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Molecular Phenotype of Spontaneously Arising 4N (G₂-Tetraploid) Intermediates of Neoplastic Progression in Barrett’s Esophagus¹

Divisions of Human Biology [M. T. B., B. J. R., P. S. R.] and Public Health Sciences [B. J. R.], Fred Hutchinson Cancer Research Center, Seattle, Washington 98104; LifeSpan Biosciences, Seattle, Washington 98121 [D. P.]; and Departments of Medicine (Gastroenterology Division) [B. J. R.], Pathology [C. P-W., J. A., P. S. R.], and Genetics [B. J. R.], University of Washington, Seattle, Washington 98195

Elevated 4N (G₂-tetraploid) cell populations are unstable intermediates in the development of many human cancers. However, 4N cell populations are intermixed with larger diploid fractions in vivo, limiting investigation of these key intermediates of neoplastic progression. Therefore, to study elevated 4N cell populations in human neoplasia, we used flow cytometry to purify populations of spontaneously arising TP53^wt and TP53^mut 4N cells from cell strains derived from premalignant Barrett’s esophagus biopsies. Using oligonucleotide arrays, we identified 625 genes differentially expressed in at least one replicate 2N/4N comparison in each strain and in hTERT-immortalized cultures of the TP53^mut strains. Strikingly, when hierarchically clustered, these data contained a large node of 124 genes that were up-regulated in 4N TP53^mut cells in the absence of condensed chromosomes. Most of these genes function in G₂-M to mediate processes such as chromosome condensation and segregation. These results describe the molecular phenotype of dysregulated G₂-M functions and cell cycle checkpoints in a key intermediate of human neoplastic progression.

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