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Open Access Research article

Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families

Francine Durocher1*, Yvan Labrie1, Penny Soucy1, Olga Sinilnikova2, Damian Labuda3, Paul Bessette4, Jocelyne Chiquette5, Rachel Laframboise6, Jean Lépine7, Bernard Lespérance8, Geneviève Ouellette1, Roxane Pichette8, Marie Plante9, Sean V Tavtigian10 and Jacques Simard111

Author Affiliations

1 Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, Centre Hospitalier Universitaire de Québec and Laval University, Québec, G1V 4G2, Canada

2 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France

3 Centre de cancérologie Charles Bruneau, Ste-Justine Hospital, Montréal, Canada

4 Service de gynécologie, Centre Hospitalier Universitaire de Sherbrooke, Fleurimont, Canada

5 Clinique des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Québec, G1S 4L8, Canada

6 Service de médecine génétique, CHUQ, Pavillon CHUL, Québec, G1V 4G2, Canada

7 Centre hospitalier régional de Rimouski, Rimouski, G5L 5T1, Canada

8 Service d'hémato-oncologie, Hôpital du Sacré-Cœur, Montréal, Canada

9 Service de gynécologie, CHUQ, L'Hôtel-Dieu de Québec, Québec, G1R 2J6, Canada

10 Unit of Genetic Cancer Susceptibility, International Agency for Research on Cancer, World Health Organization, Lyon, France

11 Canada Research Chair in Oncogenetics, Department of Anatomy and Physiology, Laval University, Québec, Canada

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BMC Cancer 2006, 6:230  doi:10.1186/1471-2407-6-230

Published: 29 September 2006



Ataxia telangiectasia-mutated and Rad3-related (ATR) is a member of the PIK-related family which plays, along with ATM, a central role in cell-cycle regulation. ATR has been shown to phosphorylate several tumor suppressors like BRCA1, CHEK1 and TP53. ATR appears as a good candidate breast cancer susceptibility gene and the current study was designed to screen for ATR germline mutations potentially involved in breast cancer predisposition.


ATR direct sequencing was performed using a fluorescent method while widely available programs were used for linkage disequilibrium (LD), haplotype analyses, and tagging SNP (tSNP) identification. Expression analyses were carried out using real-time PCR.


The complete sequence of all exons and flanking intronic sequences were analyzed in DNA samples from 54 individuals affected with breast cancer from non-BRCA1/2 high-risk French Canadian breast/ovarian families. Although no germline mutation has been identified in the coding region, we identified 41 sequence variants, including 16 coding variants, 3 of which are not reported in public databases. SNP haplotypes were established and tSNPs were identified in 73 healthy unrelated French Canadians, providing a valuable tool for further association studies involving the ATR gene, using large cohorts. Our analyses led to the identification of two novel alternative splice transcripts. In contrast to the transcript generated by an alternative splicing site in the intron 41, the one resulting from a deletion of 121 nucleotides in exon 33 is widely expressed, at significant but relatively low levels, in both normal and tumoral cells including normal breast and ovarian tissue.


Although no deleterious mutations were identified in the ATR gene, the current study provides an haplotype analysis of the ATR gene polymorphisms, which allowed the identification of a set of SNPs that could be used as tSNPs for large-scale association studies. In addition, our study led to the characterization of a novel Δ33 splice form, which could generate a putative truncated protein lacking several functional domains. Additional studies in large cohorts and other populations will be needed to further evaluate if common and/or rare ATR sequence variants can be associated with a modest or intermediate breast cancer risk.