[Show abstract][Hide abstract] ABSTRACT: Young-onset cancer is a hallmark of many familial cancer syndromes, yet the implications of young-onset disease in predicting risk of pancreatic cancer among familial pancreatic cancer (FPC) kindred members remain unclear.
To understand the relationship between age at onset of pancreatic cancer and risk of pancreatic cancer in kindred members, we compared the observed incidence of pancreatic cancer in 9040 individuals from 1718 kindreds enrolled in the National Familial Pancreas Tumor Registry with that observed in the general US population (Surveillance, Epidemiology, and End Results). Standardized incidence ratios (SIRs) were calculated for data stratified by familial vs sporadic cancer kindred membership, number of affected relatives, youngest age of onset among relatives, and smoking status. Competing risk survival analyses were performed to examine the risk of pancreatic cancer and risk of death from other causes according to youngest age of onset of pancreatic cancer in the family and the number of affected relatives.
Risk of pancreatic cancer was elevated in both FPC kindred members (SIR = 6.79, 95% confidence interval [CI] = 4.54 to 9.75, P < .001) and sporadic pancreatic cancer (SPC) kindred members (SIR = 2.41, 95% CI = 1.04 to 4.74, P = .04) compared with the general population. The presence of a young-onset patient (<50 years) in the family did not alter the risk for SPC kindred members (SIR = 2.74, 95% CI = 0.05 to 15.30, P = .59) compared with those without a young-onset case in the kindred (SIR = 2.36, 95% CI = 0.95 to 4.88, P = .06). However, risk was higher among members of FPC kindreds with a young-onset case in the kindred (SIR = 9.31, 95% CI = 3.42 to 20.28, P < .001) than those without a young-onset case in the kindred (SIR = 6.34, 95% CI = 4.02 to 9.51, P < .001). Competing risk survival analyses indicated that the lifetime risk of pancreatic cancer in FPC kindreds increased with decreasing age of onset in the kindred (hazard ratio = 1.55, 95% CI = 1.19 to 2.03 per year). However, youngest age of onset for pancreatic cancer in the kindred did not affect the risk among SPC kindred members.
Individuals with a family history of pancreatic cancer are at a statistically significantly increased risk of developing pancreatic cancer. Having a member of the family with a young-onset pancreatic cancer confers an added risk in FPC kindreds.
Journal of the National Cancer Institute 01/2010; 102(2):119-26. DOI:10.1093/jnci/djp466 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Histologic findings in 51 pancreata resected from patients with a strong family history of pancreatic cancer were compared with the findings in 40 pancreata resected from patients with sporadic pancreatic cancer. None of the patients in the familial group had a known inherited syndrome other than familial pancreatic cancer. EXPERIMENTAL DESIGN: Precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and incipient IPMN, were quantified. Invasive cancers were classified using established histologic criteria. RESULTS: The individual precursor lesions identified in both groups were histologically similar. Precursor lesions were more common in the familial cases than in the sporadic cases. The relative rate of PanINs per square centimeter was 2.75-fold higher (95% confidence interval, 2.05-3.70; adjusted for age) in familial compared with sporadic cases. PanIN-3 lesions were more common in familial versus sporadic pancreatic cancer patients (relative rate, 4.20; 95% confidence interval, 2.22-7.93; adjusted for age). High-grade incipient IPMNs were only observed in the familial cases. Nine of the 51 (18%) familial pancreatic cancers and 4 of the 40 (10%) sporadic cancers arose in association with an IPMN. No significant differences were found in the types of invasive cancers. CONCLUSIONS: Noninvasive precursor lesions are more common in patients with a strong family history of pancreatic cancer than in patients with sporadic disease, and precursor lesions are of a higher grade in patients with a strong family history of pancreatic cancer. These findings can form a basis for the design of screening tests for the early detection of pancreatic neoplasia. (Clin Cancer Res 2009;15(24):7737-43).
Clinical Cancer Research 12/2009; 15(24):7737-7743. DOI:10.1158/1078-0432.CCR-09-0004 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient's predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the identification of a gene responsible for a hereditary disease.
[Show abstract][Hide abstract] ABSTRACT: Recent studies have suggested that germ line mutations in the BRCA1 gene may confer an increased risk of developing pancreatic cancer. To determine if BRCA1 mutations explain a significant proportion of familial pancreatic cancer, we sequenced the BRCA1 gene in a large series of well-characterized patients with familial pancreatic cancer and we evaluated the pathology of breast neoplasms that developed in relatives of pancreatic cancer patients. The BRCA1 gene was fully sequenced in 66 pancreatic cancer patients enrolled in the National Familial Pancreas Tumor Registry who had at least two additional relatives with pancreatic cancer. None of the 66 (0/66: 97.5% one-side CI 0-0.054%) familial pancreatic cancer patients were found to have a deleterious mutation in the BRCA1 gene. While patients were not selected based upon their family history of breast and ovarian cancer, over half of the patients whose samples were sequenced reported a family history of breast and/or ovarian cancer. Our findings suggest that mutations in the BRCA1 gene are not highly, or even moderately, prevalent in families with a clustering of pancreatic cancer, including pancreatic cancer families who report a family history of breast and/or ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: Copy-number variants such as germ-line deletions and amplifications are associated with inherited genetic disorders including familial cancer. The gene or genes responsible for the majority of familial clustering of pancreatic cancer have not been identified. We used representational oligonucleotide microarray analysis (ROMA) to characterize germ-line copy number variants in 60 cancer patients from 57 familial pancreatic cancer kindreds. Fifty-seven of the 60 patients had pancreatic cancer and three had nonpancreatic cancers (breast, ovary, ovary). A familial pancreatic cancer kindred was defined as a kindred in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Copy-number variants identified in 607 individuals without pancreatic cancer were excluded from further analysis. A total of 56 unique genomic regions with copy-number variants not present in controls were identified, including 31 amplifications and 25 deletions. Two deleted regions were observed in two different patients, and one in three patients. The germ-line amplifications had a mean size of 662 Kb, a median size of 379 Kb (range 8.2 Kb to 2.5 Mb) and included 425 known genes. Examples of genes included in the germ-line amplifications include the MAFK, JunD and BIRC6 genes. The germ-line deletions had a mean size of 375Kb, a median size 151 Kb (range 0.4 Kb to 2.3 Mb) and included 81 known genes. In multivariate analysis controlling for region size, deletions were 90% less likely to involve a gene than were duplications (p < 0.01). Examples of genes included in the germ-line deletions include the FHIT, PDZRN3 and ANKRD3 genes. Selected deletions and amplifications were confirmed using real-time PCR, including a germ-line amplification on chromosome 19. These genetic copy-number variants define potential candidate loci for the familial pancreatic cancer gene.