Epidemiology and prospects for prevention of pancreatic cancer | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Epidemiology and prospects for prevention of pancreatic cancer

Epidemiology

Worldwide, pancreatic cancer is the 13th most common type of cancer. Its poor prognosis makes it the eighth major form of cancer-related death causing more than 227,000 deaths annually. Age-adjusted incidence rates range from 10–15 per 100,000 people in parts of Northern, Central, and Eastern Europe to less than 1 per 100,000 in areas of Africa and Asia. The highest incidence rates were observed among African American in the United States and New Zealand Maoris; the lowest rates were reported for India and Thailand. Pancreatic cancer incidence and mortality statistics are similar throughout the world. In the United States, based on cases diagnosed in 2001–2005 from 17 Surveillance Epidemiology and End Results (SEER) geographic areas, the age-adjusted incidence rate for all races was 13.0 per 100,000 men and 10.3 per 100,000 women. Based on patients died in 2001–2005, the ageadjusted death rate per 100,000 for pancreatic cancer was 12.2 for men, 9.3 for women, 15.4 for black men, 12.4 for black women, 12.1 for white men, and 9.0 for white women. Worldwide, pancreatic cancer occurs slightly more frequently in men than in women and in urban areas more than in rural regions. In the United States, while the incidence in women has increased slightly over the past two decades, the incidence in men has dropped slightly. Now the incidence is about the same for both sexes, probably as a result of the increased use of tobacco by women. The reasons for the regional and ethnic differences in the incidence of pancreatic cancer are unknown. The higher incidence in most developed countries probably reflects diagnostic capacity rather than etiology. The fact that the rates in African Americans are considerably higher than in native Africans suggests an environmental influence. Among men, the established risk factors (mainly cigarette smoking and diabetes mellitus) explain almost the entire black/white disparity in incidence. Among women, moderate/heavy alcohol consumption and elevated body mass index appear to contribute to the racial disparity.

Established risk factors

Age

Age is the most established predictor of pancreatic cancer incidence and death. The risk of pancreatic cancer is low in the first three to four decades of life but increases sharply after age 50 years, with most patients between the ages of 60 and 80 years and the median age at diagnosis of 72 years (Table I–11 (http://seer.cancer.gov/csr/1975_2005/results_single/ sect_01_table.11_2pgs.pdf )). Approximately 0.0% was diagnosed under age 20; 0.4% between 20 and 34; 2.4% between 35 and 44; 9.6% between 45 and 54; 18.9% between 55 and 64; 26.6% between 65 and 74; 29.5% between 75 and 84; and 12.5% 85+ years of age.

Hereditary risk factors

Inherited pancreatic cancers represent approximately 5–10% of all pancreatic cancers. Pancreatic cancer may be inherited as part of a known cancer syndrome or in association with hereditary pancreatitis or cystic fibrosis.

Hereditary breast-ovarian cancer syndrome is associated with mutations in BRCA1 or BRCA2. BRCA2 is a tumor suppressor gene on chromosome 13q12 and its protein product is involved in the repair of DNA strand breaks. Deleterious germline mutations in the BRCA2 gene have been found in 17% of patients with familial pancreatic cancer and in 7% of patients thought to have sporadic pancreatic cancer. Such germline BRCA2 mutations represent the most common inherited predisposition to pancreatic cancer and are associated with an up to 10 times greater risk of pancreatic cancer than exists in the general population.

The familial atypical multiple-mole melanoma (FAMMM) syndrome is a rare autosomal dominant genetic disorder with incomplete penetrance caused by germline mutations in the CDKN2A (p16) tumor suppressor gene on chromosome 9p21 and is associated with the development of multiple nevi, including malignant melanoma. Among 159 families collected in the Creighton University registry of familial pancreatic cancer, 19 (12%) showed FAMMM and 8 with ascertained mutations within CDKN2A. Both early-onset and lateonset pancreatic cancer have been seen in the affected families.

Peutz-Jeghers syndrome is rare and inherited as an autosomal dominant genetic disorder characterized by the presence of multiple hamartomatous gastrointestinal polyps and mucocutaneous pigmentation and is associated with an increased risk of several gastrointestinal cancers. It is often caused by mutations in the LKB1/STK11 tumor suppressor gene on chromosome 19p13. Although patients with Peutz-Jeghers syndrome are at significant higher risk of pancreatic cancer, the exact magnitude of the risk is unclear. One study showed relative risk (RR) is 132 (95% confidence interval (CI), 44–261) with a cumulative lifetime risk of 36%.

Interestingly, biallelic inactivation of the LKB1/STK11 gene was also found in 4% of patients with resected sporadic pancreatic cancers. Lim et al. analyzed the incidence of cancer in 240 individuals with Peutz-Jeghers syndrome possessing germline mutations in STK11. All pancreatic cancers were diagnosed between age 34 and 49 years. The risk of developing pancreatic cancer was 5% at age 40, increasing to 8% at age 60 years.

Li-Fraumeni syndrome occurs among carriers of mutations within TP53 gene. TP53 is an extensively studied tumor suppressor protein with a critical role in controlling cell-cycle arrest and apoptosis. Germline mutation of p53 is known to be the underlying genetic defect in the Li-Fraumeni syndrome of childhood malignancies, bone and soft-tissue sarcomas, premenopausal breast carcinoma, brain tumors, adrenocortical carcinoma, and leukemias. Pancreatic adenocarcinoma is the only adult epithelial malignancy that has been proven to be associated with Li-Fraumeni syndrome, other than breast cancer.

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant genetic disorder caused by germline mutations in mismatch repair genes resulting in an increased risk of colorectal cancer and other cancers, including cancer of the breast, endometrium, and ovary. Patients with HNPCC may also have an increased risk of pancreatic cancer. However, the magnitude of the increased risk is not clear because the numbers of cases often are not adequate for an appropriate assessment of the risk.

Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. The genetic defect in FAP is a germline mutation in the adenomatous polyposis coli (APC) tumor suppressor gene, located on chromosome 5q21. APC encodes a multi-domain protein that plays a major role as a tumor suppressor by antagonizing the wingless-type (Wnt) signaling pathway. A study of 197 FAP pedigrees found a RR of 4.46 (95% CI, 1.2–11.4).

Hereditary pancreatitis is a rare form of pancreatitis. It has an autosomal dominant pattern of transmission with 80% penetrate. It is characterized by the development of recurrent episodes of severe chronic pancreatitis starting at an early age. The symptoms usually arise by age 40 years, but can occur before age 5 years. In approximately one-third of all cases, no etiologic factor can be found, and these patients are classified as having idiopathic disease. Mutations in the cationic trypsinogen gene (PRSS1) on chromosome 7q35 have been identified in patients with hereditary or idiopathic chronic pancreatitis. Lowenfels and colleagues obtained data on 246 patients with hereditary pancreatitis from pancreatologists in 10 countries. They found that the estimated cumulative risk of pancreatic cancer developing by age 70 was approximately 40% in this patient population. The mean age at the diagnosis of pancreatic cancer was 57 years. Idiopathic pancreatitis has been found to be associated with mutations in the cystic fibrosis gene (CFTR). Compared with the background population, the risk of pancreatic cancer is approximately 50 to 60 times greater than expected.

Familial pancreatic cancer kindreds have also been identified that are not affected by an inherited cancer syndrome. At-risk patients for familial pancreatic cancer include those with a minimum of two first-degree relatives with pancreatic cancer. A meta-analysis identified

7 case-control and 2 cohort studies involving 6,568 pancreatic cancer cases. This analysis found a significant increase in risk associated with having an affected relative, with a summary RR of 1.80 (95% CI, 1.48–2.12). Individuals with a family history of pancreatic cancer have nearly a two-fold increased risk of pancreatic cancer compared with those without such a history. The study suggested that families with two or more pancreatic cancer cases might benefit from comprehensive risk assessment that involves collection of detailed information on family history and environmental exposure, especially smoking history. Previous studies of a well-known family of familial pancreatic cancer suggested that the susceptibility locus for autosomal dominant pancreatic cancer is on chromosome 4q32–34 and Palladin might be the responsible gene. However, two later studies failed to confirm these findings in other study populations [30,31].

More details on this topic can be found in the Chapter ‘‘Genetic susceptibility – High risk groups, chronic and hereditary pancreatitis, familial pancreatic cancer syndromes’’ of this book.

Cigarette smoking

The risk factor most firmly associated with pancreatic cancer is cigarette smoking. A metaanalysis of 82 independent studies published between 1950 and 2007 containing epidemiologic information on smoking and pancreatic cancer across four continents. This analysis found the overall risk of pancreatic cancer estimated from the combined results for current and former smokers was, respectively, 1.74 (95% CI, 1.61–1.87) and 1.20 (95% CI, 1.11–1.29), compared with never smokers. For former cigarette smokers, the risk remains elevated for a minimum of 10 years after cessation and long-term smoking cessation (>10 years) reduces the risk by approximately 30% relative to the risk in current smokers. It is currently estimated that approximately 25% of cases of pancreatic cancer are due to cigarette smoking.

In animals, pancreatic malignancies can be induced through the long-term administration of tobacco-specific N-nitrosamines or the parenteral administration of other N-nitroso compounds. These carcinogens are metabolized to electrophiles that readily react with DNA, leading to the miscoding and activation of oncogenes. Indeed, the detections of carcinogen-DNA adducts in human pancreas tissues and tobacco-specific compounds in pancreatic juice further support the link between cigarette smoking and pancreatic cancer [33–35]. Recent molecular epidemiological studies have also shown that individual genetic variability in carcinogen metabolism and DNA repair may partially determine the susceptibility to smoking-related pancreatic cancer [36–40]. Previous studies have also shown an association of K-ras mutation in pancreatic tumors with cigarette smoking [41,42]. Information generated from such studies may facilitate the development of strategies in identifying high-risk individuals for the primary prevention of pancreatic cancer.

Noncigarette tobacco use has been increasing in the United States. Several previous studies have reported significant associations between use of pipe, smokeless tobacco, or cigar [43,46–48] and risk for pancreatic cancer. Compared with never smokers, the risk of pancreatic cancer for current and former pipe and/or cigar smokers was respectively 1.47 (95% CI, 1.17–1.83) and 1.29 (95% CI, 0.68–2.45) in the recent meta-analysis report.

Few studies have investigated the relation of passive smoking or environmental tobacco smoke (ETS) with risk of pancreatic cancer. A Canadian population-based cases control study including 583 pancreatic cancer cases and 4,813 controls first reported a statistically nonsignificant moderate increased risk of developing pancreatic cancer (odds ratio [OR], 1.21; 95% CI, 0.60–2.44) when childhood and adult exposure to ETS compared to non-exposure among never smokers. A hospital-based case-control study conducted at the University of Texas M. D. Anderson Cancer Center included 808 cases and 808 controls found passive smoking was significantly associated with risk of pancreatic cancer among ever smokers (OR, 1.7; 95% CI, 1.0–2.6) but not among never smokers (OR, 1.1; 95% CI, 0.8–1.6).

Similarly, one study, including two prospective cohorts, did not observe an association between passive smoking and risk among never smokers [50]. Overall these data do not support a significant role of passive smoking in pancreatic cancer.

Obesity

The positive association between obesity, as measured by high body mass index (BMI), and risk for pancreatic cancer has been observed in at least 16 out of the 27 prospective studies and 3 meta-analyses [51–53]. The first meta-analysis identified 6 case–control and 8 cohort studies involving 6,391 cases of pancreatic cancer from 1966 to 2003. The summary RR per unit increase in body mass index was 1.02 (95% CI, 1.01–1.03). The second meta-analysis of 21 independent prospective studies involving 3,495,981 individuals and 8,062 pancreatic cancer patients showed that the RR of pancreatic cancer per 5 kg/m2 increase in BMI was 1.16 (95% CI, 1.06–1.17) in men, and 1.10 (95% CI, 1.02–1.19) in women. The latest meta-analysis includes 16 prospective studies involving 3,338,001 individuals and 4,443 cases. The RR of pancreatic cancer per 5 kg/m2 increase in BMI was 1.07 (95% CI, 0.93–1.23) in men, and 1.12 (95% CI, 1.03–1.23) in women. It has been estimated that the population attributable fraction of obesity-associated pancreatic cancer is 26.9% for the U.S. population. In 2007, the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) concluded that the evidence that greater body fatness is a cause of pancreatic cancer is convincing.

Abdominal fatness is probably also a cause of pancreatic cancer. Central adiposity is associated with glucose intolerance and is a risk factor for diabetes; hence concomitantly increased insulin levels may be the mechanism through which central adiposity increases pancreatic cancer risk. A few studies have investigated central adiposity in association with risk of pancreatic cancer [55–59]. In the American Cancer Society Cancer Prevention Study II Nutrition Cohort, men and women who reported ‘‘central’’ weight gain had a RR of pancreatic cancer of 1.45 (95% CI, 1.02–2.07) compared with men and women who reported peripheral weight gain, independent of BMI. Central weight gain was defined as reported weight gain in chest and shoulders or waist, and peripheral weight gain was defined as reported weight gain in hips and thighs or equally all over. In the European Prospective Investigation into Cancer and Nutrition study (EPIC), 324 incident cases of pancreatic cancer were diagnosed in the cohort over an average of 6 years of follow-up. Larger waist-to-hip ratio and waist circumference were both associated with an increased risk of pancreatic cancer (RR per 0.1, 1.24; 95% CI, 1.04–1.48; and RR per 10 cm, 1.13; 95% CI, 1.01–1.26, respectively). In the NIH-AARP Diet and Health study, 654 pancreatic cancer cases were identified in 495,035 AARP cohort members during an average of 5 years of follow-up. Waist circumference was positively associated with pancreatic cancer (fourth против first quartile: RR, 2.53; 95% CI, 1.135.65) in women but not men. In the Women’s Health Initiative study, women in the highest quintile of waist-to -hip ratio after adjusting for potential confounders had 70% (95% CI, 10–160%) excess risk compared with women in the lowest quintile. When waist-tohip ratio was analyzed as a continuous variable, risk increased by 27% (95% CI, 7–50%) per 0.1 increase. This observation was made on the basis of 251 cases after following up 138,503 women for average of 7.7 years. In a pooled analysis of 30 cohort studies involving 519,643 Asian-Pacific participants and 324 deaths from pancreatic cancer, the RR (95% CI) was 1.08 (1.02–1.14) for every 2-cm increase in waist circumference.

Physical activity has been associated with improved glucose metabolism, increased insulin sensitivity, and decreased insulin, independent of its effects on weight. Increased physical activity may confer a reduced risk for pancreatic cancer. However, a recent systematic review found total physical activity (occupational and leisure time) was not significantly associated with risk for pancreatic cancer (4 prospective studies; summary RR, 0.76; 95% CI, 0.53–1.09). A decreased risk for pancreatic cancer was observed for occupational physical activity (3 prospective studies; RR, 0.75; 95% CI, 0.58–0.96) but not for leisure-time physical activity (14 prospective studies; RR, 0.94; 95% CI, 0.83–1.05). Measurement of physical activity is subjected to error, and the non-differential misclassification would bias the risk estimate towards the null.

Diabetes mellitus

In addition to cigarette smoking and obesity, type II diabetes is likely to be a third modifiable risk factor for pancreatic cancer. Diabetes mellitus has been implicated both as an early manifestation of pancreatic cancer and as a predisposing factor [63,64]. Related to this is the observation that pancreatic adenocarcinoma of duct cell origin can induce peripheral insulin resistance. In addition, a putative cancer-associated diabetogenic factor has been isolated from the conditioned medium of pancreatic cancer cell lines and from patient serum. From the standpoint of clinical observations, a cohort study showed that patients were at increased risk of pancreatic cancer after an initial hospitalization for diabetes, and this risk persisted for more than a decade. Two meta-analyses have investigated the risk of pancreatic cancer in relation to diabetes. The first meta-analysis conducted in 1995 and identified 20 of a total of 30 case-control and cohort studies. The second meta-analysis was conducted in 2005 that included 17 case-control and 19 cohorts or nested case-control studies published from 1996 to 2005. The summary OR (95% CI) of pancreatic cancer for diabetics relative to nondiabetics was 2.1 (1.6–2.8) and 1.82 (1.66–1.89) in the first and second meta-analysis, respectively. The first meta-analysis found requiring diabetes duration of at least 5 years resulted in an RR of 2.0 (95% CI, 1.2–3.2). The authors concluded that pancreatic cancer occurs with increased frequency among persons with long-standing diabetes. The second meta-analysis found that individuals in whom diabetes had only recently been diagnosed (<4 years) had a 50% greater risk of pancreatic cancer compared with individuals who had diabetes for 5 years (OR, 2.1 против 1.5; P = 0.005). These results support a modest causal association between type II diabetes and pancreatic cancer.

It has been estimated that approximately 1% of diabetics aged 50 years will be diagnosed with pancreatic cancer within 3 years of first meeting criteria for diabetes. Pancreatic cancer-induced hyperglycemia occurs up to 24 months prior to the diagnosis of pancreatic cancer. Therefore, it has been suggested that diabetes itself may act as a biomarker of early pancreatic cancer. Identifying the patients with cancer-associated diabetes at their diabetes onset would offer an opportunity for early detection of pancreatic cancer.

The studies on type I diabetes and risk of pancreatic cancer are rare. A systematic review and meta-analysis conducted in 2007 identified 3 cohort studies and 6 case-control studies. Based on 39 cases, the summary RR for pancreatic cancer in young-onset or type I diabetes versus no diabetes was 2.00 (95% CI, 1.37–3.01). Since this study indicates a similarly elevated risk in type I as in type II diabetes, this weighs against the involvement of b-cell activity in the etiology of pancreatic cancer in diabetes.

The causal relationship between diabetes and risk of pancreatic cancer is supported by findings from biomarker studies. Prediagnostic elevations in post-load plasma glucose, serum and plasma glucose, insulin, and plasma C-peptide levels have been associated with greater risk of pancreatic cancer. These observations suggest that insulin plays an important role in pancreatic carcinogenesis. High insulin concentrations in the microenvironment of the pancreatic duct cell may contribute to malignant transformation. In addition, the insulin-like growth factors (IGFs) may also play a role in promoting pancreatic tumor development. The prediagnostic biomarkers of IGF axis have been investigated in association with pancreatic cancer in a few prospective cohort studies. A study of 93 pancreatic cancer cases and 400 randomly selected cohort controls from the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study found no association between IGF-I, or IGF binding protein-3 (IGFBP-3), or IGF-1:IGFBP-3 molar ratio and the risk of pancreatic cancer in male smokers. In a Japanese nested case-control study including 69 cases and 207 controls, there was a positive, but statistically insignificant association between serum levels of IGF-I and risk of death from pancreatic cancer. In a pooled nested case-control study in the United States, plasma levels of IGF-1, IGF-2, or IGFBP-3 were not associated with risk of pancreatic cancer among 212 incident cases and 635 matched controls. In the same study setting including 144 pancreatic cancer cases that occurred 4 years after plasma collection and in 429 controls, lower plasma IGFBP-1 level was significantly associated with an increased risk of pancreatic cancer in never smokers (RR, 2.07; 95% CI, 1.26–3.39). The strength of the association was not substantially attenuated by the inclusion of plasma IGF-I, C-peptide, and IGFBP-3 in the multivariate models, suggesting an independent effect for IGFBP-1 on pancreatic cancer risk.

Suspected risk factors

Alcohol

Alcohol consumption is an established risk factor for pancreatitis and type II diabetes mellitus, both of which are associated with increased risk of pancreatic cancer. However, only a few studies have shown significant increased risk in association with total alcohol intake more than 30 g per day among more than 60 analytic studies [84–87]. In 2007, a panel sponsored by the WCRF and AICR concluded that the current data on the relationship between alcohol intake and pancreatic cancer risk were too inconsistent to reach a judgment on the association between alcohol intake and risk of pancreatic cancer. A recent pooled analysis of the primary data from 14 prospective cohort studies has shown a slight positive association of pancreatic cancer risk with alcohol intake (summary multivariate RR, 1.22; 95% CI, 1.03–1.45 comparing >30–0 grams/day). This association was statistically significant among women only. A recent EPIC study of 555 non-endocrine pancreatic cancer cases showed that high lifetime ethanol intake from spirits/liquor at recruitment tended to be associated with a higher risk (RR, 1.40; 95% CI, 0.93–2.10 comparing 10+ g/day против 0.1–4.9 g/day), but no associations were observed for wine and beer consumption. In the NIH-AARP Diet and Health Study, the authors identified 1,149 eligible exocrine pancreatic cancer cases among 470,681 participants during average 7.3 years of follow-up, the RR of pancreatic cancer was 1.45 (95% CI, 1.17–1.80) for heavy total alcohol use ( 3 drinks/day, 40 g alcohol/day) and 1.62 (95% CI, 1.24–2.10) for heavy liquor use, compared to the light alcohol use (<1 drink per day among ever drinkers). The increased risk was not statistically significant in women due to the fact that women tended to drink less. However, the confounding effect of smoking cannot be excluded because heavy alcohol users were more likely to be smokers. Additional large studies or meta-analysis of pooled data from existing studies are required to demonstrate the association of alcohol consumption and risk independent of smoking. Overall, moderate alcohol consumption is not a risk factor of pancreatic cancer. Heavy alcohol use, in particular heavy drink of liquor, may play a role in pancreatic cancer development. Alcohol consumption may sensitize the pancreas to inflammatory, immune, and fibrosing responses induced by genetic and environmental predisposing factors and functions as a co-factor in the development of pancreatic disease.

Pancreatitis

Alcohol is the dominant identified cause for chronic pancreatitis, although a significant number of individuals may have chronic pancreatitis of idiopathic origin. As pancreatic cancer may obstruct pancreatic enzyme flow, pancreatitis may be a consequence of pancreatic cancer. Even after exclusion of individuals diagnosed with pancreatitis in close proximity to pancreatic cancer, some have reported a continued association between a remote history of pancreatitis and/or chronic pancreatitis and pancreatic cancer, whereas others have not. For example, in a cohort study of 2,015 patients with chronic pancreatitis from six countries, Lowenfels et al. reported an increased risk of pancreatic cancer in patients with chronic pancreatitis, with the cumulative incidence of pancreatic cancer increasing with the longer duration of follow-up. Talamini and colleagues made similar observations in a study of 715 patients with chronic pancreatitis and found a 13to 18-fold increase in the incidence of pancreatic cancer. They also observed that patients with a short duration between pancreatitis and pancreatic cancer diagnosis were older, had a lower percentage of men, infrequently used tobacco and alcohol, and were more likely to be noninsulin-dependent diabetics compared to patients without pancreatic cancer or patients in whom pancreatic cancer developed late after the diagnosis of chronic pancreatitis. The authors therefore hypothesized that the cancer causes pancreatitis in some cases (as may be the case with hyperglycemia) and emphasized that, for this reason, cancer should be strongly considered in a patient diagnosed with idiopathic chronic pancreatitis without a history of significant alcohol or tobacco use, especially in the context of hyperglycemia. Somewhat in contrast, however, were the findings of Karlson and colleagues, who identified 230 patients with pancreatic cancer among 29,530 patients in the Swedish national  registry discharged 1 year or more after a hospital admission for pancreatitis. Although they found that the standardized incidence ratio (observed/expected) for pancreatic cancer increased in patients with pancreatitis (2.8; 95% CI, 2.5–3.2), after 10 years or more, the excess risk declined and was of borderline significance. The authors concluded that their data thus did not support a causal association between pancreatitis and pancreatic cancer; instead, alcohol consumption and smoking were thought to contribute significantly to the increased cancer risk associated with chronic pancreatitis. As inflammation has been implicated in the causal pathway of many other malignancies, a causal relationship between pancreatitis and pancreatic cancer is plausible, possibly through increased cell-proliferation due to chronic inflammation in the presence of growth factors. Additional studies are required to clarify the association between pancreatitis and pancreatic cancer.

Dietary factors

Various dietary factors have been examined in association with pancreatic cancer. According to the 2007 report by WCRF and AICR, there is suggestive evidence supporting associations of intakes of total energy, total fat, red meat consumption, animal protein, or fruit intake with risk of pancreatic cancer. The evidence on the role of dietary fiber, vegetables, carbohydrate and sugar, soy products, dairy products, and vitamin C supplement is limited and inconclusive; and coffee consumption is unlikely to have a substantial effect on risk of pancreatic cancer.

Meat

There is a general consensus that a higher intake of meat and animal product is associated with increased risk of pancreatic cancer. For example, the Multiethnic cohort study including 482 incident pancreatic cancers found a significant association with processed meat; those in the fifth quintile of daily intake had a 68% increased risk compared with those in the lowest quintile (RR, 1.68; 95% CI, 1.35–2.07). The authors also found that intake of total and saturated fat from meat was associated with statistically significant increases in pancreatic cancer risk but that from dairy products was not. Recent studies suggested that the method of meat preparation and subsequent intake of food mutagens might contribute to the development of pancreatic cancer [96–98]. It is known that cooking meat at high temperature, e.g., deep fry, grill or barbeque, could produce potential carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons. In a hospital-based case-control study conducted at the University of Texas M. D. Anderson Cancer Center including 626 cases and 530 noncancer controls, Li et al. investigated the dietary exposure to food mutagens and risk of pancreatic cancer. They found that a significantly greater portion of the cases than controls showed a preference to well-done pork, bacon, grilled chicken, and pan-fried chicken. The daily intakes of 2-amino-3,4,8-trimethylimidazo[4,5-f ]quinoxaline and benzo(a)pyrene, as well as the mutagenic activity, were the significant predictors for pancreatic cancer with adjustment of other confounders. The NIH-AARP Diet and Health Study including 836 patients with exocrine pancreatic cancer found total, red, and high-temperature cooked meat intake was positively associated with pancreatic cancer among men but not women. Men showed significant 50% increased risks for the highest tertile of grilled/barbecued and broiled meat intake and significant doubling of risk for the highest quintile of overall meat-mutagenic activity. The fifth quintile of the heterocyclic amine, 2-amino-3,4,8-trimethylimidazo[4,5-f ] quinoxaline intake showed a significant 29% (P trend = 0.006) increased risk in men and women combined. Interestingly, the M.D. Anderson case-control study reported a significant interaction between NAT1 (N-acetyltransferase 1) genotype and dietary mutagen intake on modifying the risk of pancreatic cancer among men but not women . The OR (95% CI) was 2.23 (1.33–3.72) and 2.54 (1.51–4.25) for men having the NAT1*10 and a higher intake of 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine and benzo[a]pyrene, respectively, compared with individuals having no NAT1*10 or a lower intake of these dietary mutagens. These studies support the hypothesis that meat intake, particularly meat cooked at high temperatures and associated mutagens, may play a role in pancreatic cancer development.

Fruits and vegetables

Many case-control studies have suggested that higher consumption of fruits and vegetables is associated with a lower risk of pancreatic cancer, whereas cohort studies do not support such an association. A Swedish cohort study with 135 cases and a recent EPIC study with 555 cases did not find an association of overall fruit and vegetable intake, subgroups of vegetables and fruits, and pancreatic cancer risk. The Multiethnic Cohort Study including 526 cases did not find an association between total or specific vegetable intake and risk of pancreatic cancer but high intake of dark green vegetables may exert protective effect among current smokers. The consumption of cruciferous vegetables and pancreatic cancer risk warrants further investigation. In a systematic review including 4 casecontrol studies and 5 cohort studies, the authors showed that an inverse association in risk of pancreatic caner with intake of citrus fruits. The results varied substantially across studies, and the apparent effect was restricted to case-control studies. In a population-based case-control study in San Francisco Bay area including 532 cases and 1,701 ageand sexmatched controls, inverse associations were found between risk of pancreatic cancer and consumption of total or specific vegetables and fruits such as dark leafy, cruciferous and yellow vegetables, carrots, beans, onions and garlic, and citrus fruits and juice. Compared with less than five servings per day of total vegetables and fruits combined, the risk of pancreatic cancer was 0.49 (95% CI, 0.36–0.68) for more than nine servings per day.

Flavonoinds, folate, lycopene

Fruit and vegetables contain many chemicals with potential anti-cancer properties including carotenoids, vitamins C and E, flavonoids, folate, selenium and plant sterols. Flavonoids, which are found in certain plant foods, are thought to lower cancer risk through their antioxidant, antiestrogenic and antiproliferative properties. In the Multiethnic Cohort Study, baseline exposure data were collected in Hawaii and California in 1993–1996. Intake of total flavonols was associated with a reduced pancreatic cancer risk (RR for the highest против lowest quintile, 0.77; 95% Cl, 0.58–1.03). Of the three individual flavonols, kaempferol was associated with the largest risk reduction (RR, 0.78; 95% CI, 0.58–1.05). Total flavonols, quercetin, kaempferol, and myricetin were all associated with a significant inverse trend among current smokers but not among never or former smokers. In the ATBC Cancer Prevention Study, the authors found flavonoid-rich diet may decrease pancreatic cancer risk in male smokers not taking supplemental alpha-tocopherol and/or beta-carotene. These two studies provide evidence for a preventive effect of flavonols on pancreatic cancer, particularly for current smokers.

Folate plays an important role in DNA synthesis and repair. A meta-analysis of 1 casecontrol study and 4 prospective cohort studies found the summary RR for the highest versus the lowest category of dietary folate intake were 0.49 (95% CI, 0.35–0.67) for pancreatic cancer. A Swedish prospective cohort study found increased intake of folate from food sources, but not from supplements, may be associated with a reduced risk of pancreatic cancer. In the ATBC Cancer Prevention Study, serum folate and pyridoxal-50 -phosphate (PLP) concentrations showed statistically significant inverse dose-response relationships with pancreatic cancer risk. In a pooled nested case control analysis, baseline serum concentrations of folate, PLP, vitamin B12, or homocysteine were not associated with risk of pancreatic cancer in general, but a modest inverse trend was observed when the analysis was restricted to nonusers of multivitamins. However, the association of folate intake and risk of pancreatic cancer was not observed in two large studies conducted in the United States [111,112]. The inconsistent observations on the association between folate intake and risk of pancreatic cancer may suggest that the influence of folate consumption may be restricted to populations that are relatively folate deficient, e.g., heavy smokers or heavy alcohol drinkers.

A Canadian case-control study of 462 histologically-confirmed pancreatic cancer cases and 4721 population-based controls found lycopene, provided mainly by tomatoes, was associated with a 31% reduction in pancreatic cancer risk among men. However, the Food and Drug Administration review found very limited evidence to support an association between tomato or lycopene consumption and reduced risk of pancreatic cancer. A meta-analysis on clinical trials could not find evidence that antioxidant supplements can prevent gastrointestinal cancers, including pancreatic cancer.

Carbohydrate, glycemic index/load

A multicenter, population-based case control study of pancreatic cancer showed an increased risk of pancreatic cancer associated with a higher intake of carbohydrate, but not all the associations were statistically significant [116,117]. Some types of carbohydrate increase the level of serum glucose and insulin more than others. Glycemic index and glycemic load are measures designed to take into consideration of these differences. The glycemic index represents the postprandial glucose response of individual food items compared with a reference food. Refined grains, such as white bread or white rice, produce a larger increase in postprandial glucose levels than foods such as whole grain foods. Glycemic load reflects both the quality (i.e., glycemic index) and the quantity of the carbohydrates that are consumed by individuals. A high dietary glycemic index/load could increase the risk of pancreatic cancer due to the adverse effect of high postprandial glucose level and resulting insulin demands. The associations of dietary carbohydrates, refined sugars, and glycemic index/load with pancreatic cancer have been investigated in many studies and the results are inconsistent. However, the seven large-scale prospective studies consistently showed null associations of carbohydrate, glycemic index and glycemic load with risk of pancreatic cancer [118–124]. Six of these studies stratified the analyses by BMI and/or physical activity subgroups, and most of these studies did not report any significant findings, with only one exception. A meta-analysis showed no significant associations between pancreatic cancer risk and either glycemic index or glycemic load in a comparison of the highest with the lowest category of intake. In line with these findings, a recent large cohort study did not show that consumption of added sugar or of sugar-sweetened foods and beverages is associated with overall risk of pancreatic cancer.

Other factors

Infectious agents

Some data suggest an association between Helicobacter pylori or hepatitis B infection and pancreatic cancer [127–129]. H. pylori may result in sub-clinical pancreatitis and can increase gastrin levels, which have a trophic effect on the pancreas. In addition, given that the gastric carriage of H. pylori is a known risk factor for peptic ulcer formation and gastric cancer, this may explain the association between gastric resection and pancreatic cancer observed in some study but not in others. In a hospital-based case-control study in Austria, a serological analysis was performed among 92 patients with histologically confirmed diagnosis of pancreatic adenocarcinoma and controls for the presence of IgG antibodies against H. pylori. In pancreatic cancer patients when compared with those suffering from colorectal cancer combined with normal controls, the OR (95% CI) was 2.1 (1.1–4.1). However, microscopic evaluation of human pancreatic cancer specimens showed no evidence for the presence of H. pylori. In 2001, a nested case-control study of 121 exocrine pancreatic cancer cases and 226 cancer-free control subjects from a Finnish cohort of older male smokers found that 82% of cases were seropositive for H. pylori antibodies, compared with 73% of controls (OR, 1.87; 95% CI, 1.05–3.34). In this study, CagA+ strains were associated with slightly greater odds of pancreatic cancer than the CagA ones (OR, 2.01; 95% CI, 1.09–3.70 and OR, 1.65; 95% CI, 0.82–3.29, respectively). However, a study in Kaiser Permanente Medical Care Program found neither H. pylori (OR, 0.85; 95% CI, 0.49–1.48) nor its CagA protein (OR, 0.96; 95% CI, 0.48–1.92) was associated with subsequent development of pancreatic cancer. Similarly, a recent nested case-control study in a Swedish cohort did not find H. pylori seropositivity was associated with pancreatic cancer (OR, 1.25; 95% CI, 0.75–2.09). However, a statistically significant association was found in never smokers adjusted for alcohol consumption. These findings should be interpreted cautiously due to the limited number of cases in the subgroup analysis. The role of infection with H. pylori is the subject of ongoing research.

A recent case-control study in 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls found a possible association between past exposure to hepatitis B virus and risk of pancreatic cancer. In this study, anti-HBc was positive in 38 cases (8%) and 35 controls (0.9%). The estimated OR (95% CI) was 1.8 (0.9–3.1) for anti-HBc+/anti-HBs+ and 3.4 (1.3–9.1) for anti-HBc+/ anti-HBs . The proximity of the liver to the pancreas and the fact that the liver and pancreas share common blood vessels and ducts may make the pancreas a potential target organ for hepatitis viruses. In fact, hepatitis B surface antigen (HBsAg), a marker for chronic HBV infection, was detected in pure pancreatic juice and pure bile juice and there was evidence of HBV replication in pancreatic cells and concurrent damage to exocrine and endocrine epithelial cells with an inflammatory response [135,136]. The possibility that viral hepatitis can lead to pancreatic damage was further supported by findings of elevated pancreatic enzyme levels in a substantial percentage of patients with acute and chronic HBV and HCV infection [137,138]. However, de Gonzalez et al. reported in a study of 201,975 Koreans including 664 cases of pancreatic cancer, no association was found between hepatitis B HBsAg positivity and pancreatic cancer (RR, 1.13; 95% CI, 0.84–1.52). The association of hepatitis B infection and pancreatic cancer needs further investigation.

Occupation

The role of occupational or industrial factors in pancreatic cancer has been investigated extensively. Increased risk of pancreatic cancer has been associated with exposures to some chemicals (e.g., organochlorines, chlorinated hydrocarbons, and formaldehyde), or some specific occupations (e.g., stone miners, cement workers, gardeners, and textile workers). However, the statistical power of most of these studies is quite low because of the rarity of pancreatic cancer. Many of these observations could be by chance alone. A meta-analysis [140,141] reviewed 261 studies published from 1969 through 1998 on pancreatic cancer and job titles including more than 3,799 observed pancreatic cancer cases. The results suggest that occupational exposures to chlorinated hydrocarbon compounds may increase the risk of pancreatic cancer; the summary RR was 2.21 (95% CI: 1.31–3.68). Suggestive weak excess was also found for exposure to insecticides. The summary RR was 1.95 (95% CI: 0.51–7.41). In spite of many investigations, there is no compelling evidence linking occupational exposure to substance to risk of pancreatic cancer. Large studies with refined exposure measurement are required to test the hypothesis generated from the previous studies. The possible interactions between occupational exposure, lifestyle factors, and genetic susceptibility remain to be elucidated.

Allergy

A number of studies have examined the association of prior allergies with risk of pancreatic cancer. A meta-analysis of 14 population-based studies (4 cohort and 10 case-control studies) with a total of 3,040 pancreatic cancer cases found history of allergy was associated with a reduced risk of pancreatic cancer (RR, 0.82; 95% CI, 0.68–0.99). The risk reduction was stronger for allergies related to atopy (RR, 0.71; 95% CI, 0.64–0.80), but not for asthma (RR, 1.01; 95% CI, 0.77–1.31). There was no association between allergies related to food or drugs and pancreatic cancer (RR, 1.08; 95% CI, 0.74–1.58). In addition, two population-based case control studies based on direct interview consistently demonstrated a 20–30% reduced risk of pancreatic cancer among individuals with any prior history of allergy [143,144]. The hyperactive immune system of allergic individuals may, therefore, in some way lead to increased surveillance and protect against pancreatic cancer development.

Non-steroidal anti-inflammatory drugs

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have received considerable interest because these agents target cyclooxygenase enzymes, therefore may inhibit tumor growth by enhancing immune responses, modulating cellular proliferation, inhibiting prostaglandin synthesis, influencing apoptosis and tumorigenesis. The Iowa Women’s Health Study of 28,283 postmenopausal women including 80 pancreatic cancer cases found a significant lower RR of pancreatic cancer for aspirin user compared to non-user (RR, 0.57; 95% CI, 0.36–0.90). However, this finding was not confirmed in a later study. A moderate increased risk was reported for women with extended period of regular aspirin use in the Nurses’ Health Study including 161 cases. In the Women’s Health Initiative study, nearly 40,000 women were randomized to receive either 100 mg aspirin every other day or placebo. No statistically significant difference was noted between tested and placebo group after average 10.1 years of follow-up [148,149]. Larsson et al. reported a meta-analysis of 11 studies conducted from 1966 to October 2006 (3 case-control studies, 7 cohort studies, and 1 randomized trial), involving 6,386 pancreatic cancer cases. Neither use of aspirin, nonaspirin NSAIDs, nor overall NSAIDs were associated with pancreatic cancer risk. In 2007, Capurso et al. conducted a meta-analysis including 8 studies (4 cohort studies, 3 case-control studies, and 1 randomized controlled trial) of 6,301 patients enrolled 1971–2004 and no association was found between use of aspirin or NSAIDs and risk of pancreatic cancer. Whether the negative findings were related to the large baseline exposure in controls in North America needs to be clarified in future study.

Statins and metformin

Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are a class of pharmacologic agents that reduce plasma cholesterol. Statins have been shown to have antitumor activity in various studies on pancreatic cancer cell lines. However, a meta-analysis till December 2007 including 12 studies (5 case–control studies, 4 cohort studies, and 3 randomized placebo-controlled trials) did not support a reduced risk of pancreatic cancer in association with low-dose intake of statins at the population level.

Conclusion

Pancreatic cancer remains a major cause of cancer-related death. Effective prevention measure depends on well-defined risk factors by epidemiological research. Unlike previous studies that universally impeded by small sample size, survivor bias, and use of proxy respondents for patients, more pooled studies and large prospective studies have emerged to provide epidemiologic evidence on risk factors of pancreatic cancer. Cigarette smoking is a well established risk factor. There is accumulating evidence supporting a role of obesity and diabetes as risk factors for this malignancy. More than 50% of the pancreatic cancer is probably preventable by adapting a healthy lifestyle. The associations of dietary factors, alcohol, pancreatitis, infectious agent, occupational and hormonal factors and risk of pancreatic cancer are inconclusive. The study findings on systematic reviews on exposure and risk of pancreatic cancer should be considered suggestive because there are great between-study heterogeneity due to different assessment tools and study populations. Publication bias is often a concern. Welldesigned large prospective studies and consortium studies are required to further define the environmental and host factors contributing to the development of pancreatic cancer. Further research on the genetic susceptibility factors and their interactions with the known risk factors for pancreatic cancer may help better understand the etiology of this disease and offer new tools for identifying high-risk individuals for preventive intervention.

Key research points

  • The percentage of pancreatic cancer cases attributable to the inherited pancreatic cancer syndromes is small. However, investigations on the molecular mechanisms underlying these inherited syndromes shed light on the pathophysiology of pancreatic tumorigenesis. These individuals may be benefited by close surveillance and screening with imaging modalities.
  • Cigarette smoking and obesity may each be responsible for causing as many as 25% of the cases of pancreatic cancer. Therefore, it is possible that as many as 50% of pancreatic cancer cases are preventable. Avoid smoking and maintaining a healthy body weight offer the best available strategy for reducing the incidence of this disease.
  • Diabetes could be the manifestation of pancreatic cancer, but long-standing type II diabetes mellitus has been implicated as a risk factor.
  • Other suspected risk factors for pancreatic cancer include heavy alcohol consumption and pancreatitis.
  • Consume of a well balanced diet with adequate amounts of fruits and vegetables, limited amounts of alcohol, and limited amounts of red meat, especially high fat or processed meat may also reduce the risk of pancreatic cancer.

Future scientific directions

  • Effective prevention measure depends on well-defined risk factors by epidemiological research.
  • The cause of pancreatic cancer involves multiple factors and complex etiology. Well-designed large prospective studies and consortium studies are required to generate sufficient amount of information on the role of environmental and host factors in pancreatic cancer development.
  • Further research on the genetic susceptibility factors and their interactions with the known risk factors for pancreatic cancer may help better understand the etiology of this disease and offer new tools for identifying high-risk individuals for monitoring and screening.
  • New molecular techniques, such as genome-wide association scan, microarray analysis of gene expression and proteomic approaches may ultimately help in discovering biomarkers for early diagnosis, which will have a major impact on reducing the mortality of pancreatic cancer.

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
  2. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR, 2007, pp. 271–274.
  3. Parkin DM, Muir CS: Cancer incidence in five continents. Comparability and quality of data. IARC Sci Publ 1992;120:45–173.
  4. Ries L, Melbert D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975–2005. Bethesda: National Cancer Institute, 2008.
  5. Anderson K, Potter JD, Mack TM: Pancreatic cancer. In Cancer Epidemiology and Prevention. Schottenfeld, D Fraumeni, JF Jr., (eds.). New York: Oxford University Press, 2006, pp. 721–762.
  6. Parkin DM: International variation. Oncogene 2004;23:6329–6340.
  7. Silverman DT, Hoover RN, Brown LM, Swanson GM, Schiffman M, Greenberg RS, Hayes RB, Lillemoe KD, Schoenberg JB, Schwartz AG, Liff J, Pottern LM, Fraumeni JF, Jr: Why do Black Americans have a higher risk of pancreatic cancer than White Americans? Epidemiology 2003;14:45–54.
  8. Greer JB, Whitcomb DC, Brand RE: Genetic predisposition to pancreatic cancer: a brief review. Am J Gastroenterol 2007;102:2564–2569.
  9. Lynch HT, Lanspa SJ, Fitzgibbons RJ, Jr., Smyrk T, Fitzsimmons ML, McClellan J: Familial pancreatic cancer (Part 1): Genetic pathology review. Nebr Med J 1989;74:109–112.
  10. Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, Hruban RH: Kern SE.Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002;62:3789–3793.
  11. Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996;56:5360–5364.
  12. Klein AP, Hruban RH, Brune KA, Petersen GM, Goggins M: Familial pancreatic cancer. Cancer J 2001;7:266–273.
  13. Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, Fontaine LS, Organic SM, Dracopoli NC, Clark WH, Jr., et al.: Increased risk of pancreatic cancer in melanomaprone kindreds with p16INK4 mutations. N Engl J Med 1995;333:970–974.
  14. Lynch HT, Brand RE, Hogg D, Deters CA, Fusaro RM, Lynch JF, Liu L, Knezetic J, Lassam NJ, Goggins M, Kern S: Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 2002;94:84–96.
  15. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998;391(6663):184–187.
  16. Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, CruzCorrea M, Offerhaus JA: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119(6):1447–1453.
  17. Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, Westerman AM, Entius MM, Goggins M, Yeo CJ, Kern SE: Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999;154 (6):1835–1840.
  18. Lim W, Olschwang S, Keller JJ, Westerman AM, Menko FH, Boardman LA, Scott RJ, Trimbath J, Giardiello FM, Gruber SB, Gille JJ, Offerhaus GJ, de Rooij FW, Wilson JH, Spigelman AD, Phillips RK, Houlston RS: Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 2004;126:1788–1794.
  19. Varley JM: Germline TP53 mutations and LiFraumeni syndrome. Hum Mutat 2003;21(3):313–320.
  20. Cowgill SM, Muscarella P: The genetics of pancreatic cancer. Am J Surg 2003;186(3):279–286.
  21. Giardiello FM, Offerhaus GJ, Lee DH, Krush AJ, Tersmette AC, Booker SV, Kelley NC, Hamilton SR: Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 1993;34 (10):1394–1396.
  22. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Jr., Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC: Ehrlich GD, Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14(2):141–145.
  23. Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK, Jr., Perrault J, Whitcomb DC: Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89(6):442–446.
  24. Keim V: Role of genetic disorders in acute recurrent pancreatitis. World J Gastroenterol 2008;14(7):1011–1015.
  25. Lowenfels AB, Maisonneuve P, Whitcomb DC: Risk factors for cancer in hereditary pancreatitis. International Hereditary Pancreatitis Study Group. Med Clin North Am 2000;84(3):565–573.
  26. Tersmette AC, Petersen GM, Offerhaus GJ, Falatko FC, Brune KA, Goggins M, Rozenblum E, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH: Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 2001;7:738–744.
  27. Permuth-Wey J: Egan KM. Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis. Fam Can 2009;8:109–117.
  28. Eberle MA, Pfutzer R, Pogue-Geile KL, Bronner MP, Crispin D, Kimmey MB, Duerr RH, Kruglyak L, Whitcomb DC, Brentnall TA: A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32–34. Am J Hum Genet 2002;70:1044–1048.
  29. Pogue-Geile KL, Chen R, Bronner MP, CrnogoracJurcevic T, Moyes KW, Dowen S, Otey CA, Crispin DA, George RD, Whitcomb DC, Brentnall TA: Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism. PLoS Med 3:2006;e516.
  30. Slater E, Amrillaeva V, Fendrich V, Bartsch D, Earl J, Vitone LJ, Neoptolemos JP, Greenhalf W: Palladin mutation causes familial pancreatic cancer: absence in European families. PLoS Med 4:2007;e164.
  31. Klein AP, de Andrade M, Hruban RH, Bondy M, Schwartz AG, Gallinger S, Lynch HT, Syngal S, Rabe KG, Goggins MG, Petersen GM: Linkage analysis of chromosome 4 in families with familial pancreatic cancer. Cancer Biol Ther 2007;6:320–323.
  32. Iodice S, Gandini S, Maisonneuve P, Lowenfels AB: Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg 2008;393:535–545.
  33. Thompson PA, Seyedi F, Lang NP, McLeod SL, Woogen GN, Anderson KE, Tang YM, Coles B, Kadlubar FF: Comparison of DNA adduct levels associated with exogenous and endogenous exposures in human pancreas in relation to metabolic genotype. Mutat Res 1999;424:263–274.
  34. Wang M-Y, Abbruzzese JL, Friess H, Hittelman WN, Evans DB, Abbruzzese MC, Chiao PL, Li D: DNA adducts in human pancreatic tissues and their potential role in carcinogenesis. Cancer Res 1998;58:38–41.
  35. Prokopczyk B, Hoffmann D, Bologna M, Cunningham AJ, Trushin N, Akerkar S, Boyiri T, Amin S, Desai D, Colosimo S, Pittman B, Ledger G, Ramadani M, Henne-Bruns D, Beger HG, ElBayoumy K: Identification of tobacco-derived compounds in human pancreatic juice. Chem Res Toxicol 2002;15:677–685.
  36. Duell EJ, Wiencke JK, Cheng T-J, Varkonyi A, Zuo ZF, Ashok TD, Mark EJ, Wain JC, Christiani DC, Kelsey KT: Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 2000;21:965–971 [published erratum appears in Carcinogenesis (Lond.) 2000;21:1457].
  37. Duell EJ, Holly EA, Bracci PM, Liu M, Wiencke JK, Kelsey KT: A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J Natl Cancer Inst 2002;4:297–306.
  38. Suzuki H, Jiao L, Li Y, Doll MA, Hein DW, Hassan MM, Day RS, Bondy ML, Abbruzzese JL, Li D: Interaction of the Cytochrome P4501A2, SULT1A1 and NAT gene polymorphisms with smoking and dietary mutagen intake in modification of the risk of pancreatic cancer. Carcinogenesis 2008;29(6):1184–1191.
  39. McWilliams RC, Bamlet WR, Cunningham JM, Goode EL, de Andrade M, Boardman LA, Petersen GM: Polymorphisms in DNA Repair Genes, Smoking, and Pancreatic Adenocarcinoma Risk Cancer Res 2008;68(12):4928–4935.
  40. Li D, Suzuki H, Liu B, Morris J, Liu J, Okazaki T, Li Y, Chang P, Abbruzzese JL. DNA repair gene polymorphisms and risk of pancreatic cancer. Clin Can Res 2009;15(2):740–746.
  41. Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL: K-ras oncogene activation in adenocarcinoma of the human
  42. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 1993;143:545–554.
  43. Jiao L, Zhu JJ, Hassan M, Abbruzzese JL, Li D: K-ras mutation and p16 and preproenkephalin promoter hypermethylation in plasma DNA of pancreatic cancer patients in relation to cigarette smoking. Pancreas 2007;34:55–62.
  44. Baker F, Ainsworth SR, Dye JT, Crammer C, Thun MJ, Hoffmann D, Repace JL, Henningfield JE, Slade J, Pinney J, Shanks T, Burns DM, Connolly GN, Shopland DR: Health risks associated with cigar smoking. JAMA 2000;284:735–740.
  45. Henley SJ, Thun MJ, Chao A, Calle EE: Association between exclusive pipe smoking and mortality from cancer and other diseases. J Natl Cancer Inst 2004;96:853–861.
  46. Boffetta P, Aagnes B, Weiderpass E, Andersen A: Smokeless tobacco use and risk of cancer of the pancreas and other organs. Int J Cancer 2005;114:992–995.
  47. Shapiro JA, Jacobs EJ, Thun MJ: Cigar smoking in men and risk of death from tobacco-related cancers. J Natl Cancer Inst 2000;92:333–337.
  48. Alguacil J, Silverman DT: Smokeless and other noncigarette tobacco use and pancreatic cancer: a casecontrol study based on direct interviews. Cancer Epidemiol Biomarkers Prev 2004;13:55–58.
  49. Hassan MM, Abbruzzese JL, Bondy ML, Wolff RA, Vauthey J-N, Pisters PW, Evans DB, Khan R, Chou T-H, Lenzi R, Jiao L, Li D: Passive smoking and use of noncigarette tobacco products and risk for pancreatic cancer: case-control study. Cancer 2007;109:2547–2556.
  50. Villeneuve PJ, Johnson KC, Mao Y, Hanley AJ: Environmental tobacco smoke and the risk of pancreatic cancer: findings from a Canadian population-based case-control study. Can J Public Health 2004;95:32–37.
  51. Gallicchio L, Kouzis A, Genkinger JM, Burke AE, Hoffman SC, Diener-West M, Helzlsouer KJ, Comstock GW, Alberg AJ: Active cigarette smoking, household passive smoke exposure, and the risk of developing pancreatic cancer. Prev Med 2006;42 (3):200–205.
  52. Berrington de Gonzalez A, Sweetland S, Spencer E: A meta-analysis of obesity and the risk of pancreatic cancer. Br J Cancer 2003;89:519–523.
  53. Larsson SC, Orsini N, Wolk A: Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies. Int J Cancer 2007;120:1993–1998.
  54. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M: Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569–578.
  55. Calle EE, Kaaks R: Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;8:579–591.
  56. Larsson SC, Permert J, Hakansson N, Naslund I, Bergkvist L, Wolk A: Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts. Br J Cancer 2005;93:1310–1315.
  57. Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE: Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer Epidemiol Biomarkers Prev 2005;14:459–466.
  58. Berrington de Gonzalez A, Spencer EA, Bueno-deMesquita HB, Roddam A, Stolzenberg-Solomon R, Halkjaer J, Tjonneland A, Overvad K, ClavelChapelon F, Boutron-Ruault MC, Boeing H, Pischon T, Linseisen J, Rohrmann S, Trichopoulou A, Benetou V, Papadimitriou A, Pala V, Palli D, Panico S, Tumino R, Vineis P, Boshuizen HC, Ocke MC, Peeters PH, Lund E, Gonzalez CA, Larranaga N, Martinez-Garcia C, Mendez M, Navarro C, Quiros JR, Tormo MJ, Hallmans G, Ye W, Bingham SA, Khaw KT, Allen N, Key TJ, Jenab M, Norat T, Ferrari P, Riboli E: Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 2006;15:879–885.
  59. Stolzenberg-Solomon RZ, Adams K, Leitzmann M, Schairer C, Michaud DS, Hollenbeck A, Schatzkin A, Silverman DT: Adiposity, physical activity, and pancreatic cancer in the National Institutes of Health-AARP Diet and Health Cohort. Am J Epidemiol 2008;167:586–597.
  60. Luo J, Margolis KL, Adami HO, LaCroix A, Ye W: Obesity and risk of pancreatic cancer among postmenopausal women: the Women’s Health Initiative (United States). Br J Cancer 2008;99:527–531.
  61. Ansary-Moghaddam A, Huxley R, Barzi F, Lawes C, Ohkubo T, Fang X, Jee SH, Woodward M: The effect of modifiable risk factors on pancreatic cancer mortality in populations of the Asia-Pacific region. Cancer Epidemiol Biomarkers Prev 2006;15:2435–2440.
  62. IARC handbooks on cancer prevention: Weight control and physical activity. Lyon, France: IARC Press, 2002.
  63. Michaud DS, Giovannucci E, Willet WC, Colditz GA, Stampfer MJ, Fuchs CS: Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 2001;286(8):921–929.
  64. Fisher WE: Diabetes: risk factor for the development of pancreatic cancer or manifestation of the disease? World J Surg 2001;25:503–508.
  65. Gullo L, Pezzilli R, Morselli-Labate AM: Diabetes and the risk of pancreatic cancer. N Engl J Med 1994;331:81–84.
  66. Valerio A, Basso D, Brigato L, Ceolotto G, Baldo G, Tiengo A, Plebani M: Glucose metabolic alterations in isolated and perfused rat hepatocytes induced by pancreatic cancer conditioned medium: a low molecular weight factor possibly involved. Biochem Biophys Res Commun 1999;257:622–628.
  67. Basso D, Valerio A, Seraglia R, Mazza S, Piva MG, Greco E, Fogar P, Gallo N, Pedrazzoli S, Tiengo A, Plebani M: Putative pancreatic cancer-associated diabetogenic factor: 2030 MW peptide. Pancreas 2002;24:8–14.
  68. Chow WH, Gridley G, Nyren O, Linet MS, Ekbom A, Fraumeni JF, Jr., Adami HO: Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden. J Natl Cancer Inst 1995;87:930–931.
  69. Everhart J, Wright D: Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 1995;273:1605–1609.
  70. Huxley RA, Ansary-Moghaddam A, de Gonzalez B, Barzi F, Woodward M: Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076–2083.
  71. Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM: Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005;129:504–511.
  72. Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, Petersen GM: Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008;134(1):95–101.
  73. Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST: Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 2008;134(4):981–987.
  74. Stevens RJ, Roddam AW, Beral V: Pancreatic cancer in type 1 and young-onset diabetes: systematic review and meta-analysis. Br J Cancer 2007;96:507–509.
  75. Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A: Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 2000;283:2552–2558.
  76. Batty GD, Shipley MJ, Marmot M, Smith GD: Diabetes status and post-load plasma glucose concentration in relation to site-specific cancer mortality: findings from the original Whitehall study. Cancer Cause Control 2004;15:873–881.
  77. Stattin P, Bjor O, Ferrari P, Lukanova A, Lenner P, Lindahl B, Hallmans G, Kaaks R: Prospective study of hyperglycemia and cancer risk. Diabetes Care 2007;30:561–567.
  78. Stolzenberg-Solomon RZ, Graubard BI, Chari S, Limburg P, Taylor PR, Virtamo J, Albanes D: Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 2005;294(22):2872–2878.
  79. Pisani P: Hyper-insulinaemia and cancer, metaanalyses of epidemiological studies. Arch Physiol Biochem 2008;114(1):63–70.
  80. Michaud DS, Wolpin B, Giovannucci E, Liu S, Cochrane B, Manson JE, Pollak MN, Ma J, Fuchs CS: Prediagnostic plasma C-peptide and pancreatic cancer risk in men and women. Cancer Epidemiol Biomarkers Prev 2007;16(10):2101–2109.
  81. Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, Chochrane BB, Rohan TE, Ma J, Pollak MN, Fuchs CS: Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts. Br J Cancer 2007;97(1):98–104.
  82. Stolzenberg-Solomon RZ, Limburg P, Pollak M, Taylor PR, Virtamo J, Albanes D: Insulin-like growth factor (IGF)-1, IGF-binding protein-3, and pancreatic cancer in male smokers. Cancer Epidemiol Biomarkers Prev 2004;13:438–444.
  83. Lin Y, Tamakoshi A, Kikuchi S, Yagyu K, Obata Y, Ishibashi T, Kawamura T, Inaba Y, Kurosawa M, Motohashi Y, Ohno Y: Serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, and the risk of pancreatic cancer death. Int J Cancer 2004;110:584–588.
  84. Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, Cochrane BB, Rohan TE, Ma J, Pollak MN, Fuchs CS: Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts. Br J Cancer 2007;97:98–104.
  85. Silverman DT, Brown LM, Hoover RN, Schiffman M, Lillemoe KD, Schoenberg JB, Swanson GM, Hayes RB, Greenberg RS, Benichou J, et al.: Alcohol and pancreatic cancer in blacks and whites in the United States. Cancer Res 1995;55:4899–4905.
  86. Hassan MM, Wolff RA, Bondy ML, Abbruzzese JL, Vauthey J-N, Pisters PW, Evans DB, Khan R, Chou T-H, Lenzi R, Jiao L, Li D: Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol 2007;102:2696–2707.
  87. Lu XH, Wang L, Li H, Qian JM, Deng RX, Zhou L: Establishment of risk model for pancreatic cancer in Chinese Han population. World J Gastroenterol 2006;12:2229–2234.
  88. Olsen GW, Mandel JS, Gibson RW, Wattenberg LW, Schuman LM: A case-control study of pancreatic cancer and cigarettes, alcohol, coffee and diet. Am J Public Health 1989;79:1016–1019.
  89. Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, Brandt PA, English DR, Freudenheim JL, Fuchs CS, Giles GG, Giovannucci
  90. E, Hankinson SE, Horn-Ross PL, Leitzmann M, Mannisto S, Marshall JR, McCullough ML, Miller AB, Douglas J, Reding KR, Rohan TE, Schatzkin A, Stevens, VL, Stolzenberg-Solomon RZ, Verhage BAJ, Wolk A, Ziegler RG, Smith-Warner SA: Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies. Cancer Epidemiol Biomarkers Prev 2009;18:765–776.
  91. Rohrmann S, Linseisen J, Vrieling A, Boffetta P, Stolzenberg-Solomon RZ, Lowenfels AB, Jensen MK, Overvad K, Olsen A, Tjonneland A, Boutron-Ruault MC, Clavel-Chapelon F, Fagherazzi G, Misirli G, Lagiou P, Trichopoulou A, Kaaks R, Bergmann MM, Boeing H, Bingham S, Khaw KT, Allen N, Roddam A, Palli D, Pala V, Panico S, Tumino R, Vineis P, Peeters PH, Hjartaker A, Lund E: Cornejo ML, Agudo A, Arriola L, Sanchez MJ, Tormo MJ, Barricarte Gurrea A, Lindkvist B, Manjer J, Johansson I, Ye W, Slimani N, Duell EJ, Jenab M, Michaud DS, Mouw T, Riboli E, Bueno-de-Mesquita HB: Ethanol intake and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition (EPIC). Cancer Cause Control 2009;20:785–794.
  92. Jiao L, Silverman DT, Schairer C, Thiebaut A, Hollenbeck A, Leitzmann M, Schatzkin A, Stolzenberg-Solomon R: Alcohol use and risk of pancreatic cancer The NIH-AARP Diet and Health Study. Am J Epidemiol 2009;169:1043–1051.
  93. Steer ML, Waxman I, Freedman S: Chronic pancreatitis. N Engl J Med 1995;332:1482–1490.
  94. Lowenfels AB, Maisonneuve P, Gavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L for The International Pancreatitis Study Group: Pancreatitis and the risk of pancreatic cancer. N Engl J Med 1993;328:1433–1437.
  95. Talamini G, Falconi M, Bassi C, Sartori N, Salvia R, Caldiron E, Frulloni L, Di Francesco V, Vaona B, Bovo P, Vantini I, Pederzoli P, Cavallini G: Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999;94:1253–1260.
  96. Karlson BM, Ekbom A, Josefsson S, McLaughlin JK, Fraumeni JF, Jr., Nyren O: The risk of pancreatic cancer following pancreatitis: an association due to confounding? Gastroenterology 1997;113:587–592.
  97. Nothlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN: Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer Inst 2005;97 (19):1458–1465.
  98. Anderson KE, Sinha R, Kulldorff M, Gross M, Lang NP, Barber C, Harnack L, DiMagno E, Bliss R, Kadlubar FF: Meat intake and cooking techniques: associations with pancreatic cancer. Mutat Res 2002;506–7:225–231.
  99. Li D, Day S, Bondy ML, Sinha R, Nguyen NT, Evans DB, Abbruzzese JL, Hassan M: Dietary mutagen exposure and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2007;16:655–661.
  100. Stolzenberg-Solomon RZ, Cross AJ, Silverman DT, Schairer C, Thompson FE, Kipnis V, Subar AF, Hellenbeck A, Schatzkin A, Sinha R: Meat and meat-mutagen intake and pancreatic cancer risk in the NIH-AARP cohort. Cancer Epidemiol Biomarkers Prev 2007;16(12):2664–2675.
  101. Gold EB, Goldin SB: Epidemiology of and risk factors for pancreatic cancer. Surg Oncol Clin N AM 1998;7:67–91.
  102. Larsson SC, Hakansson N, Naslund I, Bergkvist L, Wolk A: Fruit and vegetable consumption in relation to pancreatic cancer risk: a prospective study. Cancer Epidemiol Biomarkers Prev 2006;15:301–305.
  103. Vrieling A, Verhage BA, van Duijnhoven FJ, Jenab M, Overvad K, Tjonneland A, Olsen A, ClavelChapelon F, Boutron-Ruault MC, Kaaks R, Rohrmann S, Boeing H, Nothlings U, Trichopoulou A, John T, Dimosthenes Z, Palli D, Sieri S, Mattiello A, Tumino R, Vineis P, van Gils CH, Peeters PH, Engeset D, Lund E, Rodriguez Suarez L, Jakszyn P, Larranaga N, Sanchez MJ, Chirlaque MD, Ardanaz E: Manjer J, Lindkvist B, Hallmans G, Ye W, Bingham S, Khaw KT, Roddam A, Key T, Boffetta P, Duell EJ, Michaud DS, Riboli E, Bueno-de-Mesquita HB: Fruit and vegetable consumption and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2009;124:1926–1934.
  104. Nothlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN: Vegetable intake and pancreatic cancer risk: the multiethnic cohort study. Am J Epidemiol 2007;165:138–147.
  105. Bae JM, Lee EJ, Guyatt G: Citrus fruit intake and pancreatic cancer risk: a quantitative systematic review. Pancreas 2009;38:168–174.
  106. Chan JM, Wang F, Holly EA: Vegetable and fruit intake and pancreatic cancer in a population-based case-control study in the San Francisco bay area. Cancer Epidemiol Biomarkers Prev 2005;14:2093–2097.
  107. Nothlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN: Flavonols and pancreatic cancer risk: the multiethnic cohort study. Am J Epidemiol 2007;166:924–931.
  108. Bobe G, Weinstein SJ, Albanes D, Hirvonen T, Ashby J, Taylor PR, Virtamo J, StolzenbergSolomon RZ: Flavonoid intake and risk of pancreatic cancer in male smokers (Finland). Cancer Epidemiol Biomarkers Prev 2008;17:553–562.
  109. Larsson SC, Giovannucci E, Wolk A: Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 2006;131:1271–1283.
  110. Larsson SC, Hakansson N, Giovannucci E, Wolk A: Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. J Natl Cancer Inst 2006;98:407–413.
  111. Stolzenberg-Solomon RZ, Albanes D, Nieto FJ, Hartman TJ, Tangrea JA, Rautalahti M, Sehlub J, Virtamo J, Taylor PR: Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers. J Natl Cancer Inst 1999;91:535–541.
  112. Schernhammer E, Wolpin B, Rifai N, Cochrane B, Manson JA, Ma J, Giovannucci E, Thomson C, Stampfer MJ, Fuchs C: Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts. Cancer Res 2007;67:5553–5560.
  113. Skinner HG, Michaud DS, Giovannucci EL, Rimm EB, Stampfer MJ, Willett WC, Colditz GA, Fuchs CS: A prospective study of folate intake and the risk of pancreatic cancer in men and women. Am J Epidemiol 2004;160(3):248–258.
  114. Silverman DT, Swanson CA, Gridley G, Wacholder S, Greenberg RS, Brown LM, Hayes RB, Swanson GM, Schoenberg JB, Pottern LM, Schwartz AG, Fraumeni JF, Jr., Hoover RN: Dietary and nutritional factors and pancreatic cancer: a case-control study based on direct interviews. J Natl Cancer Inst 1998;90:1710–1719.
  115. Nkondjock A, Ghadirian P, Johnson KC, Krewski D: Dietary intake of lycopene is associated with reduced pancreatic cancer risk. J Nutr 2005;135:592–597.
  116. Kavanaugh CJ, Trumbo PR, Ellwood KC: The US Food and Drug Administration’s evidence-based review for qualified health claims: tomatoes, lycopene, and cancer. J Natl Cancer Inst 2007;99:1074–1085.
  117. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C: Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and metaanalysis. Lancet 2004;364:1219–1228.
  118. Howe GR, Ghadirian P, Bueno de Mesquita HB, Zatonski WA, Baghurst PA, Miller AB, Simard A, Baillargeon J, de Waard F, Przewozniak K, et al.: A collaborative case-control study of nutrient intake and pancreatic cancer within the search programme. Int J Cancer 1992;51(3):365–372.
  119. Howe GR Burch JD: Nutrition and pancreatic cancer. Cancer Cause Control 1996;7(1):69–82.
  120. Michaud DS, Liu S, Giovannucci E, Willett WC, Colditz GA, Fuchs CS: Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study. J Natl Cancer Inst 2002;94(17):1293–1300.
  121. Johnson KJ, Anderson KE, Harnack L, Hong CP, Folsom AR: No association between dietary glycemic index or load and pancreatic cancer incidence in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2005;14:1574–1575.
  122. Silvera SA, Rohan TE, Jain M, Terry PD, Howe GR, Miller AB: Glycemic index, glycemic load, and pancreatic cancer risk (Canada). Cancer Cause Control 2005;16:431–436.
  123. Patel AV, McCullough ML, Pavluck AL, Jacobs EJ, Thun MJ, Calle EE: Glycemic load, glycemic index, and carbohydrate intake in relation to pancreatic cancer risk in a large US cohort. Cancer Cause Control 2007;18:287–294.
  124. Nothlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN: Dietary glycemic load, added sugars, and carbohydrates as risk factors for pancreatic cancer: the Multiethnic Cohort Study. Am J Clin Nutr 2007;86:1495–1501.
  125. Heinen MM, Verhage BA, Lumey L, Brants HA, Goldbohm RA, van den Brandt PA: Glycemic load, glycemic index, and pancreatic cancer risk in the Netherlands Cohort Study. Am J Clin Nutr 2008;87:970–977.
  126. Jiao L, Flood A, Subar AF, Hollenbeck A, Schatzkin A: Stolzenberg-Solomon R. Glycemic index, available carbohydrate, glycemic load and risk of pancreatic cancer in the NIH-AARP Diet and Health Study. Cancer Epidemiol Biomarkers Prev 2009; 18(4):1144–1151.
  127. Mulholland HG, Murray LJ, Cardwell CR, Cantwell MM: Glycemic index, glycemic load, and risk of digestive tract neoplasms: a systematic review and meta-analysis. Am J Clin Nutr 2009;89:568–576.
  128. Bao Y, Stolzenberg-Solomon R, Jiao L, Silverman DT, Subar AF, Park Y, Leitzmann MF, Hollenbeck A, Schatzkin A, Michaud DS: Added sugar and sugar-sweetened foods and beverages and the risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study. Am J Clin Nutr 2008;88:431–440.
  129. Raderer M, Wrba F, Kornek G, et al.: Association between Helicobacter pylori infection and pancreatic cancer. Oncology 1998;55:16–19.
  130. Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, et al.: Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. J Nat Cancer Inst 2001;93:927–941.
  131. Hassan MM, Li D, El-Deeb A, Wolff RA, Bondy ML, Davila M, Abbruzzese JL: Hepatitis B Virus and pancreatic cancer. J Clin Oncol 2008;26 (28):4557–4562.
  132. Tersmette AC, Offerhaus GJ, Giardiello FM, et al.: Occurrence of non-gastric cancer in the digestive tract after remote partial gastrectomy: analysis of an Amsterdam cohort. Int J Cancer 1990;465:792–795.
  133. Hedberg M, Ogren M, Janzon L, et al.: Pancreatic carcinoma following gastric resection. Int J Pancreatol 1997;21:219–224.
  134. de Martel C, Llosa AE, Friedman GD, Vogelman JH, Orentreich N, Stolzenberg-Solomon RZ, Parsonnet J: Helicobacter pylori infection and development of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2008;17:1188–1194.
  135. Lindkvist B, Johansen D, Borgstrom A, Manjer J: A prospective study of Helicobacter pylori in relation to the risk for pancreatic cancer. BMC Cancer 2008;8:321.
  136. Hoefs JC, Renner IG, Askhcavai M, Redeker AG: Hepatitis B surface antigen in pancreatic and biliary secretions. Gastroenterology 1980;79(2):191–194.
  137. Yoshimura M, Sakurai I, Shimoda T, Abe K, Okano T, Shikata T: Detection of HBsAg in the pancreas. Acta Pathol Jpn 1981;31(4):711–717.
  138. Shimoda T, Shikata T, Karasawa T, Tsukagoshi S, Yoshimura M, Sakurai I: Light microscopic localization of hepatitis B virus antigens in the human pancreas. Possibility of multiplication of hepatitis B virus in the human pancreas. Gastroenterology 1981;81(6):998–1005.
  139. Taranto D, Carrato A, Romano M, Maio G, Izzo CM, Del Vecchio BC: Mild pancreatic damage in acute viral hepatitis. Digestion 1989;42(2):93–97.
  140. Katakura Y, Yotsuyanagi H, Hashizume K, Okuse C, Okuse N, Nishikawa K et al. Pancreatic involvement in chronic viral hepatitis. World J Gastroenterology 2005;11(23):3508–3513.
  141. de Gonzalez AB, Jee SH, Engels EA: No association between hepatitis B and pancreatic cancer in a prospective study in Korea. J Clin Oncol 2009;1:648.
  142. Ojaja¨rvi A, Partanen T, Ahlbom A, Boffetta P, Hakulinen T, Jourenkova N, Kauppinen T, Kogevinas M, Vainio H, Weiderpass E, Wesseling C: Risk of pancreatic cancer in workers exposed to chlorinated hydrocarbon solvents and related compounds: a meta-analysis. Am J Epidemiol 2001;153(9):841–850.
  143. Ojaja¨rvi A, Partanen T, Ahlbom A, Hakulinen T, Kauppinen T, Weiderpass E, Wesseling C: Estimating the relative risk of pancreatic cancer associated with exposure agents in job title data in a hierarchical Bayesian meta-analysis. Scand J Work Environ Health 2007;33(5):325–335.
  144. Gandini S, Lowenfels AB, Jaffee EM, Armstrong TD, Maisonneuve P: Allergies and the risk of pancreatic cancer: a meta-analysis with review of epidemiology and biological mechanisms. Cancer Epidemiol Biomarkers Prev 2005;14(8):1908–1916.
  145. Silverman DT, Schiffman M, Everhart J, Goldstein A, Lillemoe KD, Swanson GM, Schwartz AG, Brown LM, Greenberg RS, Schoenberg JB, Pottern LM, Hoover RN, Fraumeni JF, Jr: Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Brit J Cancer 1999;80(11):1830–1837.
  146. Holly EA, Eberle CA, Bracci PM: Prior history of allergies and pancreatic cancer in the San Francisco Bay area. Am J Epidemiology 2003;158(5):432–441.
  147. Anderson KE, Johnson TW, Lazovich D, Folsom AR: Association between nonsteroidal antiinflammatory drug use and the incidence of pancreatic cancer. J Natl Cancer Inst 2002;94 (15):1168–1171.
  148. Menezes RJ, Huber KR, Mahoney MC, Moysich KB: Regular use of aspirin and pancreatic cancer risk. BMC Public Health 2002;2:18.
  149. Schernhammer ES, Kang JH, Chan AT, Michaud DS, Skinner HG, Giovannucci E, Colditz GA, Fuchs CS: A prospective study of aspirin use and the risk of pancreatic cancer in women. J Natl Cancer Inst. 2004;96(1):22–28.
  150. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE: Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005;294(1):47–55.
  151. Larsson SC, Giovannucci E, Bergkvist L, Wolk A: Aspirin and nonsteroidal anti-inflammatory drug use and risk of pancreatic cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006;15 (12):2561–2564.
  152. Capurso G, Schu¨ nemann HJ, Terrenato I, Moretti A, Koch M, Muti P, Capurso L, Delle Fave G: Meta-analysis: the use of non-steroidal antiinflammatory drugs and pancreatic cancer risk for different exposure categories. Aliment Pharmacol Ther 2007;26(8):1089–1099.
  153. Bonovas S, Filioussi K, Sitaras NM: Statins are not associated with a reduced risk of pancreatic cancer at the population level, when taken at low doses for managing hypercholesterolemia: evidence from a meta-analysis of 12 studies. Am J Gastroenterol 2008;103(10):2646–2651.
  154. Jiao L, Mitrou PN, Reedy J, Graubard BI, Hollenbeck AR, Schatzkin A, Stolzenberg-Solomon R: A combined healthy lifestyle score and risk of pancreatic cancer in a large cohort study. Arch Intern Med 2009;169(8):764–770.
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