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 GA, 17-beta-hydroxysteroid dehydrogenase type 1 vIV AC, cytochrome P-450 (CYP) family 17 A2 allele TC, CYP1A1-1 MspI restriction fragment length polymorphism (RFLP) TC, CYP1A1-2 Ile462Val AG, CYP19-1 Trp39Arg TC, CYP19-2 Arg264Cys CT, CYP19-3 Cys1558Thr CT, steroid-5-alpha reductase type 2 Val89Leu GC, 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. Cancer 2004. © 2004 American Cancer Society.