Mutagen Sensitivity and DNA Repair Gene Polymorphisms in Hereditary and Sporadic Breast Cancer
Abstract
Breast cancer risk for both sporadic and familial breast cancer can better be elucidated in studies in women with BRCA1 mutations. Since the BRCA1 protein is involved in DNA repair, genotype-phenotype relationships can be established by the assessment of DNA repair efficiency and the identification of genetic polymorphisms in the BRCA1 DNA repair pathway. To study risks associated with certain polymorphisms in DNA repair genes, EBV-immortalized cells from women in the LCC Registry were used in both a phenotypic assay that measures DNA repair capacity and genotypic assays that determined genotypes that increased susceptibility to breast cancer. Ninety-five affected and 65 healthy BRCA1 mutation carriers are being analyzed in this study. Gamma radiation was used to induce chromosomal breaks and those chromosomal breaks were scored, counted and compared within each patient and between patients. Also, the BRCA1, BRCA2, and Rad51 genes are being sequenced and the genotypes whose polymorphisms code for amino acid changes in conserved and functional areas are being analyzed. We predict that polymorphisms in these genes will be highly correlated with deficient DNA repair in high risk breast cancer families. Several BRCA1 and BRCA2 polymorphisms appear to be associated with decreased DNA repair efficiency. Specifically, the N372H (OR: 7.0 CI: 0.3-140.0) polymorphism in BRCA2,the K1183R (OR: 1.8 CI:0.1-17.7) polymorphism in BRCA1, and the 5382inC mutation (OR:3.0 C1:0.3-29.8), appear to be correlated with mutagen sensitivity, but a larger sample size is needed for odds ratios to be significant In addition, we have a large population of 187delAG (n=54) and 5382insC (n=21) mutation carriers, so we can begin to look at what polymorphisms will affect risk within those mutation carriers. Ultimately, the study of the high risk families can inform, and set priorities for the study of genetic polymorphisms in sporadic breast cancer studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2005
- Accession Number
- ADA435288
Entities
People
- Luisel J. Santi-ruiz
Organizations
- Georgetown University