This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oldenburg, R. A. Articles by Devilee, P. Search for Related Content PubMed PubMed Citation Articles by Oldenburg, R. A. Articles by Devilee, P.

The CHEK2*1100delC Variant Acts as a Breast Cancer Risk Modifier in Non-BRCA1/BRCA2 Multiple-Case Families

¹ Centre for Human and Clinical Genetics, and
² Departments of Pathology and
³ Medical Decision Making, Leiden University Medical Centre, Leiden;
⁴ Departments of Clinical Genetics,
⁵ Medical Oncology, and
⁶ Pathology, Erasmus MC, Rotterdam;
⁷ Department of Human Genetics, University Medical Centre, Nijmegen; and
⁸ Netherlands Foundation for the Detection of Hereditary Tumors, Leiden, the Netherlands

The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of this variant as a candidate breast cancer susceptibility allele, we determined its prevalence in 237 breast cancer patients and 331 healthy relatives derived from 71 non-BRCA1/BRCA2 multiple-case early onset breast cancer families. Twenty-seven patients (11.4%) were carrying the CHEK2*1100delC variant. At least one carrier was found in 15 of the 71 families (21.1%). There was no evidence of cosegregation between the variant and breast cancer, but carrier patients developed breast cancer earlier than did noncarriers. We studied CHEK2 protein expression in 111, and loss of heterozygosity at CHEK2 in 88 breast tumors from these patients. Twelve of 15 tumors from carriers showed absent protein expression as opposed to 3 of 76 tumors from noncarriers (P < 0.001). CHEK2 loss of heterozygosity was associated with absence of protein expression but not with 1100delC carrier status. Thus, selecting for breast cancer cases with a strong familial background not accounted for by BRCA1 or BRCA2 strongly enriches for carriers of CHEK2*1100delC. Our results support a model in which CHEK2*1100delC interacts with an as yet unknown gene (or genes) to increase breast cancer risk.

This article has been cited by other articles:

				C Cybulski, B Gorski, T Huzarski, T Byrski, J Gronwald, T Debniak, D Wokolorczyk, A Jakubowska, P Serrano-Fernandez, T Dork, et al. Effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other CHEK2 or BRCA1 mutations J. Med. Genet., February 1, 2009; 46(2): 132 - 135. [Abstract] [Full Text] [PDF]

				C. Cybulski, B. Masojc, D. Oszutowska, E. Jaworowska, T. Grodzki, P. Waloszczyk, P. Serwatowski, J. Pankowski, T. Huzarski, T. Byrski, et al. Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers Carcinogenesis, April 1, 2008; 29(4): 762 - 765. [Abstract] [Full Text] [PDF]

				M. Weischer, S. E. Bojesen, A. Tybjaerg-Hansen, C. K. Axelsson, and B. G. Nordestgaard Increased Risk of Breast Cancer Associated With CHEK2*1100delC J. Clin. Oncol., January 1, 2007; 25(1): 57 - 63. [Abstract] [Full Text] [PDF]

				S-M Karppinen, R B Barkardottir, K Backenhorn, T Sydenham, K Syrjakoski, J Schleutker, T Ikonen, K Pylkas, K Rapakko, H Erkko, et al. Nordic collaborative study of the BARD1 Cys557Ser allele in 3956 patients with cancer: enrichment in familial BRCA1/BRCA2 mutation-negative breast cancer but not in other malignancies J. Med. Genet., November 1, 2006; 43(11): 856 - 862. [Abstract] [Full Text] [PDF]

				C Cybulski, D Wokolorczyk, T Huzarski, T Byrski, J Gronwald, B Gorski, T Debniak, B Masojc, A Jakubowska, B Gliniewicz, et al. A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer J. Med. Genet., November 1, 2006; 43(11): 863 - 866. [Abstract] [Full Text] [PDF]

				N. Sodha, T. S. Mantoni, S. V. Tavtigian, R. Eeles, and M. D. Garrett Rare Germ Line CHEK2 Variants Identified in Breast Cancer Families Encode Proteins That Show Impaired Activation. Cancer Res., September 15, 2006; 66(18): 8966 - 8970. [Abstract] [Full Text] [PDF]

				C. Cybulski, B. Gorski, T. Huzarski, T. Byrski, J. Gronwald, T. Debniak, D. Wokolorczyk, A. Jakubowska, E. Kowalska, O. Oszurek, et al. CHEK2-Positive Breast Cancers in Young Polish Women. Clin. Cancer Res., August 15, 2006; 12(16): 4832 - 4835. [Abstract] [Full Text] [PDF]

				T. Walsh, S. Casadei, K. H. Coats, E. Swisher, S. M. Stray, J. Higgins, K. C. Roach, J. Mandell, M. K. Lee, S. Ciernikova, et al. Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast Cancer JAMA, March 22, 2006; 295(12): 1379 - 1388. [Abstract] [Full Text] [PDF]

				R. A. Oldenburg, K. Kroeze-Jansema, H. Meijers-Heijboer, C. J. van Asperen, N. Hoogerbrugge, I. van Leeuwen, H. F.A. Vasen, A.-M. Cleton-Jansen, J. Kraan, J. J. Houwing-Duistermaat, et al. Characterization of Familial Non-BRCA1/2 Breast Tumors by Loss of Heterozygosity and Immunophenotyping. Clin. Cancer Res., March 15, 2006; 12(6): 1693 - 1700. [Abstract] [Full Text] [PDF]

				J. L. Bernstein, S. N. Teraoka, E. M. John, I. L. Andrulis, J. A. Knight, R. Lapinski, E. R. Olson, A. L. Wolitzer, D. Seminara, A. S. Whittemore, et al. The CHEK2*1100delC Allelic Variant and Risk of Breast Cancer: Screening Results from the Breast Cancer Family Registry. Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 348 - 352. [Abstract] [Full Text] [PDF]

				E. Honrado, A. Osorio, J. Palacios, R. L. Milne, L. Sanchez, O. Diez, A. Cazorla, K. Syrjakoski, D. Huntsman, P. Heikkila, et al. Immunohistochemical Expression of DNA Repair Proteins in Familial Breast Cancer Differentiate BRCA2-Associated Tumors J. Clin. Oncol., October 20, 2005; 23(30): 7503 - 7511. [Abstract] [Full Text] [PDF]

				A. Shaag, T. Walsh, P. Renbaum, T. Kirchhoff, K. Nafa, S. Shiovitz, J. B. Mandell, P. Welcsh, M. K. Lee, N. Ellis, et al. Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population Hum. Mol. Genet., February 15, 2005; 14(4): 555 - 563. [Abstract] [Full Text] [PDF]

				G H de Bock, M Schutte, E M M Krol-Warmerdam, C Seynaeve, J Blom, C T M Brekelmans, H Meijers-Heijboer, C J van Asperen, C J Cornelisse, P Devilee, et al. Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant J. Med. Genet., October 1, 2004; 41(10): 731 - 735. [Abstract] [Full Text] [PDF]

				C. Cybulski, T. Huzarski, B. Gorski, B. Masojc, M. Mierzejewski, T. Debniak, B. Gliniewicz, J. Matyjasik, E. Zlowocka, G. Kurzawski, et al. A Novel Founder CHEK2 Mutation is Associated with Increased Prostate Cancer Risk Cancer Res., April 15, 2004; 64(8): 2677 - 2679. [Abstract] [Full Text] [PDF]