Familial Pancreatic Cancer

  • Kieran A. Brune
  • Alison P. Klein
Part of the M. D. Anderson Solid Tumor Oncology Series book series (MDA)

In 2008, 37,680 individuals in the United States will be diagnosed with pancreatic cancer (1) and approximately 5–10% of these cases will have a familial basis (2). Because of the location of the pancreas deep in the abdominal cavity, detection of this disease in its early stages is difficult such that over 80% of pancreatic cancers have metastasized prior to diagnosis. For this reason, it is estimated that in 2008, 34,290 individuals in the United States will die from the disease this year, making the death rate from pancreatic cancer similar to its incidence. Therefore, it is important to identify individuals who are at high risk, such as those with a family history, as these patients may benefit from early detection screening, which may reduce the mortality of this disease. Furthermore, understanding the genetic basis of both inherited and noninherited pancreatic cancer will provide great insight into the etiology of this cancer.

Little is known about the etiology of pancreatic cancer, but the two best established risk factors for the development of this cancer include cigarette smoking and a family history of pancreatic cancer. The following chapter provides a brief overview of the general epidemiology of pancreatic cancer and then focuses on the role of familial risk in the development of this disease.


Pancreatic Cancer Pancreatic Cancer Risk Creatic Cancer Hereditary Pancreatitis Familial Pancreatic Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA A Cancer Journal for Clinicians, 2008, 58:71–96.CrossRefGoogle Scholar
  2. 2.
    Lynch HT, Smyrk T, Kern SE, et al. Familial pancreatic cancer: a review. Semin Oncol 1996, 23:251–275.PubMedGoogle Scholar
  3. 3. Surveillance, EaERSPwscg. SEER*Stat Database: Incidence SEER 9 Regs, Nov 2002 Sub (1973-2000). (released April 2003, based on the November 2002 submission). 2003. National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch.Google Scholar
  4. 4.
    Ferley J, Bray P, Pisani P, et al. GLOBOCAN2000: cancer incidence, mortality and prevalence worldwide, version 1.0. Lyon, IARC Press, 2001.Google Scholar
  5. 5.
    Fuchs CS, Colditz GA, Stampfer MJ, et al. A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch Intern Med 1996, 156:2255–2260.CrossRefPubMedGoogle Scholar
  6. 6.
    Silverman DT. Risk factors for pancreatic cancer: a case-control study based on direct inter-views. Teratog Carcinog Mutagen 2001, 21:7–25.CrossRefPubMedGoogle Scholar
  7. 7.
    Schenk M, Schwartz AG, O’Neal E, et al. Familial risk of pancreatic cancer. J Natl Cancer Inst 2001, 93:640–644.CrossRefPubMedGoogle Scholar
  8. 8.
    Falk RT, Pickle LW, Fontham ET, et al. Life-style risk factors for pancreatic cancer in Louisiana: a case-control study. Am J Epidemiol 1988, 128:324–336.PubMedGoogle Scholar
  9. 9.
    Howe GR, Jain M, Burch JD, et al. Cigarette smoking and cancer of the pancreas: evidence from a population-based case-control study in Toronto, Canada. Int J Cancer 1991, 47:323–328.CrossRefPubMedGoogle Scholar
  10. 10.
    Coughlin SS, Calle EE, Patel AV, et al. Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control 2000, 11:915–923.CrossRefPubMedGoogle Scholar
  11. 11.
    Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 1995, 273:1605–1609.CrossRefPubMedGoogle Scholar
  12. 12.
    Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997, 89:442–446.CrossRefPubMedGoogle Scholar
  13. 13.
    Michaud DS, Giovannucci E, Willett WC, et al. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 2001, 286:921–929.CrossRefPubMedGoogle Scholar
  14. 14.
    Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005, 129:504–511.PubMedGoogle Scholar
  15. 15.
    Coughlin SS, Calle EE, Teras LR, et al. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004, 159:1160–1167.CrossRefPubMedGoogle Scholar
  16. 16.
    Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993, 328:1433–1437.CrossRefPubMedGoogle Scholar
  17. 17.
    Lowenfels AB, Maisonneuve P, Whitcomb DC, et al. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. JAMA 2001, 286:169–170.CrossRefPubMedGoogle Scholar
  18. 18.
    Berrington de GA, Sweetland S, Spencer E. A meta-analysis of obesity and the risk of pancreatic cancer. Br J Cancer 2003, 89:519–523.CrossRefGoogle Scholar
  19. 19.
    MacDermott RP, Kramer P. Adenocarcinoma of the pancreas in four siblings. Gastroenterology 1973, 65:137–139.PubMedGoogle Scholar
  20. 20.
    Danes BS, Lynch HT. A familial aggregation of pancreatic cancer. An in vitro study. JAMA 1982, 247:2798–27802.CrossRefPubMedGoogle Scholar
  21. 21.
    Lynch HT, Fitzsimmons M, Smyrk TC. Familial pancreatic cancer: Clinicopathological study of 18 nuclear families. Am J Gastroenterol 1990, 85:54–60.PubMedGoogle Scholar
  22. 22.
    Evans JP, Burke W, Chen R, et al. Familial pancreatic adenocarcinoma: association with diabetes and early molecular diagnosis. J Med Genet 1995, 32:330–335.CrossRefPubMedGoogle Scholar
  23. 23.
    Hruban RH, Petersen GM, Ha PK, et al. Genetics of pancreatic cancer. From genes to fami-lies. Surg Oncol Clin North Am 1998, 7:1–23.Google Scholar
  24. 24.
    Petersen GM, de AM, Goggins M, et al. Pancreatic cancer genetic epidemiology consortium. Cancer Epidemiol Biomarkers Prev 2006, 15:704–710.CrossRefPubMedGoogle Scholar
  25. 25.
    Klein AP. Overview of linkage analysis: application to pancreatic cancer. Methods Mol Med 2005, 103:329–341.PubMedGoogle Scholar
  26. 26.
    Ghadirian P, Boyle P, Simard A, et al. Reported family aggregation of pancreatic cancer within a population based case-control study in the Francophone community in Montreal, Canada. Int J Pancreatol 1991, 10:183–196.PubMedGoogle Scholar
  27. 27.
    Fernandez E, LaVecchia C, D’Avanzo B, et al. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 1994, 3:209–212.PubMedGoogle Scholar
  28. 28.
    Hemminki K, Li X: Familial and second primary pancreatic cancers: a nationwide epidemio-logic study from Sweden. Int J Cancer 2003, 103:525–530.CrossRefPubMedGoogle Scholar
  29. 29.
    Amundadottir LT, Thorvaldsson S, Gudbjartsson DF, et al. Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family. PLoS Med 2004, 1:e65.CrossRefPubMedGoogle Scholar
  30. 30.
    Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004, 64:2634–2638.CrossRefPubMedGoogle Scholar
  31. 31.
    Canto M, Goggins M, Hruban R, et al. Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gast Hepatol 2006, 4(6):766–781.CrossRefGoogle Scholar
  32. 32.
    Canto MI, Goggins M, Yeo CJ, et al. Screening for pancreatic neoplasia in high-risk individu-als: an EUS-based approach. Clin Gastroenterol Hepatol 2004, 2:606–621.CrossRefPubMedGoogle Scholar
  33. 33.
    Brune K, Abe T, Canto M, et al. Multifocal neoplastic precursor lesions associated with lobu-lar atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am J Surg Pathol 2006, 30:1067–1076.PubMedGoogle Scholar
  34. 34.
    Meckler KA, Brentnall TA, Haggitt RC, et al. Familial fibrocystic pancreatic atrophy with endo-crine cell hyperplasia and pancreatic carcinoma. Am J Surg Pathol 2001, 25:1047–1053.CrossRefPubMedGoogle Scholar
  35. 35.
    Goggins M, Schutte M, Lu J, et al. Germline BRCA2 gene mutations in patients with appar-ently sporadic pancreatic carcinomas. Cancer Res 1996, 56:5360–5364.PubMedGoogle Scholar
  36. 36.
    Hahn SA, Greenhalf B, Ellis I, et al. BRCA2 germline mutations in familial pancreatic carci-noma. J Natl Cancer Inst 2003, 95:214–221.PubMedGoogle Scholar
  37. 37.
    Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002, 62:3789–3793.PubMedGoogle Scholar
  38. 38.
    Lal G, Liu G, Schmocker B, et al. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 2000, 60:409–416.PubMedGoogle Scholar
  39. 39.
    Goldstein AM, Fraser MC, Struewing JP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 1995, 333:970–974.CrossRefPubMedGoogle Scholar
  40. 40.
    Borg A, Sandberg T, Nilsson K, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2000, 92:1260–1266.CrossRefPubMedGoogle Scholar
  41. 41.
    Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 2000, 87:809–811.CrossRefPubMedGoogle Scholar
  42. 42.
    Kamb A, Shattuck-Eidens D, Eeles R, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 1994, 8:23–26.CrossRefPubMedGoogle Scholar
  43. 43.
    Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997, 57:3126–3130.PubMedGoogle Scholar
  44. 44.
    Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994, 8:27–32.CrossRefPubMedGoogle Scholar
  45. 45.
    Su GH, Hruban RH, Bansal RK, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999, 154:1835–1840.PubMedGoogle Scholar
  46. 46.
    Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000, 119:1447–1453.CrossRefPubMedGoogle Scholar
  47. 47.
    Lynch HT, Voorhees GJ, Lanspa SJ, et al. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br J Cancer 1985, 52:271–273.PubMedGoogle Scholar
  48. 48.
    Wilentz RE, Goggins M, Redston M, et al. Genetic, immunohistochemical, and clinical fea-tures of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol 2000, 156:1641–1651.PubMedGoogle Scholar
  49. 49.
    van der Heijden MS, Yeo CJ, Hruban RH, et al. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 2003, 63:2585–2588.PubMedGoogle Scholar
  50. 50.
    van der Heijden MS, Brody JR, Dezentje DA, et al. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res 2005, 11:7508–7515.CrossRefPubMedGoogle Scholar
  51. 51.
    Rogers CD, van der Heijden MS, Brune K, et al. The genetics of FANCC and FANCG in familial pancreatic cancer. Cancer Biol Ther 2004, 3:167–169.PubMedGoogle Scholar
  52. 52.
    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.PubMedGoogle Scholar
  53. 53.
    Eberle MA, Pfutzer R, Pogue-Geile KL, et al. A new susceptibility locus for autosomal domi-nant pancreatic cancer maps to chromosome 4q32-34. Am J Hum Genet 2002, 70:1044–1048.CrossRefPubMedGoogle Scholar
  54. 54.
    Pogue-Geile KL, Chen R, Bronner MP, et al. Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism. PLoS Med 2006, 3:e516.CrossRefPubMedGoogle Scholar
  55. 55.
    Earl J, Yan L, Vitone LJ, et al. Evaluation of the 4q32-34 locus in European familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2006, 15:1948–1955.CrossRefPubMedGoogle Scholar
  56. 56.
    Klein AP, de Andrade M., Hruban RH, et al. Linkage analysis of chromosome 4 in families with familial pancreatic cancer. Cancer Biol Ther 2007, 3:167–169.Google Scholar
  57. 57.
    Klein AP, Beaty TH, Bailey-Wilson JE, et al. Evidence for a major gene influencing risk of pancreatic cancer. Genet Epidemiol 2002, 23:133–149.CrossRefPubMedGoogle Scholar
  58. 58.
    Axilbund JE, Brune KA, Canto MI, et al. Patient perspective on the value of genetic coun-seling for familial pancreas cancer. Hered Cancer Clin Pract 2005, 3:115–122.PubMedGoogle Scholar
  59. 59.
    Wang W, Chen S, Brune KA, et al. Development and validation of a risk assessment tool for individuals with a family history of pancreatic cancer: PancPRO. J Clin Oncol 2007, 25 (11):1417–1422.CrossRefPubMedGoogle Scholar
  60. Chen S, Wang W, Broman KW, et al. Bayes Mendel: and R environment for Mendelian risk prediction. Stat Appl Genet Mol Biol 2004, 3.Google Scholar
  61. 61.
    Euhus D: Risk modeling in breast cancer. Breast J 2004, 10 Suppl 1:S10–S12.CrossRefPubMedGoogle Scholar
  62. 62.
    Kimmey MB, Bronner MP, Byrd DR, et al. Screening and surveillance for hereditary pancreatic cancer. Gastrointest Endosc 2002, 56:S82–S86.CrossRefPubMedGoogle Scholar
  63. 63.
    Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006, 314:268–274.CrossRefPubMedGoogle Scholar
  64. 64.
    Koopmann J, Buckhaults P, Brown DA, et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res 2004, 10:2386–2392.CrossRefPubMedGoogle Scholar
  65. 65.
    Ghadirian P, Boyle P, Simard A, et al. Reported family aggregation of pancreatic cancer within a population-based case-control study in the Francophone community in Montreal, Canada. Int J Pancreatol 1991, 10:183–196.PubMedGoogle Scholar
  66. 66.
    Fernandez E, La Vecchia C, d’Avanzo B, et al. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 1994, 3:209–212.PubMedGoogle Scholar
  67. 67.
    Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987, 316:1511–1514.PubMedCrossRefGoogle Scholar
  68. 68.
    Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene [see comments]. Nat Genet 1996, 14:141–145.CrossRefPubMedGoogle Scholar
  69. 69.
    Whitcomb D, Preston R, Aston CE, et al. A gene for hereditary pancreatitis maps to chromo-some 7q35. Gastroenterology 1996, 110:1975–1980.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Kieran A. Brune
    • 1
  • Alison P. Klein
    • 2
  1. 1.The Sol Goldman Pancreatic Cancer Research Center and the John Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.The Sidney Kimmel Comprehensive Cancer CenterJohn Hopkins University School of MedicineBaltimoreUSA

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