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A mutation hotspot at the p14ARF splice site

Oncogene volume 24, pages 4604–4608 (2005)Cite this article

Abstract

Germline mutations of CDKN2A that affect the p16INK4a transcript have been identified in numerous melanoma pedigrees worldwide. In the UK, over 50% of pedigrees with three or more cases of melanoma have been found to carry mutations of CDKN2A. Mutations that affect p14ARF exon 1β exclusively are very rare. This has led to the suggestion that it is p16INK4a and not p14ARF that plays the critical role in melanoma predisposition. We report the identification of a cluster of five different germline mutations at the p14ARF exon 1β splice donor site in melanoma pedigrees. All the five splice site variants showed evidence of being causal mutations. Three of the variants were demonstrated to result in aberrant splicing of the p14ARF mRNA, confirming their role in melanoma predisposition. No other point mutations were identified in the coding region of p14ARF. The p14ARF transcript of CDKN2A is clearly important in disease predisposition in a subset of melanoma pedigrees. Curiously, the only mutations so far reported to affect p14ARF exon 1β exclusively have been knockout mutations. Further investigation into the spectrum of mutations observed in this gene may help clarify the exact role of p14ARF in melanoma predisposition.

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Acknowledgements

We thank Linda Whitaker, Elizabeth Pinney, Veronique Bataille, Karen Griffiths, JM (Bee) Squire, Patricia Mack and Rachel Wachsmuth, who were involved in interviewing patients in the English familial melanoma research programme since 1989. We are very grateful to the families who took part, without whose gift of time and information this research would not have taken place. We are also grateful to the Clare Hall Cell Service facility and to Sharon Jackson for providing the lymphoblastoid cell lines. This work was funded by Cancer Research UK in the United Kingdom and was supported by NIH award IR01 CA083115.

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Authors and Affiliations

  1. Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, England

    Mark Harland, Kairen Kukalizch, Juliette A Randerson-Moor, D Timothy Bishop & Julia A Newton Bishop

  2. Mutation Detection Facility, Cancer Research UK Clinical Centre, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, England

    Claire F Taylor & Philip A Chambers

  3. Department of Dermatology and Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, PB 9600, The Netherlands

    Nelleke A Gruis, Femke A de Snoo & Jeanet A C ter Huurne

  4. Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, 20892-7236, USA

    Alisa M Goldstein & Margaret A Tucker

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  1. Mark Harland
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Correspondence to Julia A Newton Bishop.

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Harland, M., Taylor, C., Chambers, P. et al. A mutation hotspot at the p14ARF splice site. Oncogene 24, 4604–4608 (2005). https://doi.org/10.1038/sj.onc.1208678

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