Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

A model for evaluating the delivery of pediatric primary care services.

This evaluation model describes the components used to assess the functioning of Pediatric Resource Centers which provide primary care to high risk children in New York City. These centers are administered by the Medical and Health Research Association of New York City and are funded by the State through the New York City Department of Health. Measurements are made of: accessibility, availability, accountability, productivity and patient volumes, continuity, coordination, and comprehensiveness. Data is collected from the PRC data reporting system, site visits, chart reviews, and fiscal reports. The findings vary considerably among the different centers with compliance to the various assessments, differing not only within a given center but between centers. In spite of some methodological limitations, it is felt that these measurements are effective in pointing out problem areas in the centers and are helpful to the funding agency in focusing on program areas in need of greater support.