Abstract
Although the association of germline BRCA2 mutations with pancreatic adenocarcinoma is well established, the role of BRCA1 mutations is less clear. We hypothesized that the loss of heterozygosity at the BRCA1 locus occurs in pancreatic cancers of germline BRCA1 mutation carriers, acting as a “second-hit” event contributing to pancreatic tumorigenesis. Seven germline BRCA1 mutation carriers with pancreatic adenocarcinoma and nine patients with sporadic pancreatic cancer were identified from clinic- and population-based registries. DNA was extracted from paraffin-embedded tumor and nontumor samples. Three polymorphic microsatellite markers for the BRCA1 gene, and an internal control marker on chromosome 16p, were selected to test for the loss of heterozygosity. Tumor DNA demonstrating loss of heterozygosity in BRCA1 mutation carriers was sequenced to identify the retained allele. The loss of heterozygosity rate for the control marker was 20%, an expected baseline frequency. Loss of heterozygosity at the BRCA1 locus was 5/7 (71%) in BRCA1 mutation carriers; tumor DNA was available for sequencing in 4/5 cases, and three demonstrated loss of the wild-type allele. Only 1/9 (11%) sporadic cases demonstrated loss of heterozygosity at the BRCA1 locus. Loss of heterozygosity occurs frequently in pancreatic cancers of germline BRCA1 mutation carriers, with loss of the wild-type allele, and infrequently in sporadic cancer cases. Therefore, BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and individuals with these mutations may be considered for pancreatic cancer-screening programs.
Similar content being viewed by others
References
Abe T, Fukushima N, Brune K et al (2007) Genomewide allelotype of familial pancreatic adenocarcinoma and familial and sporadic intraductal papillary mucinous neoplasms. Clin Cancer Res 13:6019–6025
Beger C, Ramadani M, Meyer S et al (2004) Down-regulation of BRCA1 in chronic pancreatitis and sporadic pancreatic adenocarcinoma. Clinical Cancer Res 10:3780–3787
Brose MS, Rebbeck TR, Calzone KA et al (2002) Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94:1365–1372
Canadian Cancer Society/NCIC (2007) Canadian cancer statistics 2007. Canadian Cancer Society/NCIC, Toronto, Canada
Couch FJ, Johnson MR, Rabe KG et al (2007) The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 16(2):342–346
Eppel A, Cotterchio M, Gallinger S (2007) Allergies are associated with reduced pancreas cancer risk: a population-based case–control study in Ontario, Canada. Int J Cancer 121:2241–2245
Esteller M, Fraga MF, Guo M et al (2001) DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 10:3001–3007
Feldmann G, Beaty R, Hruban RH et al (2007) Molecular genetics of pancreatic intraepithelial neoplasia. J Hepatobiliary Pancreat Surg 14:224–232
Greer JB, Whitcomb DC (2007) Role of BRCA1 and BRCA2 muations in pancreatic cancer. Gut 56:601–605
Gruber SB, Petersen GM (2002) Cancer risk in BRCA1 carriers: time for the next generation of studies. J Natl Cancer Inst 94:144–145
Gudmundsdottir K, Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25:5864–5874
Hahn SA, Greenhalf B, Ellis I et al (2003) BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 95:214–221
Hall M, Olopade O (2005) Pancreatic cancer and BRCA mutation in familial breast cancer families. J Clin Oncol 23(16S):9550
Honrado E, Benitez J, Palacios J (2005) The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications. Mod Pathol 18:1305–1320
Iacobuzio-Donahue CA, van der Heijden MS, Baumgartner MR et al (2004) Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. Cancer Res 64:871–875
Jemal A, Siegel R, Ward E et al (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66
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 60:409–416
Li D, Xie K, Wolff R et al (2004) Pancreatic cancer. Lancet 363:1049–1057
Lynch HT, Deters CA, Snyder CL et al (2005) BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. Cancer Genet Cytogenet 158:119–125
McCabe N, Turner NC, Lord CJ et al (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66:8109–8115
Ozcelik H, Schmoker B, Di Nicola N et al (1997) Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 16:17–18
Peng DF, Kanai Y, Sawada M et al (2006) DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1(DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27:1160–1168
Risch HA, McLaughlin JR, Cole DEC et al (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98:1694–1706
Saif MW (2007) Controversies in adjuvant treatment of pancreatic adenocarcinoma. JOP 8:545–552
Skudra S, Staka A, Pukitis A et al (2007) Association of genetic variants with pancreatic cancer. Cancer Genet Cytogenet 179:76–78
Struewing JP, Hartge P, Wacholder S et al (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401–1408
The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316
Thompson D, Easton DF, the Breast Cancer Linkage Consortium (2002) Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358–1365
Tonin P, Weber B, Offit K et al (1996) Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Medicine 2:1179–1183
Treszezamsky AD, Kachnic LA, Feng Z et al (2007) BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II. Cancer Res 67:7078–7081
van Asperen CJ, Brohet RM, Meijers-Heijboer EJ et al (2005) Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42:711–719
Yun J, Zhong Q, Kwak JY et al (2006) Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant S-phase arrest. Oncogene 24:4009–4016
Acknowledgments
Funding for this project was provided by a grant from the Lustgarten Foundation for Pancreatic Cancer Research.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A. et al. Germline BRCA1 mutations predispose to pancreatic adenocarcinoma. Hum Genet 124, 271–278 (2008). https://doi.org/10.1007/s00439-008-0554-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-008-0554-0