期刊
NATURE
卷 520, 期 7547, 页码 353-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14347
关键词
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资金
- Cancer Research UK
- NIH NCI Intramural Program
- Academy of Finland
- Cancer Society of Finland
- PELICAN Autopsy Study family members and friends
- John and Kathe Dyson
- US National Cancer Institute [CA92234]
- American Cancer Society
- Johns Hopkins University Department of Pathology
- Women's Board of Johns Hopkins Hospital
- Grove Foundation
- Association for the Cure of Cancer of the Prostate
- American Foundation for Urologic Disease
- Bob Champion Cancer Trust
- Research Foundation - Flanders (FWO) [FWO-G.0687.12]
- Cancer Research UK [15007, 17528] Funding Source: researchfish
- The Francis Crick Institute [10202] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20406] Funding Source: researchfish
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subdones within a single primary tumour(1-4). This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths(5). However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported(6-8), recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subdonee(9,10). Here we sought definitive evidence for the existence of polydonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgendeprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subdonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
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