Mutations of the BRAF gene in human cancer

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Abstract

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS–RAF–MEK–ERK–MAP kinase pathway mediates cellular responses to growth signals1. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS1,2,3. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

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Figure 1: Mutations in the BRAF gene.
Figure 2: Sequence conservation and mutations in the BRAF activation segment and G loop.
Figure 3: BRAF and ERK activation.

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Acknowledgements

We would like to thank all the patients who donated samples for these studies, the UK Children's Cancer Study Group for provision of paediatric primary tumour samples, the NCCGP for provision of cord blood control DNA samples, and W. Haynes for assistance with preparation of the manuscript. We would also like to acknowledge the Wellcome Trust, Institute of Cancer Research and Cancer Research UK for support. C.J.M. is a Gibb life fellow of the Cancer Research UK. G.P. and A.C. are funded in part by Regione Autonoma della Sardegna. B.A.G. is supported by Breakthrough Breast Cancer.

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Correspondence to Richard Wooster.

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The authors declare that they have no competing financial interests.

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