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Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information

Oncogene volume 18, pages 5423–5434 (1999)Cite this article

Abstract

Inherited mutations in the CDKN2A/INK4a/MTS1 tumour suppressor gene on chromosome 9p21 are associated with familial predisposition to melanoma and other tumour types. Nonsense and missense mutations are also found in a variety of sporadic cancers, and over 140 sequence variants have already been recorded in the literature. In assessing the relevance of these variants and for counselling members of affected families, it is important to distinguish inactivating mutations from harmless polymorphisms. Existing functional assays have frequently reached conflicting conclusions and no single test appears adequate. Here we evaluate a number of alternatives including a novel assay based on retroviral delivery of p16INK4a cDNAs into human diploid fibroblasts. Among the 17 sequence variants analysed, three distinct categories can be distinguished: those that abrogate the binding of p16INK4a to CDK4 and CDK6, those that alter the properties of the protein without preventing it from interacting with CDKs, and those that have no discernible effect on protein function. These distinctions can be rationalized by considering the impact of the amino acid changes on the three-dimensional structure of the protein.

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Acknowledgements

We are grateful to Ronen Marmorstein and Ernest Laue for supplying crystallographic coordinates and thank Anna-Marie Frischauf and Malcolm Parker for comments on the manuscript. Margarida Ruas is supported by a Praxis XXI fellowship from Fundação para a Ciência e Tecnologia.

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  1. Imperial Cancer Research Fund, PO Box 123, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Margarida Ruas, Sharon Brookes, Neil Q McDonald & Gordon Peters

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Ruas, M., Brookes, S., McDonald, N. et al. Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information. Oncogene 18, 5423–5434 (1999). https://doi.org/10.1038/sj.onc.1202918

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