Hereditary factors in pancreatic cancer

Abstract

The incidence and the mortality rates for pancreatic cancer are the same, indicating its dismal outlook. Its natural history remains elusive. Cigarette smoking appears to be the most significant environmental culprit. Hereditary factors may account for approximately 5% of the total pancreatic cancer burden. However, when its extant heterogeneity and the reduced penetrance of causal germline mutations are considered, the hereditary incidence may significantly exceed this estimate. Even when endoscopic ultrasound (EUS), the gold standard for pancreatic cancer screening, is utilized, early detection with surgical cure has rarely been accomplished. Needed to ameliorate this problem is research into genetic and environmental risk factors and their interaction. The identification of tumor biomarkers which signal early pathogenetic events, thereby enabling pancreatic cancer to be diagnosed at its earliest possible stage before it has spread to regional lymph nodes or to more distant sites, will improve the outlook. We discuss our research approaches to this problem. Members of families with the p16 germline mutation will undergo EUS coupled with the collection of pancreatic juice for the study of a possible gradient for telomerase activity, K- ras mutations, and cytology. If changes in these putative biomarkers are observed, endoscopic retrograde cholangiopancreatography (ERCP) would be the next diagnostic step. We conclude with a discussion of ethical concerns about this research.

Evaluation of the 4q32-34 Locus in European Familial Pancreatic Cancer

“…An estimated 2.7% to 10% of pancreatic cancers occur in families where there is at least one other case (5)(6)(7)(8). In some instances, this is associated with a general familial cancer syndrome, such as familial atypical multiple-mole melanoma syndrome, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome, and Peutz-Jeghers syndrome (9)(10)(11)(12)(13), although in most cases, these syndromes are associated with isolated rather than multiple cases of pancreatic cancer. Germ line mutations in various mismatch repair genes, including both MutS homologues (hMSH2) and MutL homologues (hMLH1), are associated with pancreatic cancer in some patients in hereditary nonpolyposis colorectal cancer families (14).…”

Cigarette smoke components inhibited intercellular communication and differentiation in human pancreatic ductal epithelial cells

“…6 Although several risk factors, such as diet, have been associated with pancreatic cancer, cigarette smoking is the only unequivocal risk factor that has been identified. 1,[7][8][9] The incidence of pancreatic cancer is 50-90% higher among blacks in the United States than whites. This disparity has been linked primarily to cigarette smoking-and to a lesser extent diabetes-in men, 10 again indicating the significance of tobacco smoke in the incidence of pancreatic cancer.…”

Peutz–Jeghers syndrome and screening for pancreatic cancer

“…The guidelines included a recommendation that screening should be performed by a multidisciplinary team of pancreatic specialists 38 . Published protocols vary, one beginning with screening at 40 years of age or, at the latest, 5 years below the youngest age of onset in the family 54 , another beginning 10 years before the earliest age of onset 87 . For PJS, the risk of pancreatic cancer is less well defined than for hereditary pancreatitis or even familial pancreatic cancer, which adds even greater complexity.…”

“…EUS may be more sensitive than CT and appears to be more effective at staging the disease 71,72 . CT is not a sensitive marker for pancreatic dysplasia 73 and diagnosing PanIN must rely on EUS, endoscopic retrograde cholangiopancreatography (ERCP) and molecular analysis of pancreatic juice 68,82,87 . These lesions do not cause symptoms and are not visible macroscopically.…”