Down-regulation of BRCA1 in chronic pancreatitis and sporadic pancreatic adenocarcinoma.
OBJECTIVE
BRCA1 and BRCA2 are considered to be breast cancer susceptibility genes that may also contribute to pancreatic cancer development because family studies revealed mutation carriers to have an increased risk of developing pancreatic cancer. However, as demonstrated for breast and ovarian cancer, inactivation of BRCA in sporadic diseases is based on alteration in gene expression or functional alteration.


METHODS
To study a potential correlation of BRCA1 and BRCA2 to chronic pancreatitis and development of sporadic pancreatic adenocarcinoma, we have analyzed the expression of these genes by quantitative PCR and performed immunohistochemical analyses in normal pancreatic tissues, chronic pancreatitis, and pancreatic cancer specimens.


RESULTS
BRCA1 expression was down-regulated in chronic alcoholic pancreatitis, in particular on the RNA level. Furthermore, our data indicate suppressed BRCA1 expression in pancreatic cancer on both the RNA and protein levels. Quantitative analysis of BRCA1 protein expression demonstrated regular staining in 50% of tumor specimens tested and reduced staining in 50% of tumor specimens tested. Correlation with the clinical outcome revealed a significantly better 1-year overall survival for patients with BRCA1-regular as compared with BRCA1-reduced or BRCA1-absent tumors. In contrast, no substantial differences in BRCA2 expression were found in chronic pancreatitis and pancreatic cancer samples.


CONCLUSIONS
Our data demonstrate alteration of BRCA1 expression in chronic pancreatitis and sporadic pancreatic adenocarcinoma. We, for the first time, provide evidence for a role of BRCA1 in pancreatic carcinogenesis of noninherited tumors and for clinical outcome.
Beger
Carmela
C
Department of Pediatric Hematology, Hannover Medical School, Hannover, Germany. Beger.Carmela@mh-hannover.de
Ramadani
Marco
M
Meyer
Stephan
S
Leder
Gerd
G
Krüger
Martin
M
Welte
Karl
K
Gansauge
Frank
F
Beger
Hans G
HG
D000230:Adenocarcinoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000096:biosynthesis*; D024682:BRCA2 Protein / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D013997:Time Factors; D016896:Treatment Outcome
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D012313:RNA