Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51.
A clinical database review (2000-2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first-, second-, or third-degree relative.
One hundred twenty-nine participants with familial pancreatic cancer or with the BRCA2 gene mutation completed a baseline questionnaire prior to their first pancreatic cancer screening and genetic counseling session.
These consist of high penetrance genes including BRCA2 or PALB2, to more common genetic variation associated with a modest increase risk of pancreatic cancer such as genetic variation at the ABO blood group locus.
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.
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.
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.
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.
Previous small scale studies reported that deleterious BRCA2 and CDKN2a germline mutations contribute to a subset of families with inherited pancreatic cancer.
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.
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.
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).
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.