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. 2011;13(6):R119.
doi: 10.1186/bcr3062. Epub 2011 Nov 24.

CHEK2 contribution to hereditary breast cancer in non-BRCA families

Alexis Desrichard  1 , Yannick Bidet, Nancy Uhrhammer, Yves-Jean Bignon
Affiliations

CHEK2 contribution to hereditary breast cancer in non-BRCA families

Alexis Desrichard et al. Breast Cancer Res. 2011.

Abstract

Background: Mutations in the BRCA1 and BRCA2 genes are responsible for only a part of hereditary breast cancer (HBC). The origins of "non-BRCA" HBC in families may be attributed in part to rare mutations in genes conferring moderate risk, such as CHEK2, which encodes for an upstream regulator of BRCA1. Previous studies have demonstrated an association between CHEK2 founder mutations and non-BRCA HBC. However, very few data on the entire coding sequence of this gene are available.

Methods: We investigated the contribution of CHEK2 mutations to non-BRCA HBC by direct sequencing of its whole coding sequence in 507 non-BRCA HBC cases and 513 controls.

Results: We observed 16 mutations in cases and 4 in controls, including 9 missense variants of uncertain consequence. Using both in silico tools and an in vitro kinase activity test, the majority of the variants were found likely to be deleterious for protein function. One variant present in both cases and controls was proposed to be neutral. Removing this variant from the pool of potentially deleterious variants gave a mutation frequency of 1.48% for cases and 0.29% for controls (P = 0.0040). The odds ratio of breast cancer in the presence of a deleterious CHEK2 mutation was 5.18.

Conclusions: Our work indicates that a variety of deleterious CHEK2 alleles make an appreciable contribution to breast cancer susceptibility, and their identification could help in the clinical management of patients carrying a CHEK2 mutation.

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Figures

Figure 1
Figure 1
Position of CHEK2 mutations found in French non-BRCA HBC and control populations. FHA = Forkhead-associated domain; SQ/TQ = SQ/TQ cluster domain.
Figure 2
Figure 2
Kinase activity of recombinant Flag-CHEK2 protein. Total protein extract (1.5 μg) was tested for the ability to phosphorylate a fluorescent substrate. The slope of the resulting curve represents Flag-CHEK2 kinase activity. The slope of the wild-type (WT) Flag-CHEK2 kinase activity curve was normalized to 1. Nontransformed protein extracts (NT) and mutant c.1100delC served as controls. Each point represents an average of five measurements performed in triplicate.
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References

    1. Panda S, Isbatan A, Adami GR. Modification of the ATM/ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo. Mech Ageing Dev. 2008;129:332–340. doi: 10.1016/j.mad.2008.02.014. - DOI - PMC - PubMed
    1. Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D. Breast Cancer Susceptibility Collaboration (UK) Easton DF, Stratton MR. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39:165–167. doi: 10.1038/ng1959. - DOI - PMC - PubMed
    1. Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR. CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31:55–59. doi: 10.1038/ng879. - DOI - PubMed
    1. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D. Breast Cancer Susceptibility Collaboration (UK) Easton DF, Stratton MR, Rahman N. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38:873–875. doi: 10.1038/ng1837. - DOI - PubMed
    1. Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, Chagtai T, Jayatilake H, Ahmed M, Spanova K, North B, McGuffog L, Evans DG, Eccles D. Breast Cancer Susceptibility Collaboration (UK) Easton DF, Stratton MR, Rahman N. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38:1239–1241. doi: 10.1038/ng1902. - DOI - PubMed

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