The biggest risk factors for pancreatic cancer are increasing age, smoking,89
new onset diabetes mellitus,90
increased body mass index,89
and an inherited predisposition for pancreatic cancer (box 2).94,95
A variety of dietary factors are also associated with an increased risk of pancreatic cancer, all of which are amenable to intervention and comprise increased red and processed meat consumption96
and reduced intake of methionine97
and folate from food sources.98
Tobacco smoking is associated with a twofold increase and because of the prevalence may be account for around 30% of all cases with pancreatic ductal adenocarcinoma. Chronic pancreatitis is now recognised as a risk factor, with some series finding a 15–25-fold risk.91,92
It has been observed that patients may have chronic pancreatitis for at least 20 years before the development of pancreatic cancer. These patients tend to have severe disease, increased calcification of the gland and a higher rate of complications. The risk of developing cancer is even higher with hereditary pancreatitis, with estimates of a 70-fold increase in risk.93
This is an uncommon disorder inherited as an autosomal dominant condition with an estimated 80% penetrance and an equal gender incidence, presenting in children and younger adults. The gene responsible was identified as the PRSS1 gene, and mutations have a causative role, resulting in a gain of function of the digestive enzyme trypsin.
There is an inherited component to pancreatic cancer accounting for about 10% of observed cases.94,95
Familial pancreatic cancer itself is rare and the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) (http://www.liv.ac.uk/surgery/europac.html,
accessed 22 May 2007) has been established to provide a database of these families for long-term follow-up, with the aim of identifying people at risk and developing a screening programme in the future. Diagnostic criteria are two or more first-degree relatives with pancreatic ductal adenocarcinoma or two or more second-degree relatives with pancreatic cancer, one of whom has early-onset pancreatic cancer (age <50 years at diagnosis). Overall, the observed to expected rate of pancreatic cancer is significantly raised by ninefold, rising specifically from fourfold in families with one first-degree relative, to 6.4-fold where there are two affected relatives to 32.0-fold with three relatives with pancreatic cancer.95
There is evidence that familial pancreatic cancer is an autosomal dominant condition99
and appears to demonstrate the phenomenon of anticipation with the age of onset reducing in succeeding generations.100
The main gene and causative mutation have not yet been identified, although up to 20% of families with familial pancreatic cancer have a BRCA2 mutation.101
One candidate gene is palladin,102
which encodes a component of the cytoskeleton that controls cell shape and motility, and has been identified in the susceptibility locus 4q32–34 in a large family from Seattle, USA (called family X),103
but both the susceptibility locus and the palladin gene variant described have not been confirmed in EUROPAC families.104,105
Several studies have examined the association between genetic polymorphisms and pancreatic cancer.94
Although over the whole population none of the genetic polymorphisms for two carcinogen-metabolising enzymes (cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase (GST)) could be directly associated with the risk of pancreatic cancer, the combination of heavy smoking and a deletion polymorphism in GSTT1 was associated with an increased risk of pancreatic cancer among Caucasians.106
Polymorphisms of glutathione S-transferase M1 (GSTM1) and acetyltransferases (NAT1 and NAT2) enzymes may also be associated with a modest increase in susceptibility to pancreatic cancer and chronic pancreatitis.107
The UDP glucuronosyltransferase (UGT1A7) gene is predominantly expressed in the human pancreas. The low detoxification activity UGT1A7*3 allele has been identified as a new risk factor of pancreatic diseases, defining an interaction of genetic predisposition and environmentally induced oxidative injury.108
Box 3 Secondary screening
- All patients with an increased inherited risk of pancreatic cancer should be referred to a specialist centre offering clinical advice and genetic counselling and, where appropriate, genetic testing such as for BRCA2 mutations.
- Primary screening for pancreatic cancer in the general population is not feasible at present.
- Secondary screening for pancreatic cancer in high-risk cases should only be part of an investigational programme.
Several inherited cancer syndromes are associated with pancreatic cancer (table 1).94,101,102,109,110,111,112,113,114,115,116,117,118,119
The highest risk of pancreatic cancer in all of these cancer syndromes is in Peutz–Jeghers syndrome with a 120-fold lifetime risk and a 36% cumulative lifetime risk.112
Although responsible for this syndrome, germline mutations of the STK11/LKB1 gene are not involved in familial pancreatic cancer.120
Pancreatic cancer is the second most common cancer in the familial atypical multiple mole melanoma syndrome and is particularly significant in patients and families with the p16 Leiden mutation.109
Pancreatic cancer is also seen in some families with breast cancer and BRCA1 and BRCA2 mutations.110
The cumulative risk of pancreas cancer to age 75–years in BRCA2 carriers is 7%, and BRCA2 may account for as many as 5% of all cases of pancreatic cancer.94
It is evident that a number of these genes act as modifier genes on environmental and other genetic risk factors. RNASEL (encoding ribonuclease L) gene variants/mutations (Glu265X and Arg462Gln) implicated in sporadic and familial prostate cancer may also contribute to the tumourigenesis of sporadic and familial pancreatic cancer but do not directly cause pancreatic cancer.121
Table 1Hereditary cancer syndromes affecting the pancreas
Box 4 Pathological typing, staging and resection margins
- Most pancreatic cancers are pancreatic ductal adenocarcinomas.
- Accurate pathological typing and staging is essential to determine the most appropriate treatment and prognostic groups.
- In 20% of cases it is not possible to distinguish the tissue of origin of pancreatic cancers: “peri-ampullary cancer”.
- Chip-based technologies will lead to a more accurate typing of tissue origin.
- Resection margin status needs to be clearly defined. At present, a tumour <1 mm from the margin is reported as positive.
Patients at high risk warrant screening,122,123,124
but these programmes have not been adequately assessed and at the present time secondary screening (box 3) should only be undertaken as part of an investigational study such as that organised by EUROPAC.122,123