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

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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)555-563
Number of pages9
JournalHuman Molecular Genetics
Volume14
Issue number4
DOIs
StatePublished - Feb 15 2005
Externally publishedYes

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Alleles
Haplotypes
Breast Neoplasms
Population
Checkpoint Kinase 2
Genetic Complementation Test
Amino Acid Substitution
Heterozygote
Nuclear Family
Saccharomyces cerevisiae
Siblings
Cell Cycle
Yeasts
Mothers
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

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 journalArticle

Shaag, A, Walsh, T, Renbaum, P, Kirchhoff, T, Nafa, K, Shiovitz, S, Mandell, JB, Welcsh, P, Lee, MK, Ellis, N, Offit, K, Levy-Lahad, E & King, MC 2005, 'Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population', Human Molecular Genetics, vol. 14, no. 4, pp. 555-563. https://doi.org/10.1093/hmg/ddi052
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. / Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 4. pp. 555-563.
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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.",
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AU - Renbaum, Paul

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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

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