title: Molecular profiling of tumor cells in cerebrospinal fluid and matched primary tumors from metastatic breast cancer patients with leptomeningeal carcinomatosis.
abstract: Although leptomeningeal carcinomatosis is a well-established clinical syndrome, virtually nothing is known about the tumor cells responsible for this particularly aggressive metastatic process. To isolate cerebrospinal fluid-derived tumor cells (CSFTC) from 15 patients with metastatic breast cancer diagnosed with leptomeningeal carcinomatosis, CSF samples were subjected to a two-step method involving immunomagnetic enrichment and fluorescence-activated cell sorting (IE/FACS), a technique previously used for isolating circulating tumor cells (CTC) from blood. CSFTCs were subjected to genome-wide copy number analysis by array comparative genomic hybridization. Genomic profiling was successfully performed for 13 of 15 patients (87%). Copy number analysis in CSFTCs revealed genomic alterations commonly observed in primary breast cancer and CTCs, indicating their malignant origin. Interestingly, 12 (92%) harbored high-level gains on the 8q24 locus, which includes the MYC oncogene. Comparison of CSFTCs against corresponding archival primary tumors in six patients revealed clonal relationships with some divergence. Good concordance among serial samples attested to the reproducibility of the assay. Our approach for isolation and molecular analysis of CSFTCs yielded new insights into the molecular nature of these cells. Further genomic and functional analyses may help elucidate mechanisms by which tumor cells metastasize to the central nervous system.
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology; Helen Diller Family Comprehensive Cancer Center; and Helen Diller Family Comprehensive Cancer Center Computational Biology Core, University of California San Francisco, San Francisco, California.
authors.forename: Mark Jesus M
authors.initials: MJ
authors.lastname: Magbanua
authors.forename: Michelle
authors.initials: M
authors.lastname: Melisko
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.forename: Eduardo V
authors.initials: EV
authors.lastname: Sosa
authors.forename: Louai
authors.initials: L
authors.lastname: Hauranieh
authors.forename: Andrea
authors.initials: A
authors.lastname: Kablanian
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Eisenbud
authors.forename: Artem
authors.initials: A
authors.lastname: Ryazantsev
authors.forename: Alfred
authors.initials: A
authors.lastname: Au
authors.forename: Janet H
authors.initials: JH
authors.lastname: Scott
authors.forename: John W
authors.initials: JW
authors.lastname: Park
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D055028:Comparative Genomic Hybridization; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D055756:Meningeal Carcinomatosis / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000556:secondary; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor