Regular Article

British Journal of Cancer (1999) 79, 456–463. doi:10.1038/sj.bjc.6690071 www.bjcancer.com
Published online 14 January 1999

Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk

N Siegelmann-Danieli1,* and K H Buetow1,†

1Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA

Correspondence: N Siegelmann-Danieli, Department of Oncology, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel

*Authors' current affiliations: Department of Oncology, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel

†Authors' current affiliations: Fox Chase Cancer Center, 7701 Burlhome Avenue, Philadelphia, PA 19111, USA.

Received 15 December 1997; Revised 21 April 1998; Accepted 11 March 1998.

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Abstract

The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat polymorphism at intron 4 of the Cyp19 gene revealed the presence of six common and two rare alleles. Contingency table analysis revealed a significant difference in allelic distribution between cases and controls (chi2 5df = 13.52, P = 0.019). The allele measuring 171 bp was over-represented in cases; of 14 individuals homozygous for this allele, 13 were cases. These individuals had a higher incidence of cancer in family members and an earlier age at diagnosis than other cases. In sequencing Cyp19's coding exons and regulatory regions, we discovered a perfect association between a silent polymorphism (Gright arrowA at Val80) and the high-risk genotype. Our conclusion is that constitutional genetic variation at the Cyp19 locus is associated with the risk of developing breast cancer, with the 171-bp allele serving as the high-risk allele.

Keywords:

breast cancer, aromatase gene, oestrogens, Cyp19

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