Quantitative evidence for early metastatic seeding in colorectal cancer

被引：348

作者：

Hu, Zheng ^{[1
,2
,3
]}

Ding, Jie ^{[1
,2
,3
,12
]}

Ma, Zhicheng ^{[1
,2
,3
]}

Sun, Ruping ^{[1
,2
,3
]}

Seoane, Jose A. ^{[1
,2
,3
]}

Shaffer, J. Scott ^{[3
]}

Suarez, Carlos J. ^{[4
]}

Berghoff, Anna S. ^{[5
,6
,7
]}

Cremolini, Chiara ^{[8
]}

Falcone, Alfredo ^{[8
]}

Loupakis, Fotios ^{[9
]}

Birner, Peter ^{[5
,10
]}

Preusser, Matthias ^{[5
,6
]}

Lenz, Heinz-Josef ^{[11
]}

Curtis, Christina ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Stanford Canc Inst, Sch Med, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[5] Med Univ Vienna, Comprehens Canc Ctr, CNS Tumor Unit, Vienna, Austria

[6] Med Univ Vienna, Div Oncol, Dept Med 1, Vienna, Austria

[7] Med Univ Vienna, Inst Neurol, Vienna, Austria

[8] Univ Hosp Pisa, Dept Oncol, Pisa, Italy

[9] IRCCS, Unit Med Oncol 1, Dept Clin & Expt Oncol, Ist Oncol Veneto, Padua, Italy

[10] Med Univ Vienna, Dept Pathol, Vienna, Austria

[11] Univ Southern Calif, Keck Sch Med, Dept Med Oncol, Norris Comprehens Canc Ctr, Los Angeles, CA USA

[12] Veracyte Inc, San Francisco, CA USA

来源：

NATURE GENETICS | 2019年 / 51卷 / 07期

基金：

美国国家卫生研究院;

关键词：

INTRATUMORAL HETEROGENEITY; SEQUENCING REVEALS; BRAIN METASTASES; PATTERNS; MUTATIONS; EVOLUTION; DYNAMICS; ORIGINS; TUMORS; MODEL;

D O I：

10.1038/s41588-019-0423-x

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain. The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%07 out of 21evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01cm(3)). We validated the association between early drivers and metastasis in an independent cohort of 2,751 colorectal cancers, demonstrating their utility as biomarkers of metastasis. This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis.

引用

页码：1113 / +

页数：13

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