Format

Send to

Choose Destination
Nat Genet. 2019 Jul;51(7):1113-1122. doi: 10.1038/s41588-019-0423-x. Epub 2019 Jun 17.

Quantitative evidence for early metastatic seeding in colorectal cancer.

Hu Z1,2,3, Ding J1,2,3,4, Ma Z1,2,3, Sun R1,2,3, Seoane JA1,2,3, Scott Shaffer J3, Suarez CJ5, Berghoff AS6,7,8, Cremolini C9, Falcone A9, Loupakis F10, Birner P6,11, Preusser M6,7, Lenz HJ12, Curtis C13,14,15.

Author information

1
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA.
2
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
3
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
4
Veracyte Inc, South San Francisco, CA, USA.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
6
Comprehensive Cancer Center CNS Tumor Unit, Medical University of Vienna, Vienna, Austria.
7
Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
8
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
9
Department of Oncology, University Hospital of Pisa, Pisa, Italy.
10
Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy.
11
Department of Pathology, Medical University of Vienna, Vienna, Austria.
12
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
13
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA. cncurtis@stanford.edu.
14
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. cncurtis@stanford.edu.
15
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cncurtis@stanford.edu.

Abstract

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%, 17 out of 21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01 cm3). 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.

PMID:
31209394
DOI:
10.1038/s41588-019-0423-x

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center