BRCA2 and pancreatic cancer

Review Article

Abstract

Many factors, including a family history of cancer, have been implicated in the development of pancreatic cancer. Among these factors, germline BRCA2 mutations have been clearly associated with the development of this disease, while mutations in BRCA1 appear to have a limited role. Patients with pancreatic cancer and germline BRCA2 mutations tend to be Ashkenazi Jewish, have a younger than average age of onset, and in many cases, lack family history for breast, ovarian, or pancreatic cancers. In addition, somatic mutations of BRCA2 appear to be rare in tumors of the pancreas. The mechanism by which mutant BRCA2 contributes to development of pancreatic cancers is not well understood. However, it appears that inactivation of several independent functions of BRCA2 including regulation of gene transcription, chromatin remodeling, cell growth, DNA damage repair, and chromosomal instability may provide a pathophysiological basis for the association of BRCA2 mutations and pancreatic cancer.

Key Words

BRCA2 mutation Pancreatic cancer 

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References

  1. 1.
    Lynch HT, Fursaro L, Lynch JF. Familial pancreatic cancer: a family study. Pancreas 1992;7(5):511–515.PubMedCrossRefGoogle Scholar
  2. 2.
    Fernandez E, La Vecchia C, D’Avanzo B, et al. Family history and the risk of liver, gallbladder, and pancreas cancer. Cancer Epidemiol Biomarkers Prev 1994;3(3):209–212.PubMedGoogle Scholar
  3. 3.
    Falk RT, Pickle LW, Fonthan ET, et al. Life-style risk factors for pancreatic cancer in Louisiana: a case-control study. Am J Epidemiol 1988;128(2):324–336.PubMedGoogle Scholar
  4. 4.
    Ghadirian P, Bayle 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
  5. 5.
    Schenk M, Schwartz AG, O’Neal E, et al. Familial risk of pancreatic cancer. J Natl Cancer Inst 2001;93(8):640–644.PubMedCrossRefGoogle Scholar
  6. 6.
    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(10):915–923.PubMedCrossRefGoogle Scholar
  7. 7.
    Goldstein AM, Fraser MC, Struewing JP, et al. Increased risk of pancreatic cancer in melonoma-prone kindreds with P16INK4 mutations. N Engl J Med 1995;333(15):970–974.PubMedCrossRefGoogle Scholar
  8. 8.
    Phelan GM, Lancaster JM, Tonin P, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996;13:120–122.PubMedCrossRefGoogle Scholar
  9. 9.
    Giadiello FM, Brensiger JD, Termette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119(6):1447–1453.CrossRefGoogle Scholar
  10. 10.
    Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch Syndrome). Int J Cancer 1996;69(1):38–42.PubMedCrossRefGoogle Scholar
  11. 11.
    Tulinius H, Egilsson V, Olafsdottir GH, et al. Risk of prostate, ovarian, and endometrial cancer among relatives of women with breast cancer. Brit Med J 1992;305(6858):855–857.PubMedCrossRefGoogle Scholar
  12. 12.
    The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999;91(15):1310–1316.CrossRefGoogle Scholar
  13. 13.
    Ozcelik H, Schmocker B, DiNicola N, et al. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 1997;16:17–18.PubMedCrossRefGoogle Scholar
  14. 14.
    Lal G, Liu G, Schmocker B, et al. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germline p16, BRCA1, and BRCA2 mutations. Cancer Res 2000;60:409–416.PubMedGoogle Scholar
  15. 15.
    Figer A, Irmin L, Geva R, et al. The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumors in Israel. Brit J Cancer 2001;84(4):478–481.PubMedCrossRefGoogle Scholar
  16. 16.
    Brentnall TA. Cancer surveillance of patients from familial pancreatic cancer kindreds. Med Clin North Am 2000;84:707–718.PubMedCrossRefGoogle Scholar
  17. 17.
    White K, Held KR, Weber BHF. A BRCA2 germline mutation in familial pancreatic carcinoma. Int J Cancer 2001;91:742–744.PubMedCrossRefGoogle Scholar
  18. 18.
    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(13):3789–3793.PubMedGoogle Scholar
  19. 19.
    Goggins M, Shuttle M, Lu J, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996;56:5360–5364.PubMedGoogle Scholar
  20. 20.
    Goggins M, Hruban RH, Kern SE. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia. Am J Pathol 2000;156(5):1767–1771.PubMedGoogle Scholar
  21. 21.
    Gayther SA, Mangion J, Russell P, et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of BRCA2 gene. Nat Genet 1997;15:103–105.PubMedCrossRefGoogle Scholar
  22. 22.
    Thompson D, Easton D. Breast Cancer Linkage Consortium: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001;68(2):410–419.PubMedCrossRefGoogle Scholar
  23. 23.
    Tavtigian SV, Simard J, Rommens J, et al. The complete BRCA2 gene mutations in chromosome 13q-linked kindreds. Nat Genet 1996;12:1–6.CrossRefGoogle Scholar
  24. 24.
    Venkitaraman AR. Cancer Susceptibility and the functions of BRCA1 and BRCA2. Cell 2002;108:171–182.PubMedCrossRefGoogle Scholar
  25. 25.
    Marmorstein LY, Ouchi T, Aaronson SA. The BRCA2 gene product functionally interacts with P53 and RAD51. Proc Natl Acad Sci USA 1998;95(23):13,869–13,874.CrossRefGoogle Scholar
  26. 26.
    Milner J, Fuks F, Hughes-Davies L, et al. The BRCA2 activation domain associates with and is phosphorylated by a cellular protein kinase. Oncogene 2000;19(38):4441–4445.PubMedCrossRefGoogle Scholar
  27. 27.
    Fuks F, Milner J, Kouzarides T. BRCA2 associates with acetyl transferase activity when bound to P/CAF. Oncogene 1998;17(19):2531–2534.PubMedCrossRefGoogle Scholar
  28. 28.
    Marmorstein LY, Kinev AV, Chan GK, et al. A human BRCA2 complex containing a standrard DNA binding component influences cell cycle progression. Cell 2001;104(2):247–257.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang SC, Shao R, Pao AY, et al. Inhibition of cancer cell growth by BRCA2. Cancer Res 2002;62(5):1311–1314.PubMedGoogle Scholar
  30. 30.
    Marston NJ, Richards WJ, Hughes D, et al. Interaction between the product of the breast susceptibility gene BRCA2 and DSS1, a protein conserved from yeast to mammals. Mol Cell Biol 1999;19(7):4533–4542.Google Scholar
  31. 31.
    Liu J, Yuan Y, Huan J, et al. Inhibition of breast and breast cell growth by BCCIPalpha, an evolutionary conserved nuclear protein that interacts with BRCA2. Oncogene 2001;20(3):336–345.PubMedCrossRefGoogle Scholar
  32. 32.
    Kraakman-van der Zwet M, Overkamp WJ, Van Large RE, et al. BRCA2 (XRCC11 deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions. Mol Cell Biol 2002;22(2):669–679.PubMedCrossRefGoogle Scholar
  33. 33.
    Wong AK, Pero R, Ormonde PA, et al. RAD51 interacts with the evolutionary conserved BRC motifs in the human breast cancer susceptibility gene BRCA2. J Biol Chem 1997;272:31,941–31,944.Google Scholar
  34. 34.
    Davies AA, Masson J, Mcllwraith MJ, et al. Role of BRCA2 in control of the Rad51 recombination and DNA repair protein. Mol Cell 2001;7:273–282.PubMedCrossRefGoogle Scholar
  35. 35.
    Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology directed repair of chromosomal breaks. Mol Cell 2001;7:263–272.PubMedCrossRefGoogle Scholar
  36. 36.
    Chen CF, Chen PL, Zhong Q, et al. Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation sensitivity and loss of G(2)/M checkpoint control. J Biol Chem 1999;274(46):32,931–32,935.Google Scholar
  37. 37.
    Yang H, Jeffrey PD, Miller J, et al, BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 2002;297(5588):1837–1848.PubMedCrossRefGoogle Scholar
  38. 38.
    Yu VP, Koehler M, Steinlein C, et al. Gross chromsomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev 2000;14:1400–1406.PubMedGoogle Scholar
  39. 39.
    Abbott DW, Freeman ML, Holt J. Double-stranded break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 1998;90:6–13.CrossRefGoogle Scholar
  40. 40.
    Shyng-Shiou F, Sou-Ying L, Gang C, et al. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in-vivo. Cancer Res 1999;59:3547–3551.Google Scholar
  41. 41.
    Huichen W, Zhao-Chong Z, Tu-Auh B, et al. Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 and BRCA2. Cancer Res 2001;61:270–277.Google Scholar
  42. 42.
    Thompson LH, Schild D. The contribution of homologous recombination in preserving genome integrity in mammalian cells. Biochimie (Paris) 1999;81:87–105.Google Scholar
  43. 43.
    Chen PL, Chen CF, Chen Y, et al. The BRC repeats in BRCA2 are critical for Rad51 binding and resistance to methylmethane sulfonate treatment. Proc Natl Acad Sci USA 1998;95(9):5287–5292.PubMedCrossRefGoogle Scholar
  44. 44.
    Bogliolo M, Taylor RM, Caldecoltt KW, et al. Reduced ligation during DNA base excision repair supported by BRCA2 mutant cells. Oncogene 2000;19:5781–5787.PubMedCrossRefGoogle Scholar
  45. 45.
    Le Page F, Randrianarison V, Marot D, et al. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxaguanine in human cells. Cancer Res 2000;60(19):5548–5552.PubMedGoogle Scholar
  46. 46.
    Tutt A, Gabriel A, Bertwistle D, et al. Absence of BRCA2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr Biol 1999;9(19):1107–1110.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  1. 1.Department of Medical OncologyMayo ClinicRochester
  2. 2.Department of Laboratory Medicine and PathologyMayo Clinic and FoundationRochester
  3. 3.Department of Biochemistry and Molecular BiologyMayo ClinicRochester

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