We identified 16 of 53 participants (30%) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13%) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)].
Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization.
Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A.
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.
As the prevalence of those mutations in the setting of familial pancreatic cancer is still not well defined for the German population, we evaluated the presence of BRCA2 and CDKN2a germline mutations in a large cohort of familial pancreatic cancer (FPC) families from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa).
Participants with familial pancreatic cancer (FPC) (n = 131) endorsed higher risk perception of pancreatic cancer than the BRCA2 carriers (n = 67) (perceived lifetime risk 42 vs. 15%), but did not differ on cancer worry or general distress prior to the first study appointment.
To determine the contribution of mutations in BRCA2 to familial pancreatic cancer, we screened affected probands from 151 high-risk families identified through pancreatic cancer clinics for germ-line BRCA2 mutations.
Although up to 20% of hereditary PC cases are associated with germline mutations in the BRCA2, CDKN2A, PRSS1,STKI1, or MMR genes, the major underlying gene defect(s) is still unknown.
The BRCA2K3326X polymorphism was significantly more prevalent in individuals with familial pancreatic cancer: 8/144 (5.6%) vs 3/250 controls (1.2%) (odds ratio, 4.84; 95% CI, 1.27-18.55, P<0.01).
These findings confirm the increased risk of pancreatic cancer in individuals with BRCA2 mutations and identify germ-line BRCA2 mutations as the most common inherited genetic alteration yet identified in familial pancreatic cancer.
Hereditary pancreatic cancer (PC) appears to be exceedingly heterogeneous, as evidenced by its association with a variety of integrally associated diverse cancers and/or differing mendelian inherited cancer syndromes, which include the Lynch syndrome II variant of hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome in families with the BRCA2 mutation, hereditary pancreatitis, Peutz-Jeghers polyposis and the familial atypical multiple-mole melanoma syndrome in families with the CDKN2A (p16) germline mutation.