Skip Navigation


Human Molecular Genetics Advance Access originally published online on January 13, 2005
Human Molecular Genetics 2005 14(4):555-563; doi:10.1093/hmg/ddi052
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/4/555    most recent
ddi052v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (24)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Shaag, A.
Right arrow Articles by King, M.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shaag, A.
Right arrow Articles by King, M.-C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, Vol. 14, No. 4 © Oxford University Press 2005; all rights reserved

Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population

Avraham Shaag1,2, Tom Walsh1, Paul Renbaum2, Tomas Kirchhoff3, Khedoudja Nafa3, Stacey Shiovitz1, Jessica B. Mandell1, Piri Welcsh1, Ming K. Lee1, Nathan Ellis3, Kenneth Offit3, Ephrat Levy-Lahad2 and Mary-Claire King1,*

1Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA 98195-7720, USA, 2Shaare Zedek Medical Center, Hebrew University, Jerusalem 91031, Israel and 3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA

Received November 22, 2004; Accepted December 30, 2004

Functional and genomic approaches can be integrated to screen efficiently for pathogenic alleles in founder populations. We applied such approaches to analysis of the cancer-associated cell cycle regulator CHEK2 in the Ashkenazi Jewish population. We first identified two extended haplotypes at CHEK2 that co-segregated with breast cancer in high-risk families. We sequenced CHEK2 in a case representing each haplotype and discovered two novel amino acid substitutions, CHEK2.S428F in the kinase domain and CHEK2.P85L in the N-terminal region. To assay these alleles for loss of CHEK2 function, we tested their capacity to complement Rad53 deletion in Saccharomyces cerevisiae. CHEK2.S428F failed to complement Rad53 and thus largely abrogates normal CHEK2 function, whereas CHEK2.P85L complemented Rad53 as well as did wild-type CHEK2. Epidemiologic analyses were concordant with the functional tests. Frequencies of CHEK2.S428F heterozygotes were 2.88% (47/1632) among female breast cancer patients not selected for family history or age at diagnosis and 1.37% (23/1673) among controls (OR=2.13, 95% CI [1.26, 3.69], P=0.004), whereas frequencies of CHEK2.P85L were 0.92% among cases and 0.83% among controls. On the basis of the experience of mothers, sisters and daughters of probands, breast cancer risk due to CHEK2.S428F was estimated as 0.17 (±0.08) by age 60. We conclude that CHEK2.S428F increases breast cancer risk ~2-fold among Ashkenazi Jewish women, whereas CHEK2.P85L is a neutral allele. In general, these results suggest that selecting probands with extended haplotypes that co-segregate with disease can improve the efficiency of resequencing efforts and that quantitative complementation tests in yeast can be used to evaluate variants in genes with highly conserved function.

* To whom correspondence should be addressed. Email: mcking{at}u.washington.edu


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
T. Kirchhoff, Z.-q. Chen, B. Gold, P. Pal, M. M. Gaudet, K. Kosarin, D. A. Levine, P. Gregersen, S. Spencer, M. Harlan, et al.
The 6q22.33 Locus and Breast Cancer Susceptibility
Cancer Epidemiol. Biomarkers Prev., September 1, 2009; 18(9): 2468 - 2475.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. E. Sehl, L. R. Langer, J. C. Papp, L. Kwan, J. L. Seldon, G. Arellano, J. Reiss, E. F. Reed, S. Dandekar, Y. Korin, et al.
Associations between Single Nucleotide Polymorphisms in Double-Stranded DNA Repair Pathway Genes and Familial Breast Cancer
Clin. Cancer Res., March 15, 2009; 15(6): 2192 - 2203.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Zhang, C. M. Phelan, P. Zhang, F. Rousseau, P. Ghadirian, A. Robidoux, W. Foulkes, N. Hamel, D. McCready, M. Trudeau, et al.
Frequency of the CHEK2 1100delC Mutation among Women with Breast Cancer: An International Study
Cancer Res., April 1, 2008; 68(7): 2154 - 2157.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
K. Offit and J. E. Garber
Time to Check CHEK2 in Families With Breast Cancer?
J. Clin. Oncol., February 1, 2008; 26(4): 519 - 520.
[Full Text] [PDF]

Home page
 J. Med. Genet.Home page
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]

Home page
 Clin. Cancer Res.Home page
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]

Home page
 JAMAHome page
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]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.