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-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 555-563 |
| Number of pages | 9 |
| Journal | Human Molecular Genetics |
| Volume | 14 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 15 2005 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
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Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. / Shaag, Avraham; Walsh, Tom; Renbaum, Paul; Kirchhoff, Tomas; Nafa, Khedoudja; Shiovitz, Stacey; Mandell, Jessica B.; Welcsh, Piri; Lee, Ming K.; Ellis, Nathan; Offit, Kenneth; Levy-Lahad, Ephrat; King, Mary Claire.
In: Human Molecular Genetics, Vol. 14, No. 4, 15.02.2005, p. 555-563.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population
AU - Shaag, Avraham
AU - Walsh, Tom
AU - Renbaum, Paul
AU - Kirchhoff, Tomas
AU - Nafa, Khedoudja
AU - Shiovitz, Stacey
AU - Mandell, Jessica B.
AU - Welcsh, Piri
AU - Lee, Ming K.
AU - Ellis, Nathan
AU - Offit, Kenneth
AU - Levy-Lahad, Ephrat
AU - King, Mary Claire
PY - 2005/2/15
Y1 - 2005/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=14044272193&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=14044272193&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddi052
DO - 10.1093/hmg/ddi052
M3 - Article
C2 - 15649950
AN - SCOPUS:14044272193
VL - 14
SP - 555
EP - 563
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 4
ER -