Nature Genetics
24, 300 - 303 (2000)
doi:10.1038/73536
Mutations truncating the EP300 acetylase in human cancersSimon A. Gayther1, 3, Sarah J. Batley1, 4, Lori Linger1, 3, Andy Bannister2, 5, Karen Thorpe1, 3, Suet-Feung Chin1, 4, Yataro Daigo1, 4, Paul Russell1, 3, Annie Wilson6, Heidi M. Sowter7, Joy D.A. Delhanty8, Bruce A.J. Ponder1, 3, 4, Tony Kouzarides2, 5
& Carlos Caldas1, 41
Departments of Oncology, University of Cambridge,
Cambridge, UK. 2
Department of Pathology, University of Cambridge,
Cambridge, UK. 3
Department of Strangeways Research Laboratories, University
of Cambridge, Cambridge, UK. 4
Department of Cambridge Institute for Medical Research/The
Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, University
of Cambridge, Cambridge, UK. 5
Wellcome/CRC Institute, University of Cambridge,
Cambridge, UK. 6
Oncology Research Laboratory, Derby City General Hospital
, Derby, UK. 7
Cambridge University Department of Obstetrics and Gynaecology,
The Rosie Hospital, Cambridge, UK. 8
Department of Obstetrics and Gynaecology, University
College, London Medical School, London, UK.
Correspondence should be addressed to Carlos Caldas cc234@cam.ac.ukThe EP300 protein is a histone acetyltransferase1,
2 that
regulates transcription via chromatin remodelling3 and is important
in the processes of cell proliferation4 and differentiation5. EP300 acetylation of TP53 in response to DNA damage regulates its
DNA-binding and transcription functions6,
7,
8,
9. A role for
EP300 in cancer has been implied by the fact that it is targeted by viral
oncoproteins, it is fused to MLL in leukaemia and two missense sequence alterations
in EP300 were identified in epithelial malignancies10,
11,
12,
13.
Nevertheless, direct demonstration of the role of EP300 in tumorigenesis by
inactivating mutations in human cancers has been lacking. Here we describe
EP300 mutations, which predict a truncated protein, in 6 (3%) of 193 epithelial
cancers analysed. Of these six mutations, two were in primary tumours (a colorectal
cancer and a breast cancer) and four were in cancer cell lines (colorectal,
breast and pancreatic). In addition, we identified a somatic in-frame insertion
in a primary breast cancer and missense alterations in a primary colorectal
cancer and two cell lines (breast and pancreatic). Inactivation of the second
allele was demonstrated in five of six cases with truncating mutations and
in two other cases. Our data show that EP300 is mutated in epithelial
cancers and provide the first evidence that it behaves as a classical tumour-suppressor
gene.
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