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Emergence of Non-Random Chromosomal Alterations (Trisomy 7 and 20) Derived from Diploid Human Colonic Epithelial Cells

ABSTRACT: Aneuploidy from chromosomal instability is frequently detected in the vast majority of sporadic colorectal cancer patients 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. We have isolated and immortalized non-transformed human colonic epithelial cells (HCECs) from non-cancerous biopsy tissue from a previous CRC patient undergoing routine colonoscopy. While these cells maintain a diploid karyotype under 2% serum conditions, we have isolated derivatives in serum-free culture with an extra copy of chromosome 7 (+7), a non-random trisomy detected in over 40% of human colorectal adenomas and carcinomas. We report here that +7 HCECs were not detectable in the initial cell population and appeared from an originally diploid population under serum-free culture conditions. The emergence of +7 cells correlates with a slight growth advantage that may be attributed to aberrant regulation of the epidermal growth factor receptor. We also provide evidence that +7 HCECs have defects in cell migration. A subpopulation with trisomy 20, another non-random chromosomal alteration in CRC, emerged following stable knockdown of TP53 and expression of oncogenic K-RASV12 in +7 HCECs. We describe isogenic HCECs that represent non-random cytogenetic changes occurring in sporadic colorectal cancer progression. These unique cellular reagents may serve as useful in vitro models for studying chromosomal instability-mediated tumorigenesis and the discovery of novel chemopreventive strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24092 | GEO | 2010/09/14

SECONDARY ACCESSION(S): PRJNA130223

REPOSITORIES: GEO

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Project description:Human pluripotent stem cells (hPSCs) tend to acquire genomic aberrations in culture, the most common of which is the trisomy of chromosome 12. Interestingly, trisomy 12 is also prevalent in germ cell tumors (GCTs). Here, we aimed to dissect the cellular and molecular implications of trisomy 12 in hPSCs. A genome-wide gene expression analysis revealed that trisomy 12 profoundly affects the global gene expression profile of hPSCs, inducing a transcriptional program very similar to that of CGTs. Direct comparison of the proliferation, replication, differentiation and apoptosis between diploid and aneuploid hPSCs revealed that trisomy 12 significantly increases the proliferation rate of hPSCs. Increased replication largely accounts for the increased proliferation observed, and may explain the selection advantage that trisomy 12 confers to hPSCs. A comparison of the tumors induced by diploid and aneuploid hPSCs further demonstrated that trisomy 12 increases the tumorigenicity of hPSCs, inducing transcriptionally-distinct teratomas, from which pluripotent cells can be recovered. Lastly, a chemical screen of 89 anticancer drugs against diploid and aneuploid hPSCs discovered that trisomy 12 raises the sensitivity of hPSCs to several replication inhibitors, suggesting that the increased proliferation and tumorigenicity of these aberrant cells also makes them more vulnerable, and might potentially be used for their selective elimination from culture. Together, our findings demonstrate the extensive effect of trisomy 12 on the gene expression signature and on the cellular behavior of hPSCs, and highlight the danger posed by this trisomy for the successful use of hPSCs in basic research and in regenerative medicine. Expression data from diploid and aneuoploid human pluripotent stem cells, teratomas derived from them, and pluripotent-like cells recovered from these teratomas total RNA was isolated from undifferentiated human pluripotent stem cells grown under standard human ES conditions, or from teratomas derived from them, or from ES-like cells recovered from these teratomas.

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Emergence of Non-Random Chromosomal Alterations (Trisomy 7 and 20) Derived from Diploid Human Colonic Epithelial Cells

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