Characterization of Aneuploid Populations with Trisomy 7 and 20 Derived from Diploid Human Colonic Epithelial Cells

Abstract

Chromosomal instability leading to aneuploidy occurs in most sporadic colorectal cancers (CRCs) and is believed to be an early driving force in disease progression. Despite this observation, the cellular advantages conferred by these cytogenetic alterations are poorly understood. Here, we provide evidence that serum-free passage of originally diploid, immortalized human colonic epithelial cells (HCECs) gave rise to the acquisition of trisomy 7 (+7), an aneuploidy detected in more than 40% of colorectal adenomas. These cells remain diploid under long-term growth in 2% serum conditions. Analysis by GTG banding and fluorescent in situ hybridization detected no rare preexisting +7 cell in the original population, suggesting a conversion of diploid cells to an aneuploid state. The acquisition of +7 also precedes loss or truncation of the adenomatosis polyposis coli gene as both diploid and +7 cells express full-length, functional protein. Coculturing of fluorescent-labeled cells demonstrate that +7 HCECs have a growth advantage over diploid cells in serum-free conditions. Defects in cell migration and aberrant regulation of the epidermal growth factor receptor, located on chromosome 7p, are also detected in +7 HCECs. Interestingly, knockdown of TP53 and expression of K-Ras(V12) in +7 HCECs resulted in the emergence of trisomy 20, another nonrandom aneuploidy observed in ∼85% of CRC. In summary, we describe isogenic colonic epithelial cells that represent cytogenetic changes occurring frequently in sporadic CRC. The emergence and characterization of trisomy 7 and 20 demonstrate that these HCECs may serve as unique human cell-based models to examine the effects of chromosomal instability in CRC progression.

Single-nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome

“…Under similar conditions, aneuploid cells have been shown to occur spontaneously in other human cell types, with the potential for multiple different mosaic lines to arise in consecutive cultures from the same individual. 19–21 Aneuploid cells may also have a selective growth advantage or disadvantage compared with co-cultured euploid cells from mosaic patients and may be amplified or suppressed by current culture methods. Moreover, in comparison with euploid cells, chromosomal instability appears to be more pronounced in TS patients.…”

The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis

“…One of the copies of chromosome 12 in this cell line carries a mutation in the RAS gene [45], which may provide these cells a growth advantage. A study of immortalized human colonic epithelial cells carrying an extra copy of chromosome 7 showed better growth in serum-free medium compared to the isogenic diploid cells [46]. The growth advantage of the trisomic cells was postulated to stem from overexpression of the epidermal growth factor receptor gene located on chromosome 7.…”

Rapid proliferation of daughter cells lacking particular chromosomes due to multipolar mitosis promotes clonal evolution in colorectal cancer cells

“…47 These findings have also been replicated in experiments with aneuploid cells that possess a measurable growth advantage under serum-deprived conditions in colorectal cancer cells. 48 Despite increased information about the characteristics of cellular proliferation obtained from mouse or yeast cells, the data reported thus far from human cancer-derived cells is still lacking. In our study, we demonstrate that karyotype evolution is associated with the loss of a chromosome copy (Fig.…”