Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping.

We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genome-wide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a "validation" set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a "field" set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a "test" set of 57 probands from breast cancer kindreds (4 or more cases/kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs.

Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification.

The Bloom syndrome gene, BLM, encodes a RecQ DNA helicase that when absent from the cell results in genomic instability and cancer predisposition. We show here that BLM is a substrate for small ubiquitin-like modifier (SUMO) modification, with lysines at K317, K331, K334 and K347 being preferred sites of modification. Unlike normal BLM, a double mutant BLM protein with lysine to arginine substitutions at residues 317 and 331 was not modified by SUMO, and it failed to localize efficiently to the PML nuclear bodies.

Localization of cancer susceptibility genes by genome-wide single-nucleotide polymorphism linkage-disequilibrium mapping.

With the large numbers of single nucleotide polymorphisms (SNPs) available and new technologies that permit high throughput genotyping, we have investigated the possibility of the localization of disease genes with genome-wide panels of SNP markers and taking advantage of the linkage-disequilibrium (LD) between the disease gene and closely linked markers. For this purpose, we selected cases from the Ashkenazi Jewish population, in which the mutant alleles are expected to be identical by descent from a common founder and the regions of LD encompassing these mutant alleles are large. As a validation of this approach for localization, we performed two trials: one in autosomal recessive Bloom syndrome, in which a unique mutation of the BLM gene is present at elevated frequencies in cases, and the other in autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC), in which a unique mutation of MSH2 is present at elevated frequencies.