Unexpectedly, these drugs did not suppress the growth of BRCA2-deficient pancreatic cancer cell lines from humans or gene-targeted mice expressing active Kras and trans-dominant inhibitory mutant Trp53.
PALB2 is a breast and pancreas cancer susceptibility gene whose protein is closely associated with BRCA2 and is essential for BRCA2 anchorage to nuclear structures.
We used nine human cell lines, four with nonmutated BRCA1/2 (MCF7, MDA-MB-231, and HCC1937-BRCA1 [breast cancer] and OSEC-2 [ovarian surface epithelial]), two with mutated BRCA1 (MDA-MB-436 and HCC1937 [breast cancer]), one with mutated BRCA2 (CAPAN-1 [pancreatic cancer]), one that was heterozygous for BRCA2 (OSEC-1 [ovarian surface epithelial]), and one with epigenetically silenced BRCA1 (UACC3199 [breast cancer]), and two Chinese hamster ovary cell lines, parental AA8 and XRCC3 mutated IRS 1SF.
Previous small scale studies reported that deleterious BRCA2 and CDKN2a germline mutations contribute to a subset of families with inherited pancreatic cancer.
The screening protocol includes genetic counselling, transcutaneous abdominal ultrasound, magnetic resonance imaging, and blood collection and eligible participants included individuals with a family history of pancreatic cancer or BRCA2 mutation carriers.
Most of the genes listed are responsible for various well-defined cancer syndromes, such as CDKN2A (familial atypical mole-multiple melanoma, FAMMM), the mismatch repair genes (Lynch Syndrome), TP53 (Li-Fraumeni syndrome), APC (familial adenomatous polyposis), and BRCA2 (breast-ovarian familial cancer), where PC is part of the cancer spectrum of the disease.
Additionally, mean ages of diagnosis of pancreatic cancer in BRCA1/2 families differ significantly from the SEER mean (P = 0.0014 for BRCA1 and P = 0.011 for BRCA2 by unpaired t-test).
Our case is the first clinical piece of evidence that demonstrates an increased sensitivity to camptothecin-11 and a reduced topoisomerase I relaxation activity in BRCA2 associated pancreatic cancer.
Mutations responsible for familial predisposition are mostly unknown, although BRCA2 mutations have been identified in some families and a mutation in the palladin gene has been shown to segregate with pancreatic cancer in one kindred.
Individuals with a high-risk genetic background require counseling, genetic testing if appropriate (BRCA2 mutation or p16INK4A inactivity) and secondary screening for pancreatic cancer in specialist centers.
A number of the genes responsible for the aggregation of pancreatic cancer in families have been discovered, including BRCA2, p16/CDKN2A, STK11 and PRSS1.
The discovery of genetic factors of which the presence predisposes pancreatic cancer to successful targeting, such as the association of BRCA2/Fanconi anemia genes defects and sensitivity to mitomycin C, will eventually lead to a more individualized treatment approach.
Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder.
In addition, germ line mutations in the BRCA2/FANCD1 Fanconi anemia complementation group gene have also been implicated in predisposition to a number of cancers including pancreatic cancer.