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

Modan B, Hartge P, Hirsch-Yechezkel G, Chetrit A, Lubin F, Beller U, Ben-Baruch G, Fishman A, Menczer J, Struewing J, Tucker M, Wacholder S.  Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001; 345(4):235-40.

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
3. Gene-environment 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: BRCA1 and BRCA2
2. Chromosome location:  17q21 (BRCA1) and 13q12.3 (BRCA2)
3. Gene product/function: Nuclear cell cycle regulated phosphoproteins of breast epithelium
4. Alleles:  185delAG, 5382insC (BRCA1) and 6174delT (BRCA2)
5. OMIM #: 113705 (BRCA1) and 600185 (BRCA2)

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

Oral contraceptives

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

Ovarian 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. Case definition: Jewish women with pathologically confirmed cancer of the ovary or primary peritoneal carcinoma who consented to be interviewed and for whom molecular analysis for founder mutations was successfully completed
2. Exclusion criteria: Women who had undergone bilateral oophorectomy and women whose history of breast cancer was unknown
3. Gender: Female
4. Race/ethnicity: Jewish (71.5% Ashkenazi, 23.0% non-Ashkenazi, 5.5% mixed ancestry
5. Age: <40 yr, n=48; 40-49 yr, n=205; 50-59 yr, n=260; 60-69 yr, n=327, >=70 yr, n=275
6. Time period: March 1, 1994, to June 30, 1999
7. Geographic location:  Israel
8. Number of participants: 832

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 definition: Women selected from the Central Population Registry
2. Matching variables: Age, area of birth, region and duration of residence in Israel
3. Exclusion criteria:  Women who had undergone bilateral oophorectomy, women whose history of breast cancer was unknown, and women whose parity was unknown
4. Gender: Female
5. Race/ethnicity: Jewish
6. Age: matched to cases
7. Time period: March 1, 1994, to June 30, 1999
8. Geographic location:  Israel
9. Number of participants: 2,257

Cohort definition
For study designs 2, 3, and 6, define the following if available:

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

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

1. Environmental factor 1: Oral Contraceptive use
2. Exposure assessment: Interviews
3. Exposure definition: Not specified
4. Participants with exposure data: 832 cases, 2,257 controls

1. Environmental factor 2: Parity
2. Exposure assessment: Interviews
3. Exposure definition: Not specified
4. Participants with exposure data: 832 cases, 2,257 controls

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

1. Gene: BRCA1 and BRCA2
2. DNA source: Blood samples (cases and controls), buccal cells (controls), paraffin embedded tissue section (cases)
3. Methodology: Multiplex PCR designed to amplify the exons containing the three mutations with the use of fluorescence-labeled primers in a single reaction. Mutations were detected as length polymorphisms using an Applied Biosystems model 310 genetic analyzer and Applied Biosystems Genescan software.  
4. Participants genotyped:  840 cases (before exclusion), 751 controls

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

BRCA1 and BRCA2 mutations in cases and controls summarized as shown:

*One patient had both the 185delAG mutation in BRCA1 and the 6174delT mutation in BRCA2; another had both the 5382insC mutation in BRCA1 and the 6174delT mutation in BRCA2.  None of the controls had more than one mutation.

 2. Gene-disease association

⁺Estimates of the odds ratios and confidence intervals are unreliable because of the small numbers of subjects.  This footnote applies to the OR’s for BRCA1 only, not to 6174 or overall. 

3. Gene-environment interaction:
Effect of parity and use of oral contraceptives on the risk of ovarian cancer, according to mutation status

 Case-control

Based on results of the case-control analysis, the authors concluded that oral contraceptive use was associated with a significant decrease in ovarian cancer risk among women without a BRCA1 or BRCA2 mutation.  However, no such protective measure was found in women with a BRCA1 or BRCA2 mutation.  Parity was found to have a protective effect in both groups of women.

Consequently, the authors suggest that the prescription of oral contraceptives for the chemoprevention of ovarian cancer in BRCA1 and BRCA2 mutation carriers is premature and that more investigation is warranted.

This is a well-conducted epidemiologic study. Ideally, the investigation of joint effects of BRCA1 mutation with risk factors (such as parity and oral contraceptive use) should involve classifying the controls into those with BRCA1/2  mutation and those without. However, as the authors mentioned, genotyping was conducted only on about one-third of controls. The conclusion that oral contraceptive use does not reduce the risk of ovarian cancer among carriers of BRCA1/2 mutations should be based on case-control analyses of women with these mutations.