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  • Oncogenomics
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Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15

Oncogene volume 22, pages 1737–1746 (2003)Cite this article

Abstract

Normal human keratinocytes possess a finite replicative lifespan. Most advanced squamous cell carcinomas (SCCs), however, are immortal, a phenotype that is associated with p53 and INK4A dysfunction, high levels of telomerase and loss of heterozygosity (LOH) at several genetic loci, suggestive of the dysfunction of other mortality genes. We show here that human chromosome 6 specifically reduces the proliferation or viability of a human SCC line, BICR31, possessing LOH across the chromosome. This was determined by an 88% reduction in colony yield (P<0.001), following the reintroduction of an intact normal chromosome 6 by monochromosome transfer. Deletion analysis of immortal segregants using polymorphic markers revealed the loss of a 2.9 Mbp interval, centred on marker D6S1045 at 6q14.3–q15, in 6/19 segregants. Crucially, allelic losses of this region were not identified in control hybrids constructed between chromosome 6 and the BICR6 SCC cell line that is heterozygous for chromosome 6 and which showed no reduction in colony formation relative to the control chromosome transfers. This indicates that the minimally deleted region at D6S1045 is not the result of fragile sites, a recombination hot spot, or a feature of the monochromosome transfer technique. LOH of D6S1045 was found in 2/9 immortal SCC lines and was part of a minimally deleted region of line BICR19. Furthermore, allelic imbalance, consistent with LOH, was detected in 3/17 advanced SCCs of the tongue. These results suggest the existence of a suppressor of SCC immortality and tumour development at chromosome 6q14.3–q15, which is important to a subset of human SCCs.

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Abbreviations

MMCT:

Microcell-mediated monochromosome transfer

LOH:

loss of heterozygosity

SCC:

squamous cell carcinoma

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Acknowledgements

We thank Dr Andrew Mungall of The Sanger Centre, Wellcome Trust Genome Campus, Cambridgeshire, UK for helpful discussions regarding the sequencing of human chromosome 6 and provision of both PAC and BAC clones across our regions of interest. In addition, we thank Professor John Wyke for critical review of the article and the Association for International Cancer Research for the financial support of the work.

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Authors and Affiliations

  1. Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Rd., Bearsden, Glasgow, G61 1BD, UK

    S A Fitzsimmons, H Ireland, N I Barr & E K Parkinson

  2. The Department of Biology and Biochemistry, Brunel University, Uxbridge, Middlesex, UBS 3PH, UK

    A P Cuthbert & R F Newbold

  3. Glasgow University Department of Pathology, Glasgow Royal Infirmary, Castle Street, Glasgow, G4 OSF, UK

    J J Going

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  1. S A Fitzsimmons
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  2. H Ireland
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  3. N I Barr
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Correspondence to E K Parkinson.

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Supported by a grant to SAF and EKP from the Association for International Cancer Research, HI was supported by Glasgow University, NIB was supported by a grant to EKP from the Association for International Cancer Research, RFN and ACP by the Cancer Research UK.

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Fitzsimmons, S., Ireland, H., Barr, N. et al. Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15. Oncogene 22, 1737–1746 (2003). https://doi.org/10.1038/sj.onc.1206295

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