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Carcinogenesis Advance Access published online on August 27, 2004
Carcinogenesis, doi:10.1093/carcin/bgh273
© 2004 by Oxford University Press
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Received April 19, 2004
Revised August 6, 2004
Accepted August 15, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Acetyl-CoA carboxylase {alpha} gene and breast cancer susceptibility

Olga M. Sinilnikova 1*, Sophie M. Ginolhac 2, Clémence Magnard 3, Mélanie Léoné 1, Olga Anczukow 4, David Hughes 2, Karen Moreau 3, Deborah Thompson 2, Christine Coutanson 2, Janet Hall 2, Pascale Romestaing 5, Jean-Pierre Gérard 6, Valérie Bonadona 7, Christine Lasset 7, David E. Goldgar 2, Virginie Joulin 8, Nicole Dalla Venezia 3, Gilbert M. Lenoir 8

1 International Agency for Research on Cancer, 150, cours A. Thomas, 69372 Lyon, France; Plate-forme mixte de génétique constitutionnelle des cancers fréquents, Hospices Civils de Lyon/Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon, France
2 International Agency for Research on Cancer, 150, cours A. Thomas, 69372 Lyon, France
3 CNRS - FRE 2692, Université Claude Bernard, avenue Rockefeller, 69373 Lyon, France
4 International Agency for Research on Cancer, 150, cours A. Thomas, 69372 Lyon, France; CNRS - FRE 2692, Université Claude Bernard, avenue Rockefeller, 69373 Lyon, France
5 Centre Hospitalier Lyon-Sud, Pierre-Bénite, Cedex, France
6 Centre Hospitalier Lyon-Sud, Pierre-Bénite, Cedex, France; Centre Antoine-Lacassagne, Nice Cedex 2, France
7 Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon, France
8 CNRS - UMR 8125, Institut Gustave Roussy, rue C. Desmoulins, 94805 Villejuif, France

* To whom correspondence should be addressed. E-mail: sinilnikova{at}iarc.fr.


  Abstract

The identification of an interaction between BRCA1 and acetyl-CoA carboxylase {alpha} (ACC{alpha}), a key enzyme in lipid synthesis, led us to investigate the role of ACC{alpha} in breast cancer development, where it might contribute to the energy-sensing mechanisms of malignant transformation. In order to investigate if certain ACC{alpha} alleles may be high-risk breast cancer susceptibility alleles, 37 extended breast and breast/ovarian cancer families negative for BRCA1 and BRCA2 mutations were exhaustively screened for sequence variations in the entire coding sequence, intron-exon junctions, 5'UTR, 3'UTR and the promoter regions of the ACC{alpha} gene. Two possibly disease-associated ACC{alpha} variants were each identified in a single family and were not present in 137 controls. Multiple polymorphisms were detected in breast cancer families, including twelve SNPs where the frequency of the rare allele estimated in controls was >0.10. The observed lack of variation in the ACC{alpha} coding region along with the presence of extended areas of linkage disequilibrium and low haplotype diversity indicates an overall high preservation of this gene. The prevalence of the ACC{alpha} haplotypes composed of common polymorphisms was determined in 453 breast cancer cases and 469 female controls. One haplotype was found to be associated with a substantial and highly significant increase in breast cancer risk (OR = 3.10, 95% CI 1.87-5.14, P<0.0001), whereas three other haplotypes were found to have a protective effect. Our results indicate that mutations in the ACC{alpha} gene are unlikely to be a major cause of high-risk breast cancer susceptibility, however, certain common ACC{alpha} alleles may influence breast cancer risk. This study provides a first insight into the involvement of the ACC{alpha} gene in breast cancer predisposition and calls for further, large-scale studies that will be needed to understand the role of ACC{alpha} in tumour susceptibility and development.

Keywords: Acetyl-CoA carboxylase {alpha} gene; BRCA1; breast cancer; mutation; SNP.
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