The life history of 21 breast cancers.
The life history of 21 breast cancers.
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DOI：
10.1016/j.cell.2012.04.023
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发表时间：
2012-05-25
期刊：
影响因子：
64.5
通讯作者：
Breast Cancer Working Group of the International Cancer Genome Consortium
中科院分区：
文献类型：
--
作者：
Nik-Zainal S;Van Loo P;Wedge DC;Alexandrov LB;Greenman CD;Lau KW;Raine K;Jones D;Marshall J;Ramakrishna M;Shlien A;Cooke SL;Hinton J;Menzies A;Stebbings LA;Leroy C;Jia M;Rance R;Mudie LJ;Gamble SJ;Stephens PJ;McLaren S;Tarpey PS;Papaemmanuil E;Davies HR;Varela I;McBride DJ;Bignell GR;Leung K;Butler AP;Teague JW;Martin S;Jönsson G;Mariani O;Boyault S;Miron P;Fatima A;Langerød A;Aparicio SA;Tutt A;Sieuwerts AM;Borg Å;Thomas G;Salomon AV;Richardson AL;Børresen-Dale AL;Futreal PA;Stratton MR;Campbell PJ;Breast Cancer Working Group of the International Cancer Genome Consortium
随着克隆扩增在不断变化的选择压力、突变过程和破坏的癌基因的驱动下相互取代，癌症动态地演变。这些过程标记基因组，使得癌症的生活史在存在的体细胞突变中被加密。我们开发了算法来破译这种叙述，并将其应用于21种乳腺癌。突变过程在癌症的整个生命周期中不断演变，其中许多出现较晚，但贡献了广泛的遗传变异。亚克隆多样化是突出的，大多数突变仅在一小部分肿瘤细胞中发现。每个肿瘤都有一个占优势的亚克隆谱系，占肿瘤细胞的50%以上。这些亚克隆的最小扩增发生，直到积累了数百至数千个突变，这意味着存在长寿命的静止细胞谱系，其能够在获得使能的基因组变化后大量增殖。因此，优势亚克隆扩展到可感知的质量可能代表乳腺癌发展的最后限速步骤，从而触发诊断。21种乳腺癌中随时间出现的突变的全基因组分析21种乳腺癌中随着时间出现的突变的亚克隆的最小扩增直到数千种突变积累为止22追踪每个肿瘤的时间演变和最终将触发诊断的主导亚克隆的出现。
Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis. ► Genome-wide analyses of mutations emerging through time in 21 breast cancers ► Minimal expansion of subclones occurs until thousands of mutations have accumulated ► Cancer-specific signatures of point mutations and genomic instability emerge late ► ERBB2 amplification begins early but continues to evolve over long molecular time Newly developed algorithms allow the reconstruction of the genomic history of different breast cancers, tracing the temporal evolution of each tumor and the emergence of the dominant subclones that will eventually trigger diagnosis.
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通讯作者：
Wigler M