Abstract 1855: Genome-wide search for linkage in Icelandic high-risk breast cancer families

Abstract

Abstract Genetic susceptibility to breast cancer (BC) may be categorized by the degree of risk (low, moderate or high penetrance) and by the population frequency of the risk alleles. Approximately 5-10% of the BC incidence is hereditary, as exposed by notable familial aggregation of cases. As yet this is caused by rare high-risk variants whenever the causative gene is known, most often involving BRCA1 or BRCA2. A significant proportion of the families still has an unknown genetic cause but intense genome-wide searches (GWS) suggest close to 20 candidate loci. Further analyses are confounded by genetic heterogeneity and polygenic effects involving alleles of low- or moderate-risk combinations. Published studies emphasize the need to study populations where genetic heterogeneity may be reduced. We therefore performed GWS on 12 Icelandic multiple-case non-BRCA1/2 families and followed up signs of candidate chromosomal positions by genotyping relevant markers in another 13 Nordic families. From pedigrees of >400 probands diagnosed with BC in Iceland, we selected 12 multiple-case families, after excluding carriers of BRCA1 and BRCA2 mutations. DNA from 60 affected cases and 42 unaffected relatives was genotyped at 811 microsatellite markers providing a ∼5 cM resolution. Multipoint LOD scores were calculated using parametric and nonparametric methods. As initial results highlighted three chromosomal regions, markers therein were also typed in an additional 13 Nordic non-BRCA1/2 families. In the combined dataset, the highest LOD scores were seen at chromosomes 6q, 2p and 14q (parametric dominant model: HLOD 3.09, 2.21, 1.31; nonparametric, exponential model, S-all scoring: LOD 3.23, 2.72, 2.28; S-pairs scoring: 1.82, 1.54, 1.14). The 2p and 14q regions overlap with previously reported candidate BC loci. One Icelandic family contributed high LOD scores (2.63-3.03, parametric dominant model) at all three positions and common haplotypes at 6q and 14q cosegregated with 13 meioses to nine affected cases in this family. No LOD scores exceeding 1.5 by family were seen among the remaining families. Since the families studied here were relatively large and informative, this does not suggest involvement of rare high-risk genes but rather conforms to a polygenic model with frequent alleles, sometimes cosegregating and sometimes being replaced by variants of different lineage or of other genes. In conclusion, hereditary non-BRCA1/2 breast cancer in Iceland, as elsewhere, seems to fit a polygenic model, with low- or moderate-penetrance alleles jointly contributing to the risk. A candidate combination of such genes may be found at chromosomes 2p, 6q and 14q. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1855.