Familial Cancer

, Volume 9, Issue 3, pp 335–343 | Cite as

Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families

  • Emily P. Slater
  • Peter Langer
  • Volker Fendrich
  • Nils Habbe
  • Brunhilde Chaloupka
  • Elvira Matthäi
  • Mercedes Sina
  • Stephan A. Hahn
  • Detlef K. Bartsch
Article

Abstract

Previous small scale studies reported that deleterious BRCA2 and CDKN2a germline mutations contribute to a subset of families with inherited pancreatic cancer. As the prevalence of those mutations in the setting of familial pancreatic cancer is still not well defined for the German population, we evaluated the presence of BRCA2 and CDKN2a germline mutations in a large cohort of familial pancreatic cancer (FPC) families from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Fifty-six FPC families with at least two-first-degree relatives with confirmed pancreatic cancer that did not fulfill the criteria of other tumor predisposition syndromes, were analyzed for BRCA2 and CDKN2a germline mutations by DHPLC and/or direct sequencing. No deleterious CDKN2a mutations were identified in our families suggesting that CDKN2a mutations are unlikely to predispose PC in FPC families without melanoma. No deleterious BRCA2 mutations, but 6 unclassified variants, were detected in our FPC collection. Combining the prevalence of deleterious BRCA2 germline mutations from our previous separate study with the data from this study we were able to much more accurately estimate the BRCA2 carrier frequency for FPC families in the German population. A total of two mutations and 6 unclassified variants (mutation range: 2.8–11.4%) were thus identified in 70 German FPC families, indicating that the prevalence of BRCA2 mutations in the German FPC population is less frequent than previously reported.

Keywords

BRCA2 CDKN2a Hereditary cancer Mutation analysis Pancreatic cancer 

Abbreviations

FaPaCa

German National Case Collection for Familial Pancreatic Cancer

FAMMM

Familial atypical multiple mole melanoma

FPC

Familial Pancreatic Cancer

PC

Pancreatic cancer

UV

Unclassified variant

Notes

Acknowledgments

We would like to thank all family members who participated in the study. We are indebted to Mrs. Margarete Schneider for her intensive work in the study office. We gratefully acknowledge support from the Deutsche Krebshilfe (No. 106 925).

Conflict of interest statement

None of the authors of this study has a conflict of interest to report.

References

  1. 1.
    Hruban RH, Petersen GM, Ha PK et al (1998) Genetics of pancreatic cancer. From genes to families. Surg Oncol Clin N Am 7:1–23PubMedGoogle Scholar
  2. 2.
    Applebaum SE, Kant JA, Whitcomb DC et al (2000) 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 84:575–588CrossRefPubMedGoogle Scholar
  3. 3.
    Bartsch DK, Sina-Frey M, Ziegler A et al (2001) Update of familial pancreatic cancer in Germany. Pancreatology 1:510–516CrossRefPubMedGoogle Scholar
  4. 4.
    Klein AP, Brune KA, Petersen GM et al (2004) Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 64:2634–2638CrossRefPubMedGoogle Scholar
  5. 5.
    McFaul CD, Greenhalf W, Earl J et al (2005) Anticipation in familial pancreatic cancer. Gut 55:252–258CrossRefPubMedGoogle Scholar
  6. 6.
    Hruban RH, Petersen GM, Goggins M et al (1999) Familial pancreatic cancer. Ann Oncol 10:69–73CrossRefPubMedGoogle Scholar
  7. 7.
    Murphy KM, Brune KA, Griffin C et al (2002) Evaluation of candidate genes MAP2K4, MADH4, ACVR1B and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 62:3789–3793PubMedGoogle Scholar
  8. 8.
    Grützmann R, McFaul CD, Bartsch DK et al (2004) No evidence for germline mutations of the LKB1/STK11 gene in familial pancreatic carcinoma. Cancer Lett 214:63–68CrossRefPubMedGoogle Scholar
  9. 9.
    Bartsch D, Fendrich V, Slater E et al (2005) RNASEL germline variants are associated with pancreatic cancer. Int J Cancer 117:718–722CrossRefPubMedGoogle Scholar
  10. 10.
    Bartsch DK, Krysewski K, Sina-Frey M et al (2006) Low frequency of CHEK2 mutations in familial pancreatic cancer. Fam Cancer 5(4):305–308CrossRefPubMedGoogle Scholar
  11. 11.
    Bartsch D, Sina-Frey M, Lang S et al (2002) CDKN2A germline mutations in familial pancreatic cancer. Ann Surg 236:730–737CrossRefPubMedGoogle Scholar
  12. 12.
    Lynch H, Brand R, Hogg D et al (2002) Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 94:84–96CrossRefPubMedGoogle Scholar
  13. 13.
    Schutte M, da Costa LT, Hahn SA et al (1995) Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci USA 92:5950–5954CrossRefPubMedGoogle Scholar
  14. 14.
    Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316CrossRefGoogle Scholar
  15. 15.
    Gershoni-Baruch R, Patael Y, Dagan et al (2000) Association of the I1307 K APC mutation with hereditary and sporadic breast/ovarian cancer: more questions than answers. Br J Cancer 83:153–155CrossRefPubMedGoogle Scholar
  16. 16.
    Goggins M, Schutte M, Lu J et al (1996) Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56:5360–5364PubMedGoogle Scholar
  17. 17.
    Ozçelik H, Schmocker B, Di Nicola N et al (1997) Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 16:17–18CrossRefPubMedGoogle Scholar
  18. 18.
    Hahn SA, Greenhalf W, Ellis I et al (2003) BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 95:214–221CrossRefPubMedGoogle Scholar
  19. 19.
    Martin ST, Matsubayashi H, Rogers CD et al (2005) Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer. Oncogene 24:3652–3656CrossRefPubMedGoogle Scholar
  20. 20.
    Couch FJ, Johnson MR, Rabe KG et al (2007) The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 16:342–346CrossRefPubMedGoogle Scholar
  21. 21.
    Gerdes B, Kress R, Rieder H et al (2002) Familial pancreatic cancer–concept for study of the National Case Collection and early diagnosis program for high risk people. Z Arztl Fortbild Qualitatssich 96:251–255PubMedGoogle Scholar
  22. 22.
    Rieder H, Sina-Frey M, Ziegler A et al (2002) German national case collection of familial pancreatic cancer—clinical-genetic analysis of the first 21 families. Onkologie 25:262–266CrossRefPubMedGoogle Scholar
  23. 23.
    Brand RE, Lerch MM, Rubinstein WS et al (2007) Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut 56:1460–1469CrossRefPubMedGoogle Scholar
  24. 24.
    Wagner T, Stoppa-Lyonnet D, Fleischmann E et al (1999) Denaturing high-performance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. Genomics 62:369–376CrossRefPubMedGoogle Scholar
  25. 25.
    Lynch HT, Kaurah P, Wirtzfeld D et al (2008) Hereditary diffuse gastric cancer. Cancer 112:2655–2663CrossRefPubMedGoogle Scholar
  26. 26.
    Langer P, Kann PH, Fendrich V et al (2009) 5 Years of prospective screening of high risk individuals from familial pancreatic cancer families. Gut 58:1410–1418CrossRefPubMedGoogle Scholar
  27. 27.
    Hu N, Wang C, Han XY et al (2004) Evaluation of BRCA2 in the genetic susceptibility of familial esophageal cancer. Oncogene 23:852–858CrossRefPubMedGoogle Scholar
  28. 28.
    Borg A, Sandberg T, Nilsson K et al (2000) High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 92:1260–1266CrossRefPubMedGoogle Scholar
  29. 29.
    Goldstein A, Fraser M, Struewing J et al (1995) Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 333:970–974CrossRefPubMedGoogle Scholar
  30. 30.
    Rulyak S, Brentnall T, Lynch H et al (2003) Characterization of the neoplastic phenotype in the familial atypical multiple-mole melanoma-pancreatic carcinoma syndrome. Cancer 98:798–804CrossRefPubMedGoogle Scholar
  31. 31.
    Vasen H, Gruis N, Frants R et al (2000) 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 87:809–811CrossRefPubMedGoogle Scholar
  32. 32.
    Rozenblum E, Schutte M, Goggins M et al (1997) Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 57:1731–1734PubMedGoogle Scholar
  33. 33.
    Lal G, Liu G, Schmocker B et al (2000) Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 60:409–416PubMedGoogle Scholar
  34. 34.
    Pollock PM, Pearson JV, Hayward NK (1996) Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions. Genes Chromosomes Cancer 15:77–88CrossRefPubMedGoogle Scholar
  35. 35.
    Ranade K, Hussussian CJ, Sikorski RS et al (1995) Mutations associated with familial melanoma impair p16INK4 function. Nat Genet 10:114–116CrossRefPubMedGoogle Scholar
  36. 36.
    Beristain E, Martíneuz-Bouzas C, Guerra I et al (2007) Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling. Breast Cancer Res Treat 106:255–262CrossRefPubMedGoogle Scholar
  37. 37.
    Hahn SA, Schmiegel WH (1998) Recent discoveries in cancer genetics of exocrine pancreatic neoplasia. Digestion 59:493–501CrossRefPubMedGoogle Scholar
  38. 38.
    Lynch HT, Brand RE, Lynch JF et al (2000) Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families. Gastroenterology 119:1756–1760CrossRefPubMedGoogle Scholar
  39. 39.
    German Consortium for Hereditary Breast and Ovarian Cancer (2002) Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 97:472–480CrossRefGoogle Scholar
  40. 40.
    Brentnall TA, Bronner MP, Byrd DR et al (1999) Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med 131:247–255PubMedGoogle Scholar
  41. 41.
    Canto MI, Goggins M, Hruban RH et al (2006) Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 4:766–781CrossRefPubMedGoogle Scholar
  42. 42.
    van der Heijden MS, Brody JR, Dezentje DA et al (2005) In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res 11:7508–7515CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Emily P. Slater
    • 1
  • Peter Langer
    • 1
  • Volker Fendrich
    • 1
  • Nils Habbe
    • 1
  • Brunhilde Chaloupka
    • 1
  • Elvira Matthäi
    • 1
  • Mercedes Sina
    • 2
  • Stephan A. Hahn
    • 3
  • Detlef K. Bartsch
    • 1
  1. 1.Department of Visceral-, Thoracic and Vascular SurgeryPhilipps-University MarburgMarburgGermany
  2. 2.Institute of Clinical GeneticsPhilipps-UniversityMarburgGermany
  3. 3.Department of Internal MedicineUniversitätsklinik KnappschaftskrankenhausBochumGermany

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