gazdar8, Thomas Giordano15, Heidi Greulich1,2, Megan Hanna1,2, Bruce E. Johnson1, Mark G. Kris11, Alex Lash11, Ling Lin5, Neal Lindeman3,16, Elaine R. Mardis5, John D. McPherson19, John D. Minna8, Margaret B. Morgan19, Mark Nadel1,2, Mark B. Orringer14, John R. Osborne5, Brad Ozenberger20, Alex H. Ramos1,2, James Robinson2, Jack A. Roth21, Valerie Rusch11, Hidefumi Sasaki18, Frances Shepherd25, Carrie Sougnez2, Margaret R. Spitz22, Ming-Sound Tsao25, David Twomey2, Roel G. W. Verhaak2, George M. Weinstock19, David A. Wheeler19, Wendy Winckler1,2, Akihiko Yoshizawa11, Soyoung Yu1, Maureen F. Zakowski11, Qunyuan Zhang6, David G. Beer14, Ignacio I. Wistuba23,24, Mark A. Watson7, Levi A. Garraway1,2, Marc Ladanyi11,12, William D. Travis11, William Pao11,12, Mark A. Rubin2,3, Stacey B. Gabriel2, Richard A. Gibbs19, Harold E. Varmus13, Richard K. Wilson5, Eric S. Lander2,17,26 & Matthew Meyerson1,2,16
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
Institute of Pathology, University of Ulm, Ulm 89081, Germany
Genome Sequencing Center,
Division of Statistical Genomics and,
Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, Missouri 63130, USA
University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max-Planck Society and the Medical Faculty of the University of Cologne, Cologne 50931, Germany
Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, Cologne 50931, Germany
Departments of Medicine, Surgery, Pathology, and Computational Biology,
Human Oncology and Pathogenesis Program,
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
Section of Thoracic Surgery, Department of Surgery and,
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
Department of Pathology and,
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
Department of Surgery, Nagoya City University Medical School, Nagoya 467-8602, Japan
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Thoracic and Cardiovascular Surgery,
Department of Epidemiology,
Department of Pathology and,
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
University Health Network and Princess Margaret Hospital, Toronto M5G 2C4, Canada
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
These authors contributed equally to this work.
Correspondence to: Matthew Meyerson1,2,16 Correspondence and requests for materials should be addressed to M.M. (Email: [email protected]).
Somatic alterations in cellular DNA underlie almost all human cancers1. The prospect of targeted therapies2 and the development of high-resolution, genome-wide approaches3, 4, 5, 6, 7, 8 are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
