Pervasive lesion segregation shapes cancer genome evolution

被引：37

作者：

Aitken, Sarah J. ^{[1
,2
,3
]}

Anderson, Craig J. ^{[4
]}

Connor, Frances ^{[1
]}

Pich, Oriol ^{[5
]}

Sundaram, Vasavi ^{[1
]}

Feig, Christine ^{[1
]}

Rayner, Tim F. ^{[1
]}

Lukk, Margus ^{[1
]}

Aitken, Stuart ^{[4
]}

Luft, Juliet ^{[4
]}

Kentepozidou, Elissavet ^{[6
]}

Arnedo-Pac, Claudia ^{[5
]}

Beentjes, Sjoerd V. ^{[7
]}

Davies, Susan E. ^{[3
]}

Drews, Ruben M. ^{[1
]}

Ewing, Ailith ^{[4
]}

Kaiser, Vera B. ^{[4
]}

Khamseh, Ava ^{[4
,8
]}

Lopez-Arribillaga, Erika ^{[5
]}

Redmond, Aisling M. ^{[1
]}

Santoyo-Lopez, Javier ^{[9
]}

Sentis, Ines ^{[5
]}

Talmane, Lana ^{[4
]}

Yates, Andrew D. ^{[6
]}

Semple, Colin A. ^{[4
]}

Lopez-Bigas, Nuria ^{[5
,10
,11
]}

Flicek, Paul ^{[1
]}

Odom, Duncan T. ^{[1
,12
]}

Taylor, Martin S. ^{[4
]}

机构：

[1] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England

[2] Univ Cambridge, Dept Pathol, Cambridge, England

[3] Cambridge Univ Hosp NHS Fdn Trust, Dept Histopathol, Cambridge, England

[4] Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[5] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona, Spain

[6] European Bioinformat Inst, European Mol Biol Lab, Hinxton, England

[7] Univ Edinburgh, Sch Math & Maxwell Inst, Edinburgh, Midlothian, Scotland

[8] Univ Edinburgh, Higgs Ctr Theoret Phys, Edinburgh, Midlothian, Scotland

[9] Univ Edinburgh, Edinburgh Genom Clin, Edinburgh, Midlothian, Scotland

[10] Univ Pompeu Fabra UPF, Barcelona, Spain

[11] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain

[12] German Canc Res Ctr, Div Regulatory Genom & Canc Evolut, Heidelberg, Germany

来源：

NATURE | 2020年 / 583卷 / 7815期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.1038/s41586-020-2435-1

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：

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion(1,2). Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

引用

页码：265 / +

页数：25

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