期刊
INTERNATIONAL JOURNAL OF CANCER
卷 137, 期 2, 页码 332-344出版社
WILEY
DOI: 10.1002/ijc.29399
关键词
circulating tumor cells (CTCs); breast cancer; metastasis; genome profiling
类别
资金
- Canadian Breast Cancer Foundation, Ontario
- Canadian Institute for Health Research [MOP-119469]
Levels of circulating tumor cells (CTCs) in blood have prognostic value in early and metastatic breast cancer. CTCs also show varying degrees of concordance with molecular markers of primary tumors they originate from. It is expected that individual cells reflect the heterogeneity and evolution of tumor cells as they acquire new functions and differential responses to chemotherapy. However, a degree of commonality is also plausible, highlighting alterations that allow tumor cells to perform CTC-defining activities such as invasion and intravasation. Using a matched tumor-normal approach, we performed high-resolution copy number profiling of CTCs from breast cancer to identify occult changes occurring during progression to metastasis. We identified a signature of recurrent gain in CTCs, consisting of 90 minimal common regions (MCRs) of copy number gain. These were predominantly found across chromosome 19 and were identified at low frequencies (3-4%) in 787 primary breast carcinomas examined. CTC genomic signatures clustered into two groups independent of subtype: a dormancy-related signature with 16 MCRs (AKT2, PTEN, CADM2); and a tumor-aggressiveness related signature with 358 MCRs (ANGPTL4, BSG, MIR-373). There were two MCRs in common between the groups on 19q13 and 21q21, containing genes involved in resistance to anoikis, TGF-signaling and metastasis (TFF3, LTBP4, NUMBL). Furthermore, a region harboring the ERBB2 gene was gained in a majority of patients. Regions 20q13 and 15q24 were associated with distant metastasis. The distinctiveness of CTC signatures highlights cell populations with different functional or metastatic potential. Such novel targets could help to specifically identify and block dissemination. What's new? People die of breast cancer not from the primary tumors, but because of uncontrolled metastasis, and circulating tumor cells (CTCs) could be the key to detecting it. In this paper, the authors examined the DNA of CTCs looking for identifying features that could help spot these harbingers of metastasis. They found certain copy number changes, predominantly on chromosome 19 that may indicate the cell's ability to travel. The changes fell into two categories: one associated with dormancy, the other with tumor aggressiveness. Detection of these genetic signatures could help target the most mobile cells and thwart metastasis.
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