PubMed · 9718385
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A Morley. 1998-08-27. Quantifying leukemia.. https://doi.org/10.1056/nejm199808273390911
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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.
Hematological disorders often have complex karyotypes with multiple markers. Proper assignment of chromosome number or aberration or both can be difficult. Specific identification of chromosomal abnormalities aids in the diagnosis and selection of treatment of patients. Fluorescence in situ hybridization (FISH) has been applied to the identification of translocations, markers, and other chromosomal abnormalities in clinical cytogenetics. However, the standard FISH technique is unable to detect the entire genome in a single experiment. This report presents the use of a cross-species comparative genomic hybridization color-banding technique (RxFISH) that permits examination of an entire karyotype at one time. Specimens from two patients, one with acute lymphocytic leukemia (ALL) and the other with multiple myeloma (MM), were studied. Metaphases were prepared by standard culture techniques. Conventional cytogenetic analysis (GTG banding) showed multiple clones in each of the cases. These clones were hyperdiploid metaphases with complex chromosomal abnormalities and multiple markers. The slides were then hybridized with FITC-, Cy-3-, and Cy-5-labeled RxFISH probes; the results were analyzed by a digital imaging system. The RxFISH color banding confirmed the hyperdiploid metaphases and identified multiple chromosomal abnormalities. In the specimen from the patient with ALL, several chromosomes, which had been classified as markers by G-banding, were found to be specific chromosomes. This study suggests that RxFISH can provide more accurate and specific identification of complex chromosomal abnormalities. RxFISH is a useful complement to the clinical cytogenetic laboratory armamentarium.
Patients with myelodysplastic syndromes (MDS) have high frequencies of cytogenetic abnormalities and evidence is accumulating of associations between exposure history and primary MDS. The objective of this article is to examine the relationship between histories of occupational or environmental exposure and presence of cytogenetic abnormalities. A case control study of MDS patients estimated lifetime exposure to more than 90 potential hazards in 400 age, sex, and area of residence matched patient and control pairs. A parallel cytogenetics study undertaken at time of diagnosis, independently of any knowledge of exposure history, identified 75 cytogenetically abnormal and 139 normal (186 not studied). Odds ratios of MDS patients and their matched controls were compared for 3 groups: cytogenetically abnormal, normal, and not known. The odds ratios for all exposures combined were possibly higher among cytogenetically abnormal 2.0 (95% confidence interval 0.8-5.9) than among normal 1.0 (0.6-1.8). This pattern was observed for exposure to semimetals, abnormal 4.0 (0.4-195.1) and normal 0.5 (0.1-1.0) and inorganic dusts, 1.6 (0. 6-3.8) and 0.4 (0.1-1.4) respectively. The pattern was principally in abnormalities in chromosomes 5 and 7. For organic chemicals and radiation, the odds ratios for both cytogenetically abnormal and normal were marginally raised: organic 1.8 (0.6-6.0) and 1.3 (0.6-2.9), respectively, and radiation 1.7 (0.5-5.6) and 1.3 (0.4-4.7) respectively. For radiation, abnormalities were mostly in chromosome 8. This study of association between exposures and cytogenetics in primary MDS complements those previously reported in secondary MDS and may provide some insight into pathogenetic mechanisms that lead to development of MDS. (Blood. 2000;95:2093-2097)