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

Gershoni-Baruch R, Dagan E, Israeli D, Kasinetz L, Kadouri E, Friedman E.  Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women.  Eur J Cancer  2000;36:2313-2316.

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: MTHFR
2. Chromosome location: 1p36.3
3. Gene product/function:  Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methlytetrahydrofolate, the primary circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine.
4. Alleles:  C677T
5. OMIM #:  236250
   

1. Gene name:  BRCA1
2. Chromosome location: 17q21
3. Gene product/function:  BRCA1 is a nuclear cell cycle regulated phosphoprotein of breast epithelial cells.
4. Alleles:  185delAG and 5382insC
5. OMIM #:  113705
   

1. Gene name:  BRCA2
2. Chromosome location: 13qq12.3
3. Gene product/function:  BRCA2 is a nuclear cell cycle-regulated phosphoprotein of breast epithelial cells.
4. Alleles:  6174delT
5. OMIM #:  600185

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. Breast cancer
2. 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 selection criteria: Jewish women with breast or ovarian cancer referred for counseling services at the Sheba and Rambam medical centers.
2. Exclusion criteria: Not specified
3. Gender: Female
4. Race/ethnicity: Jewish
5. Age: Not specified
6. Time period: 1997-1998
7. Geographic location:  Israel
8. Number of participants: 560

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

N/A

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

1. Gene:  MTHFR, BRCA1, BRCA2
2. DNA source:  Blood lymphocytes
3. Methodology:  Mutations were detected by PCR amplification with specific primers that produce a modified restriction enzyme digest made to distinguish the wild-type allele from the mutant allele.
4. Participants genotyped: All

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

1. Prevalence among breast or ovarian cancer patients with or without BRCA1/2 mutations and among asymptomatic BRCA1/2 carriers

Linkage disequilibrium between the VNTR and HPA-2 polymorphisms of GP Ib

2. Gene-disease association

a) Association between 677T homozygosity and BRCA1/2 carrier status

Odds Ratio = 1.06 (95% CI, 0.64–1.49)

b) Association between 677T homozygosity and multiple primary tumors (bilateral breast cancer and breast/ovarian cancer)

Odds Ratio = 2.35 (95% CI, 1.79–2.91)

4.  Gene-gene interaction

Logistic regression analysis showed that the combined contribution of the 677T homozygous genotype and a BRCA1/2 mutation to the development of a second primary tumor equals 13%, of which 29% is attributed to 677T homozygosity (P=0.0037) and 14% to the BRCA1/2 mutation (P=0.06)

Disruptions in folate metabolism may enhance breast or ovarian tumorigenesis.  Results indicate that breast or ovarian cancer patients homozygous for the 677T mutation could be at greater risk of acquiring a second primary tumor.  This observation applies both to BRCA1/2 carriers and noncarriers.

Data documenting the role of MTHFR activity in breast and ovarian cancer risk are scarce.  Additional research is needed to ascertain the relationship of 677T homozygosity with breast or ovarian cancer and in women with multiple primary tumors.  The association with disease could not be adequately evaluated in this study due to the small number of control subjects (69 asymptomatic patients).  To better evaluate gene-disease associations and effect modification by BRCA1/2 mutations, future studies should include sufficient numbers of control subjects of BRCA1/2 carrier and noncarrier status.