Clinical and Morphological Characteristics of Sporadic Genetically Determined Pancreatitis as Compared to Idiopathic Pancreatitis: Higher Risk of Pancreatic Cancer in CFTR Variants

Abstract

Background/Aims: Idiopathic pancreatitis is considered to be a multigenic and multifactorial disease. Genetically determined pancreatitis is associated with mutations in the PRSS1,SPINK1 and CFTR genes. This study aimed at examining the clinical and morphological characteristics of patients diagnosed with genetically determined sporadic pancreatitis. Methods: Inclusion criteria were the presence of PRSS1,CFTR or SPINK1 gene mutations in patients with idiopathic recurrent or chronic pancreatitis. Patients with hereditary pancreatitis were excluded. Age- and sex-matched patients with idiopathic pancreatitis and negative genetic testing served as controls (n = 68). Results: Genetic testing was performed in 351 probands referred to our centre since 1999. Sixty-one patients (17.4%) carried at least 1 detected mutation in 1 of the 3 tested genes (34 CFTR, 10 PRSS1 and 13 SPINK1 mutations), and 4 patients showed a combination of mutations. Follow-up has been currently extended to a median of 5 years (range 1-40). Similar clinical features were noted in the case and matched groups except for an earlier age of onset of pancreatic symptoms and a higher incidence of pancreatic cancer in the case group and in patients with CFTR mutations compared to the control group (p < 0.05). The standardized incidence ratio, the ratio of observed to expected pancreatic cancers, averaged 26.5 (95% confidence interval 8.6-61.9). All pancreatic cancer patients were smokers. Conclusion: Clinical parameters of patients with sporadic idiopathic pancreatitis and gene mutations are similar to those of age- and sex-matched patients without gene mutations, except for the age of pancreatic disease onset. A significantly higher occurrence of pancreas cancer was observed in the case group, particularly in those patients carrying CFTR mutations. We therefore suggest to include patients with CFTR variants presenting with risk factors in a screening and surveillance programme and to strongly advise them to stop smoking.

Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers

“…Even though the overall cancer risk in CF patients is similar to that of the general population, CF patients are at elevated risk (6.5 fold) of developing gastrointestinal cancers including pancreatic cancer [32] . The results from the cohort studies indicate an increased risk for pancreatic cancer among CF patients, which is supported by two recent reports [33,34] , in which multiple CFTR mutations were analyzed. These studies also found that patients who are CFTR mutant carriers develop pancreatic cancer earlier than those who carry normal CFTR.…”

“…CF patients suffer from chronic pancreatic damage and inflammation, which may predispose them to malignancy [33] . Even though the overall cancer risk in CF patients is similar to that of the general population, CF patients are at elevated risk (6.5 fold) of developing gastrointestinal cancers including pancreatic cancer [32] .…”

“…These studies also found that patients who are CFTR mutant carriers develop pancreatic cancer earlier than those who carry normal CFTR. While there are reports that do not support the view that CFTR mutations increase the risk of pancreatic cancer [35,36] , Maisonneuve et al [23] concluded that there is a consistent increased risk of pancreatic cancer in CF patients, which is supported by retrospective studies that recruited a large amount of cases and screened multiple CFTR mutations [33,34] . The difference between the reported associations of pancreatic risk and CFTR variation could be due to multiple reasons such as limited case number, different parameters regarding selection of the control population, mutations investigated in the study, and environmental factors including smoking and alcohol consumption.…”

Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis

“…One variant (p.K170E) caused slightly increased trypsinogen secretion, which, similarly to the copy number mutations, may translate to increased risk for pancreatitis (46). Variant p.E79K should be highlighted because this is the only rare PRSS1 variant that was found not only in patients but also in unrelated controls (3,7,20,23,41,50,59). Early biochemical studies demonstrated an increased propensity of this mutant to transactivate anionic trypsinogen; however, this small phenotypic change is unlikely to be of pathological consequence (59).…”

Pancreatic cancer risk in hereditary pancreatitis

“…Inheritance from unaffected carrier parents, uncertain paternity and spontaneous de novo mutations must be considered in such cases (Simon et al, 2002). A recent study by Hamoir et al identified a total of 17.4% carriers of CFTR , PRSS1 , or SPINK1 mutations in a cohort of 351 Belgium patients with idiopathic recurrent or CP and no family history (Hamoir et al, 2013). The authors claim that the clinical features were not influenced by the presence of a gene mutation except for an earlier age at onset and a higher incidence of pancreatic cancer, especially in patients with a CFTR mutation (four cancer patients had CFTR mutations, one a PRSS1 mutation).…”