Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify pr edisposition loci for breast cancer by using mathematical models to identif y early somatic genetic deletions in tumor tissues followed by targeted lin kage analysis. Comparative genomic hybridization was used to study 61 breas t tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 m utations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping rev ealed segregation of a shared 13q21 germ-line haplotype in the family. Targ eted linkage analysis was carried out in a set of 77 Finnish, Icelandic, an d Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations . A maximum parametric two-point logarithm of odds score of 2.76 was obtain ed for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evalu ated by simulation to assess the probability of obtaining significant evide nce in favor of linkage by chance as well as to take into account the possi ble influence of the BRCA2 locus, located at a recombination fraction of 0. 25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative bre ast cancer predisposition locus in other populations.