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Background: Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families. Patients and methods: A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated. Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1. Results: With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from pancreatic cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively. These indications of anticipation could be the result of bias. Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p = 0.002 and p,0.001). To minimise bias further, an iterative analysis to predict cancer numbers was developed. No single risk category could be applied that accurately predicted cancer cases in every generation. Using three risk categories (low with no pancreatic cancer in earlier generations, high with a single earlier generation, and very high where two preceding generations were affected), incidence was estimated without significant error. Anticipation was independent of smoking. Conclusion: This study provides the first strong evidence for anticipation in familial pancreatic cancer and must be considered in genetic counselling and the commencement of secondary screening for pancreatic cancer.

Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.

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Pancreatic hamartoma is a rare benign lesion and may be mistaken for a malignancy, as demonstrated by two cases. The first case was a 29-year-old man who presented with a 7-month history of intermittent upper abdominal pain, nausea and vomiting and a 15-kg weight loss. CT and MRI revealed a mass in the head of the pancreas. The second case was a 62-year-old man who presented with a 2-year history of intermittent abdominal pain, vomiting and a 25-kg weight loss. Although positron emission tomography was normal, CT revealed thickening of the duodenal wall and endoluminal ultrasonography revealed a tumour in the head of the pancreas. Both patients recovered from uneventful Kausch-Whipple pancreatoduodenectomy (in the first patient, it was pylorus-preserving), and in each case the histological diagnosis was hamartoma. Pancreatic hamartoma can present with vague, non-specific symptoms which, despite modern diagnostic tools, can be difficult to diagnose. Surgical resection with histopathological examination is required to confirm the diagnosis.