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

Siegelmann‐Danieli, Nava; Buetow, Kenneth H.

doi:10.1038/sj.bjc.6690071

Cited by 99 publications

(62 citation statements)

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“…The contrasting findings with previous studies (Watanabe et al, 1997;Siegelmann-Danieli and Buetow, 1999;Healey et al, 2000;Miyoshi et al, 2000) may be because of the differences in subject selection (noncomparable controls in the above studies), sample size (less than 200 in both cases and controls), and inadequate statistical power, marked differences in frequency of Cys allele (52 -54% for Japanese women, 39% for Korean women, and less than 10% for Caucasian), and different genotyping methods (single-strand conformation polymorphism, sequencing, and dynamic allele-specific hybridisation). The Arg 264 Cys polymorphism is located in or near recognition site of CYP19 aromatase and thus, it might enhance the oestrogen synthesis and exposure to endogenous oestrogen.…”

Section: Discussioncontrasting

confidence: 87%

“…The genotype distributions in the control subjects agreed with those predicted by the Hardy -Weinberg equilibrium. The frequency of CYP19 Cys allele-containing genotypes (39%) was somewhat lower than that previously found in Japanese women (52 -54%) (Watanabe et al, 1997;Miyoshi et al, 2000), whereas the frequency of CYP19 Cys allele-containing genotypes was very low, less than 10% for Caucasians (Siegelmann-Danieli and Buetow, 1999;Healey et al, 2000). The frequency of CYP1B1 Val allele-containing genotype (21%), on the other hand, was similar to that (29%) found in Japanese women (Watanabe et al, 2000).…”

Section: Resultssupporting

confidence: 48%

“…To date, several polymorphisms have been found in the CYP19 gene (i.e. Polymeropulous et al, 1991;Sourdaine et al, 1994;Siegelmann-Danieli and Buetow, 1999;Healey et al, 2000;Miyoshi et al, 2000). One of these, a C-to-T variation in exon 7 resulting in an Arg 264 Cys amino-acid exchange, has been shown to be very common in Asians (Watanabe et al, 1997;Miyoshi et al, 2000) and could thus be an important modifier of breast cancer risk in this ethnic group.…”

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confidence: 99%

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Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women

Lee

Abel

et al. 2003

Br J Cancer

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A case -control study was performed to assess the potential influence of CYP19 Arg 264 Cys and CYP1B1 Leu 432 Val polymorphisms on breast cancer risk in a series of Korean breast cancer patients and controls. The results suggest that the CYP19 Arg 264 Cys polymorphism modifies breast cancer risk (OR ¼ 1.5, 95% CI ¼ 1.1 -2.2), especially in association with alcohol consumption (P for interaction ¼ 0.04), whereas the CYP1B1 Leu 432 Val polymorphism appears to play no role here. Breast cancer is the second most frequent cancer in Korean women and its incidence is increasing (Yoo et al, 1998). Lifetime cumulative exposure to oestrogens is known as the most important risk factor for breast cancer (Yager, 2000). A variety of different enzymes are involved in the synthesis of oestrogen from cholesterol and further metabolism of oestrogen (Thompsen and Ambrosone, 2000). Polymorphisms of genes encoding for these proteins are regarded as the candidates for elevated breast cancer risk.The CYP19 gene encodes aromatase, which catalyses the formation of oestrogens from testosterone and androstenedione. To date, several polymorphisms have been found in the CYP19 gene (i.e. Polymeropulous et al, 1991;Sourdaine et al, 1994;Siegelmann-Danieli and Buetow, 1999;Healey et al, 2000;Miyoshi et al, 2000). One of these, a C-to-T variation in exon 7 resulting in an Arg 264 Cys amino-acid exchange, has been shown to be very common in Asians (Watanabe et al, 1997;Miyoshi et al, 2000) and could thus be an important modifier of breast cancer risk in this ethnic group.The CYP1B1 enzyme is known to be involved in the formation of 4-hydroxyoestradiol, which is a catechol metabolite of oestrogen (Hayes et al, 1996). A C-to-G variation in exon 3 of the CYP1B1 gene results in a Leu 432 Val amino-acid exchange. The Leu/Leu genotype has been associated with increased breast cancer risk in an Asian population (Zheng et al, 2000) but controversial results have been reported as well (Bailey et al, 1998;Watanabe et al, 2000).In this study, we have evaluated the potential influence of CYP19 Arg 264 Cys and CYP1B1 Leu 432 Val polymorphisms on the breast cancer risk among Korean women as an extension of our previous work in this study population (Park et al, 2000;Yim et al, 2001). MATERIALS AND METHODS Study subjectsThe criteria of subject selection and details of data collection on lifestyle have been described elsewhere (Park et al, 2000;Yim et al, 2001). Eligible study population consisted of 389 incident breast cancer cases and 346 controls with no other known cancer or systemic disease, admitted in 1995 -2001 to three teaching hospitals located in Seoul, Korea (Seoul National University Hospital, Borame Hospital, and Asan Medical Center). Each patient was frequency-matched to one control in the following age groups : under 30, 30 -34, 35 -39, 40 -44, 45 -49, 50 -54, 55 -59, 60 -69, and over 70 years; 288 cases and 288 controls were selected and genotyped for CYP19. Informed consents were obtained at the time of blood withdrawal. Information on demogr...

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Section: Discussioncontrasting

confidence: 87%

Section: Resultssupporting

confidence: 48%

mentioning

confidence: 99%

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Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women

Lee

Abel

et al. 2003

Br J Cancer

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“…This deletion has, however, been described previously in a Japanese study (Kurosaki et al, 1997). From their study, Siegelmann-Danieli and Buetow (1999) conclude that the 171 bp allele represents a high-risk allele, whereas the 187 bp and 191 bp alleles (corresponding to 11 and 12 repeats respectively, from our data) are considered to confer low risk. These conclusions are contradictory to those drawn by Kristensen et al (1998).…”

Section: Discussionmentioning

confidence: 99%

A polymorphic tetranucleotide repeat in the CYP19 gene and male breast cancer

et al. 2000

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“…Selected CYP19 polymorphisms have been investigated for their possible association with the therapeutic efficacy of aromatase inhibitors and with sex hormone levels or risk for estrogendependent diseases (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Although the results of those studies are controversial, they suggest an important role for genetic variation in aromatase function and, as a result, in estrogen production.…”

Section: Introductionmentioning

confidence: 99%

Functional Genetic Polymorphisms in the Aromatase Gene CYP19 Vary the Response of Breast Cancer Patients to Neoadjuvant Therapy with Aromatase Inhibitors

Ma¹,

Ellis²

2010

Yearbook of Oncology

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Aromatase (CYP19) is a critical enzyme for estrogen biosynthesis, and aromatase inhibitors (AIs) are established endocrine therapy for post-menopausal women with breast cancer. DNA samples were obtained from 52 women pre-and post-AI treatment in the neoadjuvant setting. 82 breast cancer and 19 normal breast samples were resequenced to test the hypothesis that single nucleotide polymorphisms (SNPs) in the CYP19 gene might contribute to response to neoadjuvant AI therapy. There were no differences in CYP19 sequence between tumor and germline DNA in the same patient. Forty-eight CYP19 SNPs were identified, with four being novel when compared with previous resequencing data. Genotype-phenotype association studies performed with levels of aromatase activity, estrone, estradiol and tumor size pre-and post-AI treatment indicated that two tightly linked SNPs, rs6493497 and rs7176005 in the 5'-flanking region of CYP19 exon 1.1, were significantly associated with a greater change in aromatase activity after AI treatment. A follow-up study in 200 women with early breast cancer treated with adjuvant anastrozole showed that these same two SNPs were also associated with higher plasma estradiol levels pre-and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed the potential functional effects of these two SNPs on transcription regulation. These studies provide insight into the role of common genetic polymorphisms in CYP19 in variation in response to AIs by breast cancer patients.

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

Cited by 99 publications

References 45 publications

Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women

Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women

A polymorphic tetranucleotide repeat in the CYP19 gene and male breast cancer

Functional Genetic Polymorphisms in the Aromatase Gene CYP19 Vary the Response of Breast Cancer Patients to Neoadjuvant Therapy with Aromatase Inhibitors

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