INHERITANCE OF PANCREATIC CANCER IN PANCREATIC CANCER–PRONE FAMILIES

Pancreatic cancer is the fifth leading cause of death from malignant disease in Western society and constitutes a major public health issue. The prognosis for pancreatic cancer is poor, with fewer than 20% of individuals with pancreatic cancer surviving the first year after diagnosis and only 3% surviving 5 years. 63 Primarily, this survival rate is a consequence of the inaccessibility of the pancreas such that tumors in the pancreas often remain undetected until the cancer reaches a late stage. By the time individuals with pancreatic cancer are diagnosed, 80% to 90% of tumors have metastasized. 65 With increased surveillance leading to earlier detection, this prognosis may be improved. Current noninvasive methods of detection, however, such as computed tomography, are not suited to screening of a general population. Identification of specific groups at high risk for increased surveillance would improve efficiency. Little is known about the genetic or environmental factors that predispose an individual to pancreatic cancer. One such high-risk group is the relatives of individuals with pancreatic cancer, provided that a familial or genetic basis for at least a portion of pancreatic cancer cases was established. The occurrence of pancreatic cancer over multiple generations in many families suggests a possible genetic cause; genes are believed to be responsible for familial aggregations of pancreatic cancer. 41 In so-called cancer families, the genetic changes leading to the development of tumors are inherited in the germline. These patients have a uniform inherited genetic abnormality that leads to the development of carcinomas. 35 Falk et al 17 found an increased risk of pancreatic cancer among close relatives of two cases ( close as determined by the individual reporting) (odds ratio [OR], 1.86, with a 95% confidence interval [CI], 1.42–2.44). This study revealed a significant familial effect on pancreatic cancer, greater than that found in the more common cancers of the breast and colon. 17 A study conducted in Montreal investigated the familial occurrence of pancreatic cancer in French Canadians by matching the environmental risk factor exposures found in individuals with a positive family history of the disease with those who had a negative family history. There was a 13-fold difference in the frequency of family history of pancreatic cancer between individuals with pancreatic cancer and individuals without the disease. 21 Fernandez et al 18 studied the relationship of family history in first-degree relatives of 362 patients with pancreatic cancer and 1408 controls. There was a relative risk (RR) of 3.0 (95% CI, 1.4–6.6) for those with a family history of pancreatic cancer in the cases as compared with the controls. About 3% of newly diagnosed cases were estimated to be familial. 18 There are many reports of pancreatic cancer appearing in multiple family members of the same generation. These reports raise the possibility of a hereditary susceptibility to pancreatic cancer. In any disease with more than 100,000 new cases internationally each year, however, some aggregations are possibly caused by chance. Nevertheless, studies of extended families 16,36,38,40,42 have shown a pattern of pancreatic cancer occurrence suggestive of an autosomal dominant mode of inheritance. Further suggestion of a genetic cause in pancreatic cancer arises from the high incidence of pancreatic cancer in families segregating a known genetic disorder. Genetic disorders predisposing to pancreatic cancer include hereditary pancreatitis, 9,10,11,46 ataxia-telangiectasia heterozygote state, 35 multiple endocrine neoplasia I, 58 glucagonoma syndrome, 5,62 pancreatic cancer as part of the tumor spectrum in hereditary nonpolyposis colorectal cancer, 19,37,42 Gardner syndrome, 53 a subset of familial atypical multiple mole melanoma syndrome individuals, 4,39 and a single report of a family with autosomal dominant inheritance of pancreatic cancer with insulin-dependent diabetes mellitus with exocrine insufficiency. 16 Most of these disorders follow an autosomal dominant mode of inheritance. Despite these promising beginnings, the relatively late age of onset of pancreatic cancer and its poor prognosis and survival make pancreatic cancer families difficult to collect and investigate. Individuals with pancreatic cancer are often older in age compared with individuals with other cancers, and because pancreatic cancer causes death soon after its diagnosis, collecting families with individuals who are old enough to have been diagnosed with pancreatic cancer but who are still alive is difficult, as is finding families with more than one living affected individual. Children and young adults rarely are diagnosed with pancreatic cancer, and often only the oldest generation in families is diagnosed with pancreatic cancer. Pancreatic cancer–prone families with multiple affected members provide a sufficient number of at-risk individuals for DNA collection in the hope that eventually gene linkage and cloning of the responsible gene will occur. Such research could help identify patients who might benefit from targeted screening and control strategies. 41 Once high-risk persons are identified, they may become candidates for gene linkage and molecular genetic studies, similar to those that have helped determine the genetic bases of breast cancer, colorectal cancer, and the Li-Fraumeni syndrome. High-risk individuals can also be studied to search for potential environmental factors that contribute to the development of pancreatic cancer. Finally, screening and chemoprevention strategies, once available, can be targeted to individuals who are at greatest risk. 41 This article reports the initial analysis of a large collection of pancreatic cancer families aimed at determining whether there is evidence of a single susceptibility gene of major effect predisposing individuals to pancreatic cancer. The families included in this analysis are part of the National Registry for Familial Pancreatic Cancer, now at the University of Oklahoma, formerly at the University of Pittsburgh and the National Cancer Institute (NCI). Of pancreatic cancers, 95% arise from the exocrine pancreas, with ductal adenocarcinoma as the most common tumor type. The head, neck, and uncinate process of the exocrine pancreas are involved in 70% of these tumors, with another 20% occurring in the body and 5% to 10% occurring in the tail. 60 Consequently, this analysis includes only families with cases of adenocarcinoma of the exocrine pancreas. A preliminary report has appeared elsewhere. 54