Estrogen-metabolizing gene polymorphisms in the assessment of breast carcinoma risk and fibroadenoma risk in Caucasian women.
BACKGROUND
Genes encoding enzymes involved in estrogen metabolism are held to be candidate genes for associations with breast disease. In these candidate genes, no critical combination of single-nucleotide polymorphisms (SNPs) for assessing breast carcinoma risk has been reported to date.


METHODS
In a large case-control study, the authors investigated 10 estrogen-metabolizing SNPs in 396 patients with breast carcinoma, 154 patients with fibroadenoma, and 1936 healthy control patients without breast carcinoma in their personal history. The following 10 SNPs were analyzed using sequencing-on-chip technology via a solid-phase polymerase chain reaction assay performed on oligonucleotide microarrays: catechol-O-methyltransferase Val158Met G-->A, 17-beta-hydroxysteroid dehydrogenase type 1 vIV A-->C, cytochrome P-450 (CYP) family 17 A2 allele T-->C, CYP1A1-1 MspI restriction fragment length polymorphism (RFLP) T-->C, CYP1A1-2 Ile462Val A-->G, CYP19-1 Trp39Arg T-->C, CYP19-2 Arg264Cys C-->T, CYP19-3 Cys1558Thr C-->T, steroid-5-alpha reductase type 2 Val89Leu G-->C, and vitamin D receptor BsmI RFLP. A total of 21,350 genotypes were evaluated. Associations and two-way interaction models were calculated using stepwise logistic regression.


RESULTS
In a multiple model, CYP1A1-1 (P = 0.004) and CYP1A1-2 (P = 0.03) were found to be associated with significantly decreased and increased risks of breast carcinoma, respectively. When two-way interactions involving investigated SNPs were ascertained, no significant interactions among polymorphisms were noted. Comparison of patients with fibroadenoma with control patients revealed significantly increased and decreased risks of fibroadenoma when the mutant alleles of CYP17 (P = 0.02) and CYP1A1-1 (P = 0.04), respectively, were present.


CONCLUSIONS
The authors obtained the first SNP data indicating that CYP17 and CYP1A1-1 play a role in the pathogenesis of fibroadenoma. Although the authors were not able to develop interaction models involving SNPs, they did provide evidence that CYP1A1 is a low-penetrance susceptibility gene with respect to breast carcinoma in a large series of Caucasian women.
Hefler
Lukas A
LA
Department of Obstetrics and Gynecology, Medical University Vienna, Vienna, Austria. likas.hefler@meduniwien.ac.at
Tempfer
Clemens B
CB
Grimm
Christoph
C
Lebrecht
Antje
A
Ulbrich
Eva
E
Heinze
Georg
G
Leodolter
Sepp
S
Schneeberger
Christian
C
Mueller
Manfred W
MW
Muendlein
Axel
A
Koelbl
Heinz
H
D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D018226:Fibroadenoma / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D044465:White People
D004967:Estrogens; D019363:Cytochrome P-450 CYP1A1; D013254:Steroid 17-alpha-Hydroxylase