Concomitant inactivation of p53 and Chk2 in breast cancer.
The structure and expression of the human Rad53 homologue Chk2 was analysed in breast cancer. The previously described silent polymorphism at nucleotide 252 in codon 84 (GAA>GAG) was observed in 5/141 cases. Somatic Chk2 coding mutations were detected in 7/141 cases, these occurring in 4/18 BRCA1-associated breast cancers, 1/78 sporadic breast cancers and 2/25 typical medullary carcinomas. Each of the BRCA1-associated cancers with Chk2 mutations also contained mutations in p53, whereas the single sporadic cancer with Chk2 mutation was wild-type for p53. Expression of Chk2 was ubiquitously detected in normal ductal epithelium of the breast, but there was loss of expression in a significant proportion of breast carcinomas, and this occurred in cancers both with and without p53 mutation. A CpG island was identified 5' of the Chk2 transcriptional start site, but there was no evidence of cytosine methylation in any of the cancers with down-regulated Chk2 expression. Analysis of the germ-line of 45 individuals with hereditary or early onset breast cancer revealed wild-type Chk2 sequence in all cases. Thus, despite the rarity of somatic mutations in Chk2 in sporadic breast carcinomas, our results nevertheless reveal that concomitant loss of function in Chk2 (via down-regulation of expression) and p53 (via mutation) occurs in a proportion of sporadic cases. However, consistent with other studies, we show that germ-line mutations in Chk2 are unlikely to account for a significant proportion of non BRCA1-, non BRCA2-associated hereditary breast cancers.
Sullivan
Alexandra
A
Ludwig Institute for Cancer Research, Imperial College Faculty of Medicine, St Mary's Campus, Norfolk Place, London W2 1PG, UK.
Yuille
Martin
M
Repellin
Claire
C
Reddy
Archana
A
Reelfs
Olivier
O
Bell
Alexandra
A
Dunne
Barbara
B
Gusterson
Barry A
BA
Osin
Peter
P
Farrell
Paul J
PJ
Yulug
Isik
I
Evans
Abigail
A
Ozcelik
Tayfun
T
Gasco
Milena
M
Crook
Tim
T
D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D064447:Checkpoint Kinase 2; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53 / Q000235:genetics*; D005854:Germ Cells; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases