Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3 (original) (raw)

Nature Genetics volume 25, pages 315–319 (2000)Cite this article

Abstract

Allelic loss at the short arm of chromosome 3 is one of the most common and earliest events in the pathogenesis of lung cancer, and is observed in more than 90% of small-cell lung cancers (SCLCs) and in 50–80% of non-small-cell lung cancers1,2 (NSCLCs). Frequent and early loss of heterozygosity and the presence of homozygous deletions suggested a critical role of the region 3p21.3 in tumorigenesis2,3,4 and a region of common homozygous deletion in 3p21.3 was narrowed to 120 kb (ref. 5). Several putative tumour-suppressor genes located at 3p21 have been characterized, but none of these genes appear to be altered in lung cancer. Here we describe the cloning and characterization of a human RAS effector homologue (RASSF1) located in the 120-kb region of minimal homozygous deletion. We identified three transcripts, A, B and C, derived from alternative splicing and promoter usage. The major transcripts A and C were expressed in all normal tissues. Transcript A was missing in all SCLC cell lines analysed and in several other cancer cell lines. Loss of expression was correlated with methylation of the CpG-island promoter sequence of RASSF1A. The promoter was highly methylated in 24 of 60 (40%) primary lung tumours, and 4 of 41 tumours analysed carried missense mutations. Re-expression of transcript A in lung carcinoma cells reduced colony formation, suppressed anchorage-independent growth and inhibited tumour formation in nude mice. These characteristics indicate a potential role for RASSF1A as a lung tumour suppressor gene.

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Acknowledgements

We thank C.A. Tessler for technical support. This work was supported by a grant from the University of California Tobacco Related Disease Research Program (6RT-0361 to G.P.P.).

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Authors and Affiliations

  1. Department of Biology, Beckman Research Institute, City of Hope Medical Center, Duarte, California, USA
    Reinhard Dammann, Chun Li, Jung-Hoon Yoon, Philip L. Chin, Steven Bates & Gerd P. Pfeifer

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  1. Reinhard Dammann
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  2. Chun Li
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  3. Jung-Hoon Yoon
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  4. Philip L. Chin
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  5. Steven Bates
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  6. Gerd P. Pfeifer
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Correspondence toGerd P. Pfeifer.

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Dammann, R., Li, C., Yoon, JH. et al. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3.Nat Genet 25, 315–319 (2000). https://doi.org/10.1038/77083

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