Familial Cancer

, Volume 3, Issue 3–4, pp 233–240 | Cite as

Familial pancreatic carcinoma in Jews

  • Henry T Lynch
  • Carolyn A Deters
  • Jane F Lynch
  • Randall E Brand
Article

Abstract

Abstract Pancreatic cancer (PC) is the most fatal of all gastrointestinal cancers, wherein its mortality compares strikingly with its incidence. Unfortunately, 80--90% of PCs are diagnosed in the nonresectable stage. While the lifetime risk of PC in developed countries is approximately 1–3%, it is the fifth most common cause of cancer deaths among both males and females in Western countries. It occurs in excess in Jews. Approximately 5–10% of PC shows familial clustering. Examination of such familial clusters must take into consideration cancers of diverse anatomic sites, such as malignant melanoma in the familial atypical multiple melanoma (FAMMM) syndrome due to the CDKN2A (p16) germline mutation, and combinations of colorectal and endometrial carcinoma, ovarian carcinoma, and several other cancers in hereditary nonpolyposis colorectal cancer (HNPCC), which are due to mismatch repair germline mutations, the most common of which are MSH2 and MLH1. Other hereditary disorders predisposing to PC include Peutz–Jeghers syndrome, due to the STK11 mutation, familial pancreatitis due to the cationic trypsinogen gene, site-specific familial pancreatic cancer which may be due to the 4q32–34 mutation, hereditary breast–ovarian cancer (HBOC) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1, familial adenomatous polyposis due to the ATP gene, and ataxia telangiectasia due to the ATM germline mutation. This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC. Unfortunately, there are no PC screening programs with acceptable sensitivity and specificity. However, the gold standard for screening at this time is endoscopic ultrasound. Clearly, there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity. Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews. Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the disease's pathogenesis, as well as screening and control, may take place.

excess occurrence in Ashkenazi Jews FAMMM syndrome integrally associated cancers malignant melanoma morbidity and mortality pancreatic cancer 

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References

  1. 1.
    Ghadirian P, Liu G, Gallinger S et al.Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. Int J Cancer 2002; 97: 807–10.PubMedGoogle Scholar
  2. 2.
    Parkin DM, Pisani P, Ferlay J. Global cancer statistics.CA Cancer J Clin 1999; 49: 33–64.PubMedGoogle Scholar
  3. 3.
    Jemal A, Murray T, Samuels A et al. Cancer statistics, 2003.CA Cancer J Clin 2003; 53: 5–26.Google Scholar
  4. 4.
    International Agency for Research on Cancer.Globocan 2000. Lyon, France: International Agency for Research on Cancer 2002._ Accessed at: Retrieved from http: //www.dep.iarc.fr/globocan/ globocan.html on 12 November 2003.Google Scholar
  5. 5.
    Parkin DM, Whelan SL, Ferlay J et al.(eds)Cancer Incidence in Five Continents, Vol.VII.IARC Scientific Publications No.143. Lyon, France: IARC 1997.Google Scholar
  6. 6.
    Chappuis PO, Ghadirian P, Foulkes WD.The role of genetic factors in the etiology of pancreatic adenocarcinoma: an update. Cancer Invest 2001; 19: 65–75.Google Scholar
  7. 7.
    Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet 1999; 15: 786–92.Google Scholar
  8. 8.
    Yeo CJ, Cameron JL. Pancreatic cancer. Curr Probl Surg 1999; 36: 59–152.PubMedGoogle Scholar
  9. 9.
    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: 183–96.PubMedGoogle Scholar
  10. 10.
    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: 324–36.PubMedGoogle Scholar
  11. 11.
    Bartsch DK. Familial pancreatic cancer. Br J Surg 2003; 90: 386–7.PubMedGoogle Scholar
  12. 12.
    Lynch HT, Lanspa SJ, Fitzgibbons Jr. RJ et al. Familial pancre-atic cancer (Part 1): genetic pathology review. Nebr Med J 1989; 74: 109–12.PubMedGoogle Scholar
  13. 13.
    Lynch HT, Fitzsimmons ML, Smyrk TC et al. Familial pancreatic cancer: clinicopathologic study of 18 nuclear families. Am J Gastroenterol 1990; 85: 54–60.PubMedGoogle Scholar
  14. 14.
    Lynch HT, Smyrk T, Kern SE et al. Familial pancreatic cancer: a review. Semin Oncol 1996; 23: 251–75.PubMedGoogle Scholar
  15. 15.
    Ghadirian P, Lynch HT, Krewski D. Epidemiology of pancreatic cancer: an overview.Cancer Detect Prev 2003; 27: 87–93.PubMedGoogle Scholar
  16. 16.
    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: 209–12.PubMedGoogle Scholar
  17. 17.
    Hruban RH, Wilentz RE, Goggins M et al. Pathology of incipient pancreatic cancer. Ann Oncol 1999; 10(Suppl 4): S9–S11.PubMedGoogle Scholar
  18. 18.
    Chappuis PO, Kapusta L, Be ´gin LR et al. Germline BRCA1/2 mutations and p27 Kip1 protein levels independently predict out-come after breast cancer. J Clin Oncol 2000; 18: 4045–52.PubMedGoogle Scholar
  19. 19.
    Lynch HT, Voorhees GJ, Lanspa SJ et al. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study.Br J Cancer 1985; 52: 271–3.PubMedGoogle Scholar
  20. 20.
    Lynch HT, Watson P, Tinley S et al. An update on DNA-based BRCA1/BRCA2 genetic counseling in hereditary breast cancer. Cancer Genet Cytogenet 1999; 109: 91–8.PubMedGoogle Scholar
  21. 21.
    Wooster R, Bignell G, Lancaster J et al. Identification of the breast cancer susceptibility gene BRCA2 [see comments].Nature 1995; 378: 789–92[published erratum appears in Nature 1996; 379: 749 ].PubMedGoogle Scholar
  22. 22.
    Goggins M, Schutte M, Lu J et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carci-nomas.Cancer Res 1996; 56: 5360–4.PubMedGoogle Scholar
  23. 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: 247–55.PubMedGoogle Scholar
  24. 24.
    Lowenfels AB, Maisonneuve P, Whitcomb DC et al. Risk factors for cancer in hereditary pancreatitis. Med Clin North Am 2000; 84: 565–73.PubMedGoogle Scholar
  25. 25.
    Lowenfels AB, Maisonneuve P, DiMagno EP et al. Hereditary pancreatitis and the risk of pancreatic cancer. J Natl Cancer Inst 1997; 89: 442–6.PubMedGoogle Scholar
  26. 26.
    Gorry MC, Gabbaizedeh D, Furey W et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 1997; 113: 1063–8.PubMedGoogle Scholar
  27. 27.
    Whitcomb DC, Gorry MC, Preston RA et al. Hereditary pancre-atitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14: 141–5.PubMedGoogle Scholar
  28. 28.
    Giardiello FM, Welsh SB, Hamilton SR et al. Increased risk of cancer in the Peutz–Jeghers syndrome. N Engl J Med 1987; 316: 1511–4.PubMedGoogle Scholar
  29. 29.
    Su GH, Hruban RH, Bova GS et al. Germline and somatic mutations of the STK11/LKB1 Peutz–Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999; 154: 1835–40.PubMedGoogle Scholar
  30. 30.
    Lynch HT, Frichot BC, Lynch P et al. Family studies of malignant melanoma and associated cancer. Surg Gynecol Obstet 1975; 141: 517–22.PubMedGoogle Scholar
  31. 31.
    Bergman W, Watson P, de Jong J et al. Systemic cancer and the FAMMM syndrome.Br J Cancer 1990; 61: 932–6.PubMedGoogle Scholar
  32. 32.
    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: 409–16.PubMedGoogle Scholar
  33. 33.
    Vasen HFA, 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: 809–11.PubMedGoogle Scholar
  34. 34.
    Bullock GJ, Green JL, Baron PL. Impact of p16 expression on surgical management of malignant melanoma and pancreatic carcinoma.Am J Surg 1999; 177: 15–8.PubMedGoogle Scholar
  35. 35.
    Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997; 57: 2140–3.PubMedGoogle Scholar
  36. 36.
    Moskaluk CA, Hruban RH, Lietman A et al. Novel germline p16 INK4 allele (Asp145Cys)in a family with multiple pancreatic carcinomas. Human Mutat 1997; 12: 70 (Abstract).Google Scholar
  37. 37.
    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: 3126–30.PubMedGoogle Scholar
  38. 38.
    Eberle MA, Pfu ¨tzer R, Pogue-Geile KL et al. A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromo-some 4q32–34._Am J Hum Genet 2002; 70: 1044–8.PubMedGoogle Scholar
  39. 39.
    Mack TM, Berkel J, Bernstein L et al. Religion and cancer in Los Angeles County.J Natl Cancer Inst Monogr 1985; 69: 235–45.Google Scholar
  40. 40.
    MacMahon B. The ethnic distribution of cancer mortality in New York City, 1955.Acta Un Int Contra Cancer 1960; 16: 1716–24.Google Scholar
  41. 41.
    Greenwald P, Korns RF, Nasca PC et al. Cancer in United States Jews.Cancer Res 1975; 35: 3507–12.PubMedGoogle Scholar
  42. 42.
    Mack TM, Paganini-Hill A. Epidemiology of pancreas cancer in Los Angeles.Cancer 1981; 47: 1474–83.PubMedGoogle Scholar
  43. 43.
    Naderi A, Couch FJ.BRCA2 and pancreatic cancer. Int J Gastrointest Cancer 2002; 31: 99–106.PubMedGoogle Scholar
  44. 44.
    Hahn SA, Greenhalf B, Ellis I et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003; 95: 214–21.PubMedGoogle Scholar
  45. 45.
    Kiffmeyer WR, Langer E, Davies SM et al. Genetic polypmor-phisms in the Hmong population Implications for cancer etiology and survival. Cancer 2004; 100: 411–7.PubMedGoogle Scholar
  46. 46.
    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: 3789–93.PubMedGoogle Scholar
  47. 47.
    Petersen GM, Hruban RH. Familial pancreatic cancer: where are we in 2003? J Natl Cancer Inst 2003; 95: 180–1.PubMedGoogle Scholar
  48. 48.
    Tersmette AC, Petersen GM, Offerhaus GJA et al. Increased risk of incident pancreatic cancer among rst-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 2001; 7: 738–44.PubMedGoogle Scholar
  49. 49.
    White K, Held KR, Weber BHF. A BRCA2 germ-line mutation in familial pancreatic carcinoma. Int J Cancer 2001; 91: 742–4.PubMedGoogle Scholar
  50. 50.
    Struewing JP, Hartge P, Wacholder S et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews [see comments ]. N Engl J Med 1997; 336: 1401–8.PubMedGoogle Scholar
  51. 51.
    Figer A, Irmin L, Geva R et al. The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastroin-testinal tract tumours in Israel. Br J Cancer 2001; 84: 478–81.PubMedGoogle Scholar
  52. 52.
    Wang S-C, Shao R, Pao AY et al. Inhitibion of cancer cell growth by BRCA2. Cancer Res 2002; 62: 1311–4.PubMedGoogle Scholar
  53. 53.
    Lynch HT, Brand RE, Hogg D et al. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical multiple mole melanoma-pancreatic carcinoma syndrome. Cancer 2002; 94: 84–96.PubMedGoogle Scholar
  54. 54.
    Gerdes B, Bartsch DK, Ramaswamy A et al. Multiple primary tumors as an indicator for p16 INK4a germline mutations in pancreatic cancer patients? Pancreas 2000; 21: 369–75.PubMedGoogle Scholar
  55. 55.
    Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001; 344: 1052–6.PubMedGoogle Scholar
  56. 56.
    Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a speci c inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–42.PubMedGoogle Scholar
  57. 57.
    Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a speci c inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–7.PubMedGoogle Scholar
  58. 58.
    Beghini A, Tibiletti MG, Roversi G et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastroin-testinal stromal tumors and urticaria pigmentosa.Cancer 2001; 92: 657–62.PubMedGoogle Scholar
  59. 59.
    Nishida T, Hirota S, Taniguchi M et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 1998; 19: 323–4.PubMedGoogle Scholar
  60. 60.
    Isozaki K, Terris B, Belghiti J et al. Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am J Pathol 2000; 157: 1581–5.PubMedGoogle Scholar
  61. 61.
    Hirota S, Nishida T, Isozaki K et al. Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. Gastroenterology 2002; 122: 1493–9.PubMedGoogle Scholar
  62. 62.
    Hruban RH, Petersen GM, Ha PK et al. Genetics of pancreatic cancer: from genes to families. Surg Oncol Clin North Am 1998; 7: 1–23.Google Scholar
  63. 63.
    Bartsch DK, Sina-Frey M, Ziegler A et al. Update of familial pancreatic cancer in Germany. Pancreatology 2001; 1: 510–6.PubMedGoogle Scholar
  64. 64.
    Gerdes B, Kress R, Rieder H et al. Familial pancreatic cancer– concept for study of the National Case Collection and early diagnosis program for high risk people. Z Arztl Fortbild Quali-tatssich 2002; 96: 251–5.Google Scholar
  65. 65.
    Applebaum SE, Kant JA, Whitcomb DC et al. Genetic testing. Counseling, laboratory, and regulatory issues and the EUROPAC protocol for ethical research in multicenter studies of inherited pancreatic diseases. Med Clin North Am 2000; 84: 575–88.PubMedGoogle Scholar
  66. 66.
    Hruban RH, Petersen GM, Goggins M et al. Familial pancreatic cancer.Ann Oncol 1999; 10(4 Suppl): S69–S73.PubMedGoogle Scholar
  67. 67.
    Hemminki A, Tomlinson I, Markie D et al. Localization of a susceptibility locus for Peutz–Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet 1997; 15: 87–90.PubMedGoogle Scholar
  68. 68.
    Hemminki A, Markie D, Tomlinson I et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 1998; 391: 184–7.PubMedGoogle Scholar
  69. 69.
    Jenne DE, Reimann H, Nezu J et al. Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 1998; 18: 38–44.PubMedGoogle Scholar
  70. 70.
    Giardiello FM, Brensinger JD, Tersmette AC et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 2000; 119: 1447–53.PubMedGoogle Scholar
  71. 71.
    Sato N, Rosty C, Jansen M et al. Peutz–Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas.Am J Pathol 2001; 159: 2017–22.PubMedGoogle Scholar
  72. 72.
    Lowenfels AB, Maisonneuve P, Cavallini G et al. Pancreatitis and the risk of pancreatic cancer. N Engl J Med 1993; 328: 1433–7.PubMedGoogle Scholar
  73. 73.
    Lynch HT, Fusaro RM. Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM)syndrome. Pancreas 1991; 6: 127–31.PubMedGoogle Scholar
  74. 74.
    Goldstein AM, Fraser MC, Struewing JP et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16 INK4 mutations. N Engl J Med 1995; 333: 970–4.PubMedGoogle Scholar
  75. 75.
    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.PubMedGoogle Scholar
  76. 76.
    Wooster R, Neuhausen SL, Mangion J et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12– 13.Science 1994; 265: 2088–90.PubMedGoogle Scholar
  77. 77.
    Tulinius H, Olafsdottir GH, Sigvaldason H et al. Neoplastic diseases in families of breast cancer patients. J Med Genet 1994; 31: 618–21.PubMedGoogle Scholar
  78. 78.
    Kinzler KW, Nilbert MC, Su L-K et al. Identification of FAP locus genes from chromosome 5q21.Science 1991; 253: 661–5.PubMedGoogle Scholar
  79. 79.
    Groden J, Thliveris A, Samowitz W et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991; 66: 589–600.PubMedGoogle Scholar
  80. 80.
    Giardiello FM, Offerhaus GJ, Lee DH et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyp-osis.Gut 1993; 34: 1394–6.PubMedGoogle Scholar
  81. 81.
    Horii A, Nakatsuru S, Miyoshi Y et al. Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res 1992; 52: 6696–8.PubMedGoogle Scholar
  82. 82.
    Yashima K, Nakamori S, Murakami Y et al. Mutations of the adenomatous polyposis coli gene in the mutation cluster region: comparison of human pancreatic and colorectal cancers. Int J Cancer 1994; 59: 43–7.PubMedGoogle Scholar
  83. 83.
    Jacob S, Praz F. DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie 2002; 84: 27–47.PubMedGoogle Scholar
  84. 84.
    Goggins M, Offerhaus GJA, Hilgers W et al. Pancreatic adeno-carcinomas with DNA replication errors (RER+)are associated with wild-type K-ras and characteristic histopathology: poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 1998; 152: 1501–7.PubMedGoogle Scholar
  85. 85.
    Lynch HT, Brand RE, Deters CA et al. Hereditary pancreatic cancer. Pancreatology 2001; 1: 466–71.PubMedGoogle Scholar
  86. 86.
    Swift M, Sholman L, Perry M et al. Malignant neoplasms in the families of patients with ataxia telangiectasia. Cancer Res 1976; 36: 209–15.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Henry T Lynch
    • 1
  • Carolyn A Deters
    • 1
  • Jane F Lynch
    • 1
  • Randall E Brand
    • 2
  1. 1.Department of Preventive Medicine and Public HealthCreighton University School of MedicineOmahaUSA
  2. 2.Department of Internal MedicineEvanston Northwestern Health CareEvanstonUSA

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