Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

被引：864

作者：

de Bruin, Elza C. ^{[1
]}

McGranahan, Nicholas ^{[2
,3
]}

Mitter, Richard ^{[2
]}

Salm, Max ^{[2
]}

Wedge, David C. ^{[4
]}

Yates, Lucy ^{[4
,5
]}

Jamal-Hanjani, Mariam ^{[1
]}

Shafi, Seema ^{[1
]}

Murugaesu, Nirupa ^{[1
]}

Rowan, Andrew J. ^{[2
]}

Groenroos, Eva ^{[2
]}

Muhammad, Madiha A. ^{[1
]}

Horswell, Stuart ^{[2
]}

Gerlinger, Marco ^{[2
]}

Varela, Ignacio ^{[6
]}

Jones, David ^{[4
]}

Marshall, John ^{[4
]}

Voet, Thierry ^{[4
,7
]}

Van Loo, Peter ^{[4
,7
]}

Rassl, Doris M. ^{[8
]}

Rintoul, Robert C. ^{[8
]}

Janes, Sam M. ^{[9
]}

Lee, Siow-Ming ^{[1
,10
]}

Forster, Martin ^{[1
,10
]}

Ahmad, Tanya ^{[10
]}

Lawrence, David ^{[10
]}

Falzon, Mary ^{[10
]}

Capitanio, Arrigo ^{[10
]}

Harkins, Timothy T. ^{[11
]}

Lee, Clarence C. ^{[11
]}

Tom, Warren ^{[11
]}

Teefe, Enock ^{[11
]}

Chen, Shann-Ching ^{[11
]}

Begum, Sharmin ^{[2
]}

Rabinowitz, Adam ^{[2
]}

Phillimore, Benjamin ^{[2
]}

Spencer-Dene, Bradley ^{[2
]}

Stamp, Gordon ^{[2
]}

Szallasi, Zoltan ^{[12
,13
]}

Matthews, Nik ^{[2
]}

Stewart, Aengus ^{[2
]}

Campbell, Peter ^{[4
]}

Swanton, Charles ^{[1
,2
]}

机构：

[1] UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, London WC1E 6BT, England

[2] Canc Res UK London Res Inst, London WC2A 3LY, England

[3] UCL, Ctr Math & Phys Life Sci & Expt Biol CoMPLEX, London WC1E 6BT, England

[4] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[5] Univ Cambridge, Cambridge CB2 1TN, England

[6] Univ Cantabria, Dept Biol Mol, Inst Biomed & Biotecnol Cantabria, CSIC UC Sodercan, E-39005 Santander, Spain

[7] Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium

[8] Papworth Hosp NHS Fdn Trust, Cambridge CB23 3RE, England

[9] UCL, Lungs Living Res Ctr, London WC1E 6BT, England

[10] Univ Coll London Hosp, London NW1 2BU, England

[11] Thermo Fisher Sci, Carlsbad, CA 92008 USA

[12] Tech Univ Denmark, DK-2800 Lyngby, Denmark

[13] Harvard Univ, Sch Med, Childrens Hosp Informat Program, Boston, MA 02115 USA

来源：

SCIENCE | 2014年 / 346卷 / 6206期

基金：

英国医学研究理事会; 欧洲研究理事会;

关键词：

CHROMOSOMAL INSTABILITY; MUTATIONS; ADENOCARCINOMA; REARRANGEMENTS; HETEROGENEITY; MUTAGENESIS; RESISTANCE; SIGNATURES; PATTERNS;

D O I：

10.1126/science.1253462

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

引用

页码：251 / 256

页数：6

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