The last decade has witnessed the emergence of international ethics guidelines discussing the importance of disclosing global and also, in certain circumstances, individual genetic research results to participants. This discussion is all the more important considering the advent of pharmacogenomics and the increasing incidence of 'translational' genetic research in the post-genomic era. We surveyed both the literature and the ethical guidelines using selective keywords. We then analyzed our data using a qualitative method approach and singled out countries or policies that were representative of certain positions. From our findings, we conclude that at the international level, there now exists an ethical duty to return individual genetic research results subject to the existence of proof of validity, significance and benefit. Even where these criteria are met, the right of the research participant not to know also has to be taken into consideration. The existence of an ethical duty to return individual genetic research results begs several other questions: Who should have the responsibility of disclosing such results and when? To whom should the results be disclosed? How? Finally, will this ethical 'imperative' become a legally recognized duty as well?

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

Women who carry mutations in the BRCA1 gene on chromosome 17q have an 85% lifetime risk of breast cancer, and a 60% risk of ovarian cancer. We have identified BRCA1 mutations in 12 of 30 (40%) Canadian families with breast and/or ovarian cancer, including six of the eight families (75%) that contained two cases of early-onset breast cancer and two cases of ovarian cancer. Six frameshift mutations account for all 12 mutant alleles, including nucleotide insertions (two mutations) and deletions (four mutations). Four independent families carried the same 1 basepair (bp) insertion mutation in codon 1755 and four other families shared a 2 bp deletion mutation in codons 22-23. These families were not known to be related, but haplotype analysis suggests that the carriers of each of these mutations have common ancestors.

The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with minor allele frequencies >.1, since these are most comparable to the common disease-susceptibility polymorphisms that association studies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chromosome 22q13.3-which have been extensively mapped. These markers were examined in approximately 1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Finns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse relationship was found between LD and distance in each genomic region and in each population. Mean D' is.68 for marker pairs <5 kb apart and is.24 for pairs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of marker pairs at distances <5 kb display sufficient LD (delta>.3) to be useful in association studies. Results of the present study, if representative of the whole genome, suggest that a whole-genome scan searching for common disease-susceptibility alleles would require markers spaced < or = 5 kb apart.