Leading article Inherited predisposition to pancreatic cancer

Pancreatic cancer is the fifth leading cause of death from cancer in men and women in Europe and North America. The prognosis has not changed significantly despite improvements in diagnosis and perioperative management. Traditional chemotherapy and radiotherapy regimens have been rather ineVective in providing control of the disease. The only consistent risk factor identified so far is smoking and possibly accounts for a quarter of all cases of pancreatic cancer. Diabetes mellitus is another factor associated with an increased risk for the development of pancreatic cancer although it is still unclear if diabetes is a cause or an eVect of malignant disease in the organ. Surgical resection oVers the best chance of prolongation in survival. Unfortunately, in more than 80% of cases, at the time of diagnosis the cancer is either locally advanced or disseminated thus excluding curative resection. Hope for making an appreciable impact on survival has been focused on two areas: early diagnosis of pancreatic precancer and introduction of new therapeutic modalities based on the molecular and genetic abnormalities identified in the disease. Studies have shown an increased risk of pancreatic cancer among relatives of patients with pancreatic cancer (7.8% compared with 0.6% in controls), with no apparent diVerences in the environmental risk exposures observed in the two groups. Similar observations were made by Fernandez et al in a study in which 362 histologically confirmed pancreatic cancer cases were compared with 1408 patients admitted to hospital for acute, benign, non-digestive tract disorders. A significant association was noted between a family history of pancreatic cancer and the risk of developing pancreatic cancer (odds ratio 3.0, 95% confidence intervals 1.4–6.6). Even after adjustment for factors such as tobacco consumption, alcohol intake, pancreatitis, and diabetes, the risk of pancreatic cancer remained almost the same in patients with a positive family history (odds ratio 2.8, 95% confidence intervals 1.3–6.3). The same study suggested the existence of a genetic component in 3% of newly diagnosed pancreatic cancers. Two recent studies, one population based and the other derived from the National Familial Pancreas Tumor Registry, revealed that cancer risk increases in first and second degree relatives when there are two or more aVected members in a family (odds ratio approximating 3.5). 7 Some cases of pancreatic cancer exhibit a definite familial clustering and it is estimated that 5–10% of cases are due to hereditary factors. At the University of Washington the following selection criteria have been used to identify individuals with an increased risk of developing pancreatic cancer in a pancreatic cancer surveillance programme: x an individual with two or more first degree relatives with pancreatic adenocarcinoma, x an individual with one first degree relative who developed pancreatic adenocarcinoma at a young age (younger than 50 years), x an individual with two or more second degree relatives with pancreatic adenocarcinoma, one of whom developed the cancer at an early age. 17 The increased risk of pancreatic cancer in pancreatic cancer prone families is associated either as part of a known syndrome, where predisposition to pancreatic cancer is one part of the cancer spectrum that these families develop, or alternatively it can occur as the only type of cancer that is inherited.