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Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines

Oncogene volume 23, pages 9090–9101 (2004)Cite this article

Abstract

Chromosomal aberrations are common in cancers. However, the search for chromosomal aberrations leading to development of specific solid tumors has been severely hindered because the majority of solid tumors have complex chromosomal aberrations that differ within the same tumor types. A similar phenomenon exists in immortalized cell lines. The underlying mechanisms driving these diverse aberrations are largely unknown. Telomeres play crucial roles in protecting the integrity of eucaryotic chromosomes and maintaining genomic stability of human cells. Telomere lengths on individual chromosomes in normal human somatic cells are heterogeneous and undergo progressive shortening with aging process. In this study, for the first time, a molecular cytogenetic method using sequential telomere quantitative fluorescence in situ hybridization and spectral karyotyping on the same human metaphases was applied successfully to examine the dynamic profiles of individual telomere shortening and their relationship to chromosome aberrations in multiple human cell lines undergoing immortalization. Human ovarian surface epithelial cells and esophageal epithelial cells were immortalized by the expression of HPV16 E6 and E7, which drive cells to proliferate by inactivating p53 and Rb genes. In these cell lines, we consistently detected large-scale differences in telomere signal intensities not only among nonhomologous chromosome arms but also between some homologous chromosome arms. The cell lines derived from different donors had different profiles of critically short telomeres (lacking telomere signals). Strikingly, the different profiles of chromosomal structural aberrations in multiple immortalized cell lines were highly significantly associated with the distinct distributions of critically short telomeres in whole-genome. Since cellular immortalization is one of the hallmarks of cancer, our findings suggest that distinct profiles of critically short telomeres in different human individuals might play an essential role in determining the complex and individual-specific chromosomal structural aberrations in human solid tumors.

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Acknowledgements

We thank Drs PM Lansdorp and SSS Poon (BC Cancer Research Center, Canada) for the Q-FISH software (TFL-TELO); the Department of Pediatrics & Adolescent Medicine, University of Hong Kong, for use of SKY facilities; J Cheung, A Li, T Chan and B Lau for technical assistance. This study was supported by a grant from the Research Grants Council of Hong Kong Special Administrative Region, China (Project No. HKU 7385/03M) and a research grant from the University of Hong Kong CRCG (No. 10204355/07419/20200/323/01).

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Authors and Affiliations

  1. Department of Anatomy, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China

    Wen Deng, Sai Wah Tsao, Hua Xin Si & Annie L M Cheung

  2. Department of Clinical Oncology, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong, SAR, China

    Xin-Yuan Guan

  3. Lawrence Livermore National Laboratory, University of California, Livermore, 94550, CA, USA

    Joe N Lucas

  4. Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong, SAR, China

    Chi Shing Leung & Priscilla Mak

  5. Laboratory for Cancer Research, Experimental Center for Medicine, Henan Medical University, Zhengzhou, Henan Province, China

    Li Dong Wang

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  1. Wen Deng
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Correspondence to Annie L M Cheung.

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Deng, W., Tsao, S., Guan, XY. et al. Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines. Oncogene 23, 9090–9101 (2004). https://doi.org/10.1038/sj.onc.1208119

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