1: Breast Cancer Res. 2004;6(4):R366-71. Epub 2004 May 14. 

No germline mutations in the histone acetyltransferase gene EP300 in BRCA1 and
BRCA2 negative families with breast cancer and gastric, pancreatic, or
colorectal cancer.

Campbell IG, Choong D, Chenevix-Trench G; Kathleen Cuningham Foundation
Consortium for Research into Familial Breast Cancer.

Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory, Peter
MacCallum Cancer Centre, Victoria, Australia. ian.campbell@petermac.org

INTRODUCTION: Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for
many, but not all, multiple-case breast and ovarian cancer families. The histone
acetyltransferase gene EP300 may function as a tumour suppressor gene because it
is sometimes somatically mutated in breast, colorectal, gastric and pancreatic
cancers, and is located on a region of chromosome 22 that frequently undergoes
loss of heterozygosity in many cancer types. We hypothesized that germline
mutations in EP300 may account for some breast cancer families that include
cases of gastric, pancreatic and/or colorectal cancer. METHODS: We screened the
entire coding region of EP300 for mutations in the youngest affected members of
23 non-BRCA1/BRCA2 breast cancer families with at least one confirmed case of
gastric, pancreatic and/or colorectal cancer. These families were ascertained in
Australia through the Kathleen Cuningham Foundation Consortium for Research into
Familial Breast Cancer. RESULTS: Denaturing HPLC analysis identified a
heterozygous alteration at codon 211, specifically a GGC to AGC (glycine to
serine) alteration, in two individuals. This conservative amino acid change was
not within any known functional domains of EP300. The frequency of the Ser211
variant did not differ significantly between a series of 352 breast cancer
patients (4.0%) and 254 control individuals (2.8%; P = 0.5). CONCLUSION: The
present study does not support a major role for EP300 mutations in breast and
ovarian cancer families with a history of gastric, pancreatic and/or colorectal
cancer.

PMID: 15217503 [PubMed - indexed for MEDLINE]


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2: Nat Genet. 2000 Mar;24(3):300-3. 

Mutations truncating the EP300 acetylase in human cancers.

Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF, Daigo Y,
Russell P, Wilson A, Sowter HM, Delhanty JD, Ponder BA, Kouzarides T, Caldas C.

Department of Oncology, University of Cambridge, Cambridge, UK.

The EP300 protein is a histone acetyltransferase that regulates transcription
via chromatin remodelling and is important in the processes of cell
proliferation and differentiation. EP300 acetylation of TP53 in response to DNA
damage regulates its DNA-binding and transcription functions. 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 malignancies. 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.

PMID: 10700188 [PubMed - indexed for MEDLINE]


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