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Chromosome 5p aberrations are early events in lung cancer: implication of glial cell line-derived neurotrophic factor in disease progression

Oncogene volume 24, pages 4806–4812 (2005)Cite this article

Abstract

Lung cancer is the most widely diagnosed malignancy in the world. Understanding early-stage disease will give insight into its pathogenesis. Despite the fact that pre-invasive lesions are challenging to isolate, and often yield insufficient DNA for the analysis of multiple loci, genomic profiling of such lesions will lead to the discovery of causal genetic alterations, which may be otherwise masked by the gross instability associated with tumors. In this study, we report the identification of multiple early genetic events on chromosome 5p in lung cancer progression. Using a high-resolution 5p-specific genomic array, which contains a tiling path of DNA segments for comparative genomic hybridization, nine novel minimal regions of loss and gain were discovered in bronchial carcinoma in situ (CIS) specimens. Within these regions we identified two candidate genes novel to lung cancer. The 0.27 Mbp region at 5p15.2 contains a single gene, Triple Functional Domain, which we determined to be differentially expressed in tumors. The 0.34 Mbp region at 5p13.2 contains Glial Cell Line-Derived Neurotrophic Factor (GDNF), which is a ligand for the RET oncogene product and is normally expressed during lung development (but absent in adult lung tissue). Our data showed not only that GDNF is overexpressed at the transcript level in squamous non-small-cell lung carcinoma, but also that the GDNF protein is present in early-stage lesions. Reactivation of the fetal lung expressed GDNF in early lesions and its amplification in CIS suggests an early role in tumorigenesis. These results highlight the value of examining the genomes of pre-invasive stages of cancer at tiling resolution.

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Acknowledgements

We thank Drs James Hogg and Kim Lonergan for providing tumor specimens and cDNA samples, Dr Jean LeRiche for histopathology evaluation, Chris Dawe and Arek Siwoski for microdissection, Bradley P Coe, Spencer K Watson, and Chad A Malloff for array synthesis, and Jennifer Campbell, Ni Liu, and James Ho for their technical assistance. This work was supported by funds from the National Cancer Institute of Canada (#15184 and #011436) Canadian Institute of Health Research, Genome British Columbia/Genome Canada, and scholarships to CG and JJD from the Michael Smith Foundation of Health Research and the National Science Engineering Research Council.

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  1. British Columbia Cancer Research Centre, 601 West 10th Avenue, Vancouver, V5Z 3L1, BC, Canada

    Cathie Garnis, Jonathan J Davies, Timon P H Buys, Calum MacAulay, Stephan Lam & Wan L Lam

  2. Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada

    Ming-Sound Tsao

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  1. Cathie Garnis
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Correspondence to Cathie Garnis.

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Garnis, C., Davies, J., Buys, T. et al. Chromosome 5p aberrations are early events in lung cancer: implication of glial cell line-derived neurotrophic factor in disease progression. Oncogene 24, 4806–4812 (2005). https://doi.org/10.1038/sj.onc.1208643

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