Acetyl-CoA carboxylase alpha gene and breast cancer susceptibility.
The identification of an interaction between BRCA1 and acetyl-CoA carboxylase alpha (ACCalpha), a key enzyme in lipid synthesis, led us to investigate the role of ACCalpha in breast cancer development, where it might contribute to the energy-sensing mechanisms of malignant transformation. In order to investigate if certain ACCalpha 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 (untranslated regions) and the promoter regions of the ACCalpha gene. Two possibly disease-associated ACCalpha variants were each identified in a single family and were not present in 137 controls. Multiple polymorphisms were detected in breast cancer families, including 12 single nucleotide polymorphisms where the frequency of the rare allele estimated in controls was >0.10. The observed lack of variation in the ACCalpha 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 ACCalpha 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 (odds ratio = 3.10, 95% confidence interval 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 ACCalpha gene are unlikely to be a major cause of high-risk breast cancer susceptibility; however, certain common ACCalpha alleles may influence breast cancer risk. This study provides the first insight into the involvement of the ACCalpha gene in breast cancer predisposition and calls for further, large-scale studies that will be needed to understand the role of ACCalpha in tumour susceptibility and development.
Sinilnikova
Olga M
OM
International Agency for Research on Cancer, 150, cours A. Thomas, 69372 Lyon, France. sinilnikova@iarc.fr
Ginolhac
Sophie M
SM
Magnard
Clémence
C
Léoné
Mélanie
M
Anczukow
Olga
O
Hughes
David
D
Moreau
Karen
K
Thompson
Deborah
D
Coutanson
Christine
C
Hall
Janet
J
Romestaing
Pascale
P
Gérard
Jean-Pierre
JP
Bonadona
Valérie
V
Lasset
Christine
C
Goldgar
David E
DE
Joulin
Virginie
V
Venezia
Nicole Dalla
ND
Lenoir
Gilbert M
GM
D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D000103:Acetyl-CoA Carboxylase