Nature：美科學家首次測序癌癥患者基因組

2008-11-06 科學網 www.sciencenet.cn


 
美國科學家近日首次成功測序了一個癌癥患者的基因組，這一開創性工作為利用新方法揭開癌癥的遺傳學基礎創造了條件。相關論文發表在11月6日的《自然》（Nature）雜志上。
 
測序的基因組來自于一位女性，50多歲死于急性骨髓性白血病（AML）。美國華盛頓大學的研究人員利用來自皮膚樣本的遺傳材料，測序了她2套染色體的DNA，同時根據骨髓樣本檢測了其腫瘤細胞中的遺傳突變。所有樣本均采自患者接受癌癥治療前，以防DNA受到進一步損傷。
 
隨后，研究人員將患者的腫瘤基因組與其正常基因組進行了比較，以期發現遺傳差異。在患者腫瘤基因組中接近270萬個單核苷變異中，將近98%同樣也在患者皮膚樣本的DNA中檢測到，這就大大縮小了進一步篩選的范圍。
 
研究人員最終在患者的腫瘤DNA中僅發現了10個可能與AML有關的遺傳突變，其中8個很罕見，它們所處基因之前從未被認為與AML有關。研究人員還顯示，腫瘤樣本中的每個細胞擁有9個突變，而且較少發生的那個突變可能是最后形成的。研究人員懷疑，所有這些突變對于患者的癌癥都很重要。
 
美國國立人類基因組研究所前任主管Francis Collins說：“首次確定人類癌癥基因組的完全DNA序列，并與同一個體的正常組織相比較，這在癌癥研究中是一個真正的里程碑。”
 
美國俄勒岡健康與科學大學癌癥研究所的Brian Druker說：“雖然這一研究尚不能告訴我們怎樣治療癌癥患者，但它是這條路上關鍵的第一步。它為大規模癌癥基因組測序和揭示癌癥秘密打下了基礎。”
 
目前，研究小組正在測序其他AML患者的基因組，同時他們還計劃將這種全基因組方法擴展到乳腺癌和肺癌。（科學網 梅進/編譯）
 
（《自然》（Nature），456, 66-72，Timothy J. Ley，Richard K. Wilson）
 
 
Nature 456 , 66-72 (6 November 2008) | doi :10.1038/nature07485 ; Received 28 May 2008; Accepted 16 September 2008

DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome
Timothy J. Ley 1 , 2 , 3 , 4 , 9 , Elaine R. Mardis 2 , 3 , 9 , Li Ding 2 , 3 , Bob Fulton 3 , Michael D. McLellan 3 , Ken Chen 3 , David Dooling 3 , Brian H. Dunford-Shore 3 , Sean McGrath 3 , Matthew Hickenbotham 3 , Lisa Cook 3 , Rachel Abbott 3 , David E. Larson 3 , Dan C. Koboldt 3 , Craig Pohl 3 , Scott Smith 3 , Amy Hawkins 3 , Scott Abbott 3 , Devin Locke 3 , LaDeana W. Hillier 3 , 8 , Tracie Miner 3 , Lucinda Fulton 3 , Vincent Magrini 2 , 3 , Todd Wylie 3 , Jarret Glasscock 3 , Joshua Conyers 3 , Nathan Sander 3 , Xiaoqi Shi 3 , John R. Osborne 3 , Patrick Minx 3 , David Gordon 8 , Asif Chinwalla 3 , Yu Zhao 1 , Rhonda E. Ries 1 , Jacqueline E. Payton 5 , Peter Westervelt 1 , 4 , Michael H. Tomasson 1 , 4 , Mark Watson 3 , 4 , 5 , Jack Baty 6 , Jennifer Ivanovich 4 , 7 , Sharon Heath 1 , 4 , William D. Shannon 1 , 4 , Rakesh Nagarajan 4 , 5 , Matthew J. Walter 1 , 4 , Daniel C. Link 1 , 4 , Timothy A. Graubert 1 , 4 , John F. DiPersio 1 , 4 & Richard K. Wilson 2 , 3 , 4

1. Department of Medicine,
2. Department of Genetics,
3. The Genome Center at Washington University,
4. Siteman Cancer Center,
5. Department of Pathology and Immunology,
6. Division of Biostatistics, and,
7. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63108, USA
8. Department of Genome Science s, University of Washington, Seattle, Washington 98195, USA
9. These authors contributed equally to this work.

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe. to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient’s skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cell s at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer -initiating mutations in previously unidentified genes that may respond to targeted therapies.

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