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Human Molecular Genetics Advance Access published online on January 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi052
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

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

Avraham Shaag 1, Tom Walsh 2, Paul Renbaum 3, Tomas Kirchhoff 4, Khedoudja Nafa 4, Stacey Shiovitz 2, Jessica B. Mandell 2, Piri Welcsh 2, Ming K. Lee 2, Nathan Ellis 4, Kenneth Offit 4, Ephrat Levy-Lahad 3, and Mary-Claire King 2*

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

* To whom correspondence should be addressed.
Mary-Claire King, E-mail: mcking{at}u.washington.edu


  Abstract

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-terminus. To assay these alleles for loss of CHEK2 function, we tested their capacity to complement Rad53 deletion in S. cerevisiae. CHEK2.S428F failed to complement Rad53 and thus largely abrogates normal CHEK2 function, whereas CHEK2.P85L complemented Rad53 as well as did wildtype 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. Based on 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 approximately two-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.


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