title: Identification of genomic signatures in circulating tumor cells from breast cancer.
abstract: 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, TGFβ-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.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.|The Campbell Family Institute for Breast Cancer Research at the Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Nisha
authors.initials: N
authors.lastname: Kanwar
authors.affiliation: Department of Biochemistry and Medical Genetics, George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Canada.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bedard
authors.affiliation: Division of Medical Oncology, The Ottawa Hospital Cancer Center, Ottawa, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.affiliation: Division of General Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.
authors.forename: David
authors.initials: D
authors.lastname: McCready
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.|The Campbell Family Institute for Breast Cancer Research at the Princess Margaret Cancer Centre, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Laboratory Medicine Program, University Health Network, Toronto, Canada.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Done
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D005260:Female; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D059010:Single-Cell Analysis / Q000379:methods*
keywords: breast cancer; circulating tumor cells (CTCs); genome profiling; metastasis