Reference
Complete the bibliographic reference for the article according to AJE format.

Miyoshi Y, et al. Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. European Journal of Cancer. 2003 March;39(17):2531-2537.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

1. Prevalence of gene variant
2. Gene-disease association
4. Gene-gene interaction

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: CYP19
2. Chromosome location: 15q21.1
3. Gene product/function: encodes P450 aromatase, which catalyzes the biosynthesis of estrogen
4. Alleles: TTTA repeats, specifically TTTA _7(-3bp) allele (7 repeats with additional 3bp deletion)
5. OMIM #: 107910

1. Gene name: CYP1A1
2. Chromosome location: 15q22-q24
3. Gene product/function: encodes cytochrome P450, which catalyzes the hydroxylation of estrogen
4. Alleles: ⁶²³⁵ T-->C
5. OMIM #: 108330

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

N/A

Health outcome(s)
Identification of the major health outcome(s) studied

1. Estrogen receptor- positive breast cancer
2. Estrogen receptor- negative breast cancer

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

1. Disease case definition
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Disease case definition: Women living in Osaka, Japan with histologically confirmed breast cancer that had been treated with mastectomy or breast-conserving surgery
2. Exclusion criteria: not specified
3. Gender: Women
4. Race/ethnicity: Japanese
5. Age: 27 - 78 years (Mean: 51.3 years)
6. Time period: February 1998 - March 2001
7. Geographic location: Osaka , Japan
8. Number of participants: 257

1. Control selection criteria
2. Matching variables
3. Exclusion criteria
4. Gender
5. Race/ethnicity
6. Age
7. Time period
8. Geographic location
9. Number of participants

1. Control selection criteria: Attendees of a breast cancer screening program in Osaka , Japan
2. Matching variables: None
3. Exclusion criteria: none
4. Gender: Female
5. Race/ethnicity: Japanese
6. Age: 23 - 69 years (Mean: 49.7 years)
7. Time period: April 2001 - March 2002
8. Geographic location: Osaka , Japan
9. Number of participants: 191

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (% of total eligible)

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: CYP19
2. DNA source: blood mono-nucleated cells
3. Methodology: Polymorphisms were amplified using PCR and sized by electrophoresis.
4. Number of participants genotyped: 448 (100% of total eligible)

1. Gene: CYP1A1
2. DNA source: blood mono-nucleated cells
3. Methodology: Polymorphisms were amplified using PCR and sized by electrophoresis.
4. Number of participants genotyped: 448 (100% of total eligible)

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

1. Prevalence of gene variant
Note: Though allele frequency data were presented for 8 different tetranucleotide (TTTA) repeat polymorphisms, CYP19 (TTTA) _7(-3bp) was selected for further analysis.

2. Gene-disease association
Association of polymorphisms with ER-positive breast cancer

* Odds Ratio (OR) and 95% Confidence Interval (CI) adjusted for age, family history, parity and body mass index.

* Odds Ratio (OR) and 95% Confidence Interval (CI) adjusted for age, family history, parity and body mass index.

*High-risk genotypes are (TTTA) _7(-3bp) carriers for CYP19 and ⁶²³⁵C non-
carriers for CYP1A1 .0=neither polymorphism, 1=either CYP19 (TTTA) (TTTA) _7(-3bp) or absence of CYP1A1 6235 C, and 2=at least one copy of each of these "high-risk alleles"
†Cases are women diagnosed with ER-positive breast cancer.
^Odds Ratio (OR) and 95% Confidence Interval (CI) adjusted for age, family history, parity and body mass index.

CYP19 (TTTA) _7(-3bp) carriers had increased risk for ER-positive, but not
ER-negative breast cancer.  CYP1A1 ⁶²³⁵C alone appeared to be inversely associated with ER-positive breast cancer, but the result was not statistically significant. However, the combination of the two high-risk genotypes ( CYP19 (TTTA) _7(-3bp) and absence of CYP1A1 ⁶²³⁵C) was the
greatest predictor of ER-positive breast cancer. The authors state that this information would be useful in the selection of candidates for chemoprevention with tamoxifen.

Neither CYP19 nor CYP1A1 polymorphisms, individually or combined, were significantly associated with elevated serum estrogen levels in the post-menopausal controls.

• Controls were chosen from women who attended a breast cancer screening function. Their attendance may suggest an inherent belief of increased risk due to factors such as family history. Family history was, however, controlled for in the analysis.

• Previous studies in Caucasian women have shown associations between other CYP19 TTTA repeats and increased breast cancer risk . However, in this study, the only allele associated with breast cancer was CYP19 (TTTA) ^7(-3bp).

• Smoking was not controlled for or examined for interaction with the polymorphisms. CYP1A1 is believed to be induced by and act on carcinogens found in tobacco smoke (1).

• The population attributable fraction (AF) for the presence of the high risk CYP19 variant was 22%. The AF for the presence of both high-risk genotypes with ER+ breast cancer is 20.1% in all women, 10.0% in premenopausal women, and 36.2% in post-menopausal women. It is important to note that the finding for post-menopausal women was based on only 20 cases and 13 controls. In fact, in the analysis that stratified on number of high-risk alleles and menopausal status, none of the odds ratios were statistically significant. Though this information may not be relevant to the general population, it does appear that it may be a significant source of information for women debating the use of tamoxifen.

• Currently, this prophylaxis is recommended only for high-risk women. Therefore, the prediction of ER-positive breast cancer is relevant to chemoprophylaxis only in a high-risk population. No results are presented stratified on family history. The predictive value of CYP19 (TTTA) _7(-3bp) or CYP1A1 ⁶²³⁵C) in a high-risk
  population could be different.
  

References

1. Dunning A, et al. A systematic review of genetic polymorphisms and breast cancer risk.
   Cancer Epidemiology Biomarkers & Prevention. 1999 Oct;8(10):843-54.