PubMed · 3545274
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A Jacobs. 1987. Human preleukaemia: do we have a model?. https://doi.org/10.1038/bjc.1987.1
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BACKGROUND: Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes. METHODS: We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients' primary and metastatic tissues, blood, and bone marrow. Single cells were screened for mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations. RESULTS: Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture. CONCLUSIONS: Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary case showing that CTCs from any single blood draw do not always reflect metastatic genotype, and that CTC and DTC analyses may provide independent clinical information. Isolated DTCs remain viable and can be propagated in culture while maintaining their original mutational status, potentially serving as a future resource for investigating new drug therapies.
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Myelodysplastic syndromes (MDS) are a group of relatively ill-defined hematopoietic disorders in which both qualitative and quantitative defects of the hematopoietic cells cause bone marrow dysfunction. With an incidence estimated to be approximately 1 per 100,000 persons per year, MDS mainly affects the elderly. Myelodysplastic syndromes share many features with acute nonlymphocytic leukemia; in fact, a proportion of patients with MDS eventually develop acute myeloid leukemia. To illustrate a multimodal approach in the diagnosis of patients with hematopoietic disorders, we describe a 66-year-old patient with a question of myelodysplastic syndrome, leukemia, and two translocations involving chromosome 10:t(5;10) and t(7;10). These structural rearrangements effectively gave rise to monosomy for part of the long arm of chromosome 5 and for the long arm of chromosome 7. Findings of del(5q) and del(7) in MDS have been reported in the literature. The results of chromosome morphometry, which was conducted to compare the lengths of all relevant chromosome segments, are consistent with the hypothesized chromosomal abnormalities. The investigational technique of fluorescence in situ hybridization (FISH), using both painting and alpha-satellite probes, was used as an adjunct to conventional cytogenetics to further delineate the nature of the chromosome abnormalities observed in the GTG-banded studies. Confirmatory studies utilizing the new technique of spectral karyotyping (SKY) were also carried out. Thus, the multimodal approach of hematopathology, GTG-banding, chromosome morphometry, FISH, and SKY can be very useful for delineating complex cytogenetic cases.