Genetics and Prevention of Pancreatic Cancer
Genetics and Prevention of Pancreatic Cancer
Background: Pancreatic cancer is an aggressive disease with a poor prognosis. Hereditary factors have been reported in up to 10% of cases of pancreatic cancer. The clinical characteristics and genetic abnormalities have been identified for a proportion of this high-risk group, and the development of preventive strategies for these individuals is now a primary goal of cancer clinicians.
Methods: A review of the current literature regarding the genetics, screening, and prevention of pancreatic cancer and its precursor lesions was undertaken.
Results: Risk factors for pancreatic cancer include smoking, chronic pancreatitis, and a genetic predisposition. The role of diabetes or a diet high in fat or meat remains unclear. The genetic mutations that accompany pancreatic cancer appear to occur in a temporal sequence, beginning in the earliest of precursor lesions. These mutations are detectable in pancreatic juice and, in conjunction with imaging, form the basis of screening programs for high-risk individuals. Not all precursor lesions will undergo malignant transformation, and testing is currently limited in its ability to determine which lesions will undergo transformation.
Conclusions: Avoiding tobacco smoking and minimizing risk factors associated with chronic pancreatitis are recommended to reduce the risk of pancreatic cancer. Individuals with a high-risk genetic background require counseling, genetic testing if appropriate (BRCA2 mutation or p16 INK4A inactivity) and secondary screening for pancreatic cancer in specialist centers. Risk stratification will improve as more genetic abnormalities causing pancreatic cancer are defined.
Pancreatic cancer is a leading cause of cancer-related death in the Western world, accounting for 40,000 deaths per year. In the United States, it is the second-leading cause of death attributed to neoplasms of the gastrointestinal tract and is responsible for approximately 30,000 deaths per year. In the United Kingdom, pancreatic cancer is the fifth-leading cause of cancer-related death. It is an aggressive disease that is almost uniformly fatal, with the incidence rate approaching the mortality rate. Even with improvements in surgical treatment, the prognosis remains poor, and although knowledge of specific risk factors is advancing, prevention or cure is unlikely. As a result, much focus has been placed on the identification and detection of the specific genetic abnormalities that accompany the disease and their diagnostic and therapeutic applications.
Outside of high-volume specialist centers, surgical resection is associated with a mortality rate of approximately 15% to 30%; within these centers, the rate is now of the order 5%. Without resection, the overall median survival is 4 to 6 months with an estimated 5-year survival rate of 0.4% to 5%; chemotherapy has only a modest effect in improving survival by just a few weeks or months. Resection increases median survival to 13 to 15 months with a 5-year survival rate of approximately 10%, but this may be increased to around 20 months and 24% to 30%, respectively, with adjuvant chemotherapy. Unfortunately, due to the lack of specific symptoms and current limitations in imaging, only 10% to 15% of patients are suitable for a potentially curative resection on presentation.
Tobacco smoking is the most important etiological factor but accounts for no more than 30% of all cases. The second important risk factor is a familial background, reported in approximately 5% to 10% of cases. There may be an association with diabetes and a diet high in fat or meat, although this is unclear. An increased risk is also seen in patients with chronic pancreatitis.
Recent advances in molecular biology have increased our knowledge of the molecular and genetic changes that accompany pancreatic cancer. Coupled with a greater understanding of precursor lesions, it is now possible to hypothesize a progression model for pancreatic cancer akin to the adenoma-carcinoma sequence in colorectal cancer. The recent National Cancer Institute (NCI) "Think Tank" highlighted further understanding of the biology and genetics of pancreatic cancer as a key area of research in order to decrease the mortality and develop preventative measures. Molecular analysis of clinical samples now allows us to detect the genetic mutations associated with pancreatic cancer. This detection, combined with improved risk stratification and the use of other screening modalities, has presented the possibility of detection of the disease at an early or preinvasive stage so that an effective treatment can be offered to high-risk individuals. This article presents an overview of the genetic basis of pancreatic cancer along with a discussion on how this knowledge is used to screen for the disease at an early or preneoplastic stage.
Abstract
Background: Pancreatic cancer is an aggressive disease with a poor prognosis. Hereditary factors have been reported in up to 10% of cases of pancreatic cancer. The clinical characteristics and genetic abnormalities have been identified for a proportion of this high-risk group, and the development of preventive strategies for these individuals is now a primary goal of cancer clinicians.
Methods: A review of the current literature regarding the genetics, screening, and prevention of pancreatic cancer and its precursor lesions was undertaken.
Results: Risk factors for pancreatic cancer include smoking, chronic pancreatitis, and a genetic predisposition. The role of diabetes or a diet high in fat or meat remains unclear. The genetic mutations that accompany pancreatic cancer appear to occur in a temporal sequence, beginning in the earliest of precursor lesions. These mutations are detectable in pancreatic juice and, in conjunction with imaging, form the basis of screening programs for high-risk individuals. Not all precursor lesions will undergo malignant transformation, and testing is currently limited in its ability to determine which lesions will undergo transformation.
Conclusions: Avoiding tobacco smoking and minimizing risk factors associated with chronic pancreatitis are recommended to reduce the risk of pancreatic cancer. Individuals with a high-risk genetic background require counseling, genetic testing if appropriate (BRCA2 mutation or p16 INK4A inactivity) and secondary screening for pancreatic cancer in specialist centers. Risk stratification will improve as more genetic abnormalities causing pancreatic cancer are defined.
Pancreatic cancer is a leading cause of cancer-related death in the Western world, accounting for 40,000 deaths per year. In the United States, it is the second-leading cause of death attributed to neoplasms of the gastrointestinal tract and is responsible for approximately 30,000 deaths per year. In the United Kingdom, pancreatic cancer is the fifth-leading cause of cancer-related death. It is an aggressive disease that is almost uniformly fatal, with the incidence rate approaching the mortality rate. Even with improvements in surgical treatment, the prognosis remains poor, and although knowledge of specific risk factors is advancing, prevention or cure is unlikely. As a result, much focus has been placed on the identification and detection of the specific genetic abnormalities that accompany the disease and their diagnostic and therapeutic applications.
Outside of high-volume specialist centers, surgical resection is associated with a mortality rate of approximately 15% to 30%; within these centers, the rate is now of the order 5%. Without resection, the overall median survival is 4 to 6 months with an estimated 5-year survival rate of 0.4% to 5%; chemotherapy has only a modest effect in improving survival by just a few weeks or months. Resection increases median survival to 13 to 15 months with a 5-year survival rate of approximately 10%, but this may be increased to around 20 months and 24% to 30%, respectively, with adjuvant chemotherapy. Unfortunately, due to the lack of specific symptoms and current limitations in imaging, only 10% to 15% of patients are suitable for a potentially curative resection on presentation.
Tobacco smoking is the most important etiological factor but accounts for no more than 30% of all cases. The second important risk factor is a familial background, reported in approximately 5% to 10% of cases. There may be an association with diabetes and a diet high in fat or meat, although this is unclear. An increased risk is also seen in patients with chronic pancreatitis.
Recent advances in molecular biology have increased our knowledge of the molecular and genetic changes that accompany pancreatic cancer. Coupled with a greater understanding of precursor lesions, it is now possible to hypothesize a progression model for pancreatic cancer akin to the adenoma-carcinoma sequence in colorectal cancer. The recent National Cancer Institute (NCI) "Think Tank" highlighted further understanding of the biology and genetics of pancreatic cancer as a key area of research in order to decrease the mortality and develop preventative measures. Molecular analysis of clinical samples now allows us to detect the genetic mutations associated with pancreatic cancer. This detection, combined with improved risk stratification and the use of other screening modalities, has presented the possibility of detection of the disease at an early or preinvasive stage so that an effective treatment can be offered to high-risk individuals. This article presents an overview of the genetic basis of pancreatic cancer along with a discussion on how this knowledge is used to screen for the disease at an early or preneoplastic stage.
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