Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.
Although the association of germline BRCA2 mutations with pancreatic adenocarcinoma is well established, the role of BRCA1 mutations is less clear. We hypothesized that the loss of heterozygosity at the BRCA1 locus occurs in pancreatic cancers of germline BRCA1 mutation carriers, acting as a "second-hit" event contributing to pancreatic tumorigenesis. Seven germline BRCA1 mutation carriers with pancreatic adenocarcinoma and nine patients with sporadic pancreatic cancer were identified from clinic- and population-based registries. DNA was extracted from paraffin-embedded tumor and nontumor samples. Three polymorphic microsatellite markers for the BRCA1 gene, and an internal control marker on chromosome 16p, were selected to test for the loss of heterozygosity. Tumor DNA demonstrating loss of heterozygosity in BRCA1 mutation carriers was sequenced to identify the retained allele. The loss of heterozygosity rate for the control marker was 20%, an expected baseline frequency. Loss of heterozygosity at the BRCA1 locus was 5/7 (71%) in BRCA1 mutation carriers; tumor DNA was available for sequencing in 4/5 cases, and three demonstrated loss of the wild-type allele. Only 1/9 (11%) sporadic cases demonstrated loss of heterozygosity at the BRCA1 locus. Loss of heterozygosity occurs frequently in pancreatic cancers of germline BRCA1 mutation carriers, with loss of the wild-type allele, and infrequently in sporadic cancer cases. Therefore, BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and individuals with these mutations may be considered for pancreatic cancer-screening programs.
Al-Sukhni
Wigdan
W
Gallinger Lab, Samuel Lunenfeld Research Institute, 60 Murray Street, Toronto, ON, M5G1X5, Canada. wigdan.al.sukhni@utoronto.ca
Rothenmund
Heidi
H
Borgida
Ayelet Eppel
AE
Zogopoulos
George
G
O'Shea
Anne-Marie
AM
Pollett
Aaron
A
Gallinger
Steven
S