Genetic Testing in Chronic Pancreatitis and Pancreatic Cancer -- Can You Use it in Patient Care?

Michele D. Bishop, M.D., MMSc
Michele D. Bishop, M.D., MMSc is an Assistant Professor, Mayo Medical School, Gastroenterology and Hepatology, Mayo Clinic Jacksonville

Introduction

Genetic mutations contribute to a wide range of pancreatic disorders. Three areas of genetic mutations associated with recurrent acute and chronic pancreatitis will be presented: Cystic fibrosis, which is linked to CFTR gene mutations, and Hereditary Pancreatitis which is linked to PRSS1 and SPINK1 (PRSI) gene mutations. Approximately 5% of pancreatic cancers have a hereditary origin as well, and a gene for this was identified recently. Indications for and implications of genetic testing will be discussed.

Cystic Fibrosis (CFTR) Mutations

Classic Cystic Fibrosis

Cystic fibrosis (CF) is by far the most common inherited cause of exocrine pancreatic disease in childhood. It is the most common autosomal recessive life-shortening disorder in Caucasians with an incidence between 1:2000 and 1:3000 live births.1 Identification of the cystic fibrosis gene on the long arm of chromosome 7 in 1989 led to the elucidation of its protein product, the cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic-AMP mediated chloride channel.2 Over 1000 mutations of the gene have been described to date.3 Mutations in the CFTR gene lead to chloride channel dysfunction and impaired ion transport across epithelial cell membranes. In the pancreas, this results in impairment of bicarbonate and chloride secretion, reduced fluid flow in pancreatic ducts and protein hyperconcentration with inspissation. A classification system for mutations is comprised of five classes based on chloride channel function4, with Classes I, II, and III mutations conferring complete loss of CFTR function and severe disease. Class IV and V mutations retain some CFTR function leading to milder phenotypes. Eighty-five percent of children diagnosed with the "classic" form of CF have two Class I, II or II mutations and these children have pancreatic insufficiency. These patients develop severe pulmonary disease, the males are infertile and average life expectancy is approximately 30 years. Patients with at least one Class IV or V mutation are pancreatic sufficient, do not have steatorrhea and do not require pancreatic enzyme supplementation. Pancreatic sufficient patients are diagnosed at a later age, experience normal growth during childhood and have a better overall prognosis than their pancreatic insufficient counterparts. Pancreatitis is not an uncommon finding in pancreatic sufficient CF patients5, and in fact may be the sole presenting symptom of CF.6

CFTR Mutations in Recurrent Acute and Chronic Pancreatitis

Four published studies have reported that CFTR gene mutations are present in patients with idiopathic pancreatitis.7-10 Most of these patients had mutations on only one allele and no significant pulmonary or other characteristic CF findings were present. It would be expected that patients with isolated pancreatitis, in the absence of other clinical manifestations of CF, would carry the milder Class IV or V mutations on at least one allele. At this time, most of these mild mutations are not included in standard commercially available panels used for screening for Cystic Fibrosis. Therefore, to study each of these patients the complete DNA sequencing of the CFTR gene is required to look for the more than 1000 known mutations in CFTR. When full DNA sequencing has been performed, up to 60% of patients had at least one mutation.10, 11 A considerable number of compound heterozygotes were also identified. There are individual patients with two mutations, one severe and one mild.

Finding a CFTR mutation in a patient with idiopathic pancreatitis does not infer that the patient has cystic fibrosis. A consensus statement by the CF Foundation has determined that the diagnosis of CF requires the following two criteria: i) phenotypic features characteristic of CF, a history of CF in a sibling, or a positive newborn screening test, and ii) elevated sweat chloride concentration, two proven disease-causing CFTR mutations, or in vivo demonstration of abnormal ion transport across respiratory epithelium characteristic of CF.12

Characteristic CF phenotype features include pancreatic insufficiency and recurrent pancreatitis. However, the majority of idiopathic pancreatitis patients do not meet criteria for CF. Instead, most fall somewhere on a continuum between normal and classic CF. Male patients with isolated infertility due to congenital bilateral absence of the vas deferens and CFTR mutations also fall on this continuum between normal and CF.13 It appears likely that in the next few years many diseases will be found to be the result of abnormal ion secretion across epithelial cells are due to CFTR gene abnormalities. Undoubtedly, other factors influence disease activity such as modifier genes and environmental exposures. Perhaps underlying mutations in CFTR predispose some patients to pancreatitis when exposed to certain environmental toxins, such as "social" alcohol use, or when paired with other abnormal genes not yet identified.

Genetic testing for any disease, especially ones under current investigation, must be approached with caution. There are many possible implications of genetic testing in CF, including issues regarding heredity and insurance, that should be discussed with patients prior to testing. Patients should learn that the results of any testing might be difficult to interpret at this preliminary stage of research. The implications for family members may also be impossible to predict. As there is no specific treatment for CF- related pancreatitis, the treatment for all etiologies of chronic pancreatitis is the same. More complete genetic tests are anticipated in the near future, but at this time, the most comprehensive test available for commercial use only tests for 86 of the more than 1000 known mutations. Patients may be given incomplete data if this test is used, as a negative result by no means "rules out" CF related pancreatitis. Sweat tests are more widely available, inexpensive, and safe. A confirmed positive sweat test, in the setting of recurrent pancreatitis or pancreatic insufficiency meets the criteria for classic CF. Most patients with at least one mild mutation, however, have normal or borderline sweat tests. Therefore, it is recommended that patients only undergo genetic testing as part of a research study, and that they meet with a professional genetics counselor prior to agreeing to be tested.

Hereditary Pancreatitis (PRSS1) Mutations

Hereditary pancreatitis was first described by Comfort and Steinberg in 1952.14 It is an autosomal dominant disease with variable expression, and an estimated penetrance of 80%.15 Mutations in the cationic trypsinogen gene (PRSS1) are thought to cause the disease, which was mapped to chromosome 7q35 in 1996 by Whitcomb and colleagues.15 Hereditary pancreatitis is characterized by recurrent attacks of acute pancreatitis starting in childhood or adolescence, with frequent progression to chronic pancreatitis. The majority of families are of white European ancestry, but cases have been reported in Japan, India and other ethnic groups. Several mutations have been described, but two, R122H and N29I, are confirmed to be associated with disease.16 Mutations in the cationic trypsinogen gene are thought to cause pancreatitis by the absence of a cleavage site for inactivation of trypsin, thus permitting increased trypsin activity in the pancreatic parenchyma and autodigestion.16

Patients with hereditary pancreatitis also have an increased risk for pancreatic adenocarcinoma.17 The mean age at diagnosis of cancer is 54 years, with a mean interval of 40 years from development of symptoms of pancreatitis to diagnosis of cancer. The estimated cumulative risk of pancreatic cancer to age 70 years is approximately 40%. Smoking appears to double the already high risk of pancreatic cancer in these patients, and lowers the age of onset by approximately 20 years.17

Unfortunately, there is no effective screening test for the early detection of pancreatic cancer in these high risk individuals, and no guidelines are available for the management of patients considered to be at high risk to develop pancreatic cancer. It is recommended that these individuals be managed in clinical trials which are hoping to find early diagnostic tests.

Gene therapy for hereditary pancreatitis is "beyond current technology".16 However, testing for PRSS1 mutations is now widely available commercially. A consensus statement was recently published with guidelines for indications, counseling and patient informed consent issues.18 In brief, genetic testing is recommended for families where there is a history of idiopathic recurrent acute pancreatitis or of idiopathic chronic pancreatitis.

Trypsin Inhibitor (SPINK1) Mutations

In June, 2000, Witt and colleagues reported that mutations in the serine protease inhibitor, Kazal type 1 (SPINK1 or PSTI gene), are associated with recurrent acute pancreatitis.19 Ninety-six unrelated German or Austrian children and adolescents were studied. 71% had idiopathic disease and 29% had a family history of pancreatitis. Direct DNA sequencing of the intrapancreatic trypsin inhibitor, SPINK1, identified mutations in 23% of patients. Six patients were homozygous for the missense mutation, N34S. In comparison, only one of 279 healthy control subjects in this study was found to carry the mutation. Genetic testing is not available outside of a research study at this time.

Hereditary Pancreatic Cancer

In 1999, it was estimated that 28,600 new cases of pancreatic cancer in the US would be diagnosed, and the total number of deaths due to pancreatic cancer was projected to be 28,600.20 Approximately 5% of pancreatic cancers have a hereditary association. Genetic disorders predisposing to pancreatic cancer can be found in Table 1.
 

Table 1

Genetic disorders associated
with pancreatic cancer:

Familial pancreatic adenocarcinoma seems to have an autosomal dominant pattern of inheritance. Some families report cancer in multiple generations and others in multiple siblings. There is currently no standard definition of familial pancreatic cancer. It has been described as pancreatic cancer with at least one first-degree relative with pancreatic cancer.21 In April 2002, Eberle reported the localization of the gene for familial pancreatic cancer on the long arm of chromosome 4.22 They performed DNA analysis on a family from the Seattle area with 20 affected family members (five out of six brothers affected). At this time, a genetic test is not available for family members of pancreatic cancer patients, but this may be an option in the near future. Finding a genetic mutation would prompt the need for screening.
  • Hereditary pancreatitis
  • FPC (Familial Pancreatic Cancer)
  • FAMMM syndrome (Familial Atypical Multiple Mole Melanoma)
  • Lynch syndrome II
  • Hereditary breast cancer (BRCA2)
  • Ataxia telangiectasia
  • MEN1 (Pituitary, parathyroid and pancreas)
  • HNPCC (Hereditary Non-Polyposis Colon Cancer)
  • FAP (Familial Adenomatous Polyposis)
  • Peutz-Jeghers Syndrome
  • Cystic fibrosis (case reports)

The ideal goal of screening family members at risk is to diagnose them before the development of cancer, when they have dysplasia or carcinoma-in-situ, and to perform surgery. There is no standard recommended screening regimen to identify pancreatic dysplasia, but Brentnall, has reported dysplastic lesions detected by endoscopic ultrasound. 23 This remains to be confirmed by other investigators.

Summary Concepts

  1. CFTR gene mutations have been identified in a significant number of adult patients with idiopathic recurrent acute and chronic pancreatitis, without classic findings of cystic fibrosis.
  2. Hereditary pancreatitis is caused by mutations in the cationic trypsinogen gene (PRSS1) in an autosomal dominant pattern, and carries a significantly increased risk of pancreatic cancer.
  3. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1, a pancreatic trypsin inhibitor (SPINK1), have been identified in young patients with recurrent acute pancreatitis.
  4. Approximately 5% of pancreatic cancers have a hereditary origin.
  5. Genetic testing outside of an ethics committee-approved research protocol is only recommended for Hereditary Pancreatitis (PRSS1) mutations at this time.

References

  1. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science 1992; 256:774-779.
  2. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245:1066-1073.
  3. Website: www.genet.sickkids.on.ca/cftr/ : Cystic fibrosis mutation database. Cystic Fibrosis Genetic Analysis Consortium 2001.
  4. Tsui L-C. The spectrum of cystic fibrosis mutations. Trends in Genetics 1992; 8:392.
  5. Atlas AB, Orenstein SR, Orenstein DM. Pancreatitis in young children with cystic fibrosis. J Pediatr 1992; 120:756-759.
  6. Masaryk TJ, Achkar E. Pancreatitis as initial presentation of cystic fibrosis in young adults. Dig Dis Sci 1983; 28:874-878.
  7. Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339:645-652.
  8. Cohn JA, Friedman KJ, Noone PG, et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339:653-658.
  9. Ockenga J, Stuhrmann M, Ballmann M, et al. Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis. Am J Gastroenterol 2000; 95:2061-2067.
  10. Noone PG, Zhou Z, Silverman LM, et al. Cystic Fibrosis Gene Mutations and Pancreatitis Risk: Relation to Epithelial Ion Transport and Trypsin Inhibitor Gene Mutations. Gastroenterology 2001; 121:1310-1319.
  11. Bishop MD, Freedman SD, Zielenski J, et al. Does complete DNA analysis identify a higher percentage of cystic fibrosis mutations in patients with idiopathic chronic and recurrent acute pancreatitis? (Abstract) Gastroenterology 1999; 116:A1113.
  12. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: A consensus statement. J Pediatr 1998; 132:589-595.
  13. Chillon M, Casals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with congenital bilateral absence of the vas deferens. N Engl J Med 1995; 332:1475-1480.
  14. Comfort M, Steinberg A. Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 1952; 21:54.
  15. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14:141-145.
  16. Whitcomb DC. Genetic predispositions to acute and chronic pancreatitis. Medical Clinics of North America 2000; 84:531-547.
  17. Lowenfels AB, Maisonneuve P, Whitcomb DC. Risk factors for cancer in hereditary pancreatitis. Medical Clinics of North America 2000; 84:565-573.
  18. Ellis I, Lerch MM, Whitcomb DC, et al. Genetic Testing for Hereditary Pancreatitis: Guidelines for Indications, Counseling, Consent and Privacy Issues. Pancreatology 2001; 1:405-415.
  19. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000; 25:213-216.
  20. Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1999. CA Cancer J Clin 1999; 49:8-31.
  21. Hruban RH, Petersen GM, Ha PK, et al. Genetics of pancreatic cancer: From genes to families. Surg Oncol Clin N Am 1998; 7:1-23.
  22. Eberle MA, Pfutzer R, Pogue-Geile KL, et al. A New Susceptibility Locus for Autosomal Dominant Pancreatic Cancer Maps to Chromosome 4q32-34. Am J Hum Genet 2002; 70:1044-1048.
  23. Brentnall TA, Bronner MP, Byrd DR, et al. Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med 1999; 131:247-255.
Jacksonville Medicine / June/July, 2002

What's New · Northeast Florida Medicine Journal · Know Your Physician · Legal & Legislative
· DCMS Alliance · Academy of Medicine · Member Websites · Community Health
About the DCMS · Meetings Calendar · Member Benefits · Employment Connection · Home

Duval County Medical Society   ·   555 Bishopgate Lane  ·   Jacksonville, FL  32204
Phone: (904) 355-6561   ·     FAX:  (904) 353-5848   
General Email: dcms@dcmsonline.org    ·   Webmaster's Email: mdoran@dcmsonline.org
Privacy Policy and Disclaimers