Dataset Information

A genome wide linkage search for breast cancer susceptibility genes.

ABSTRACT: Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.

SUBMITTER: Smith P

PROVIDER: S-EPMC2714969 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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A genome wide linkage search for breast cancer susceptibility genes.

Smith Paula P McGuffog Lesley L Easton Douglas F DF Mann Graham J GJ Pupo Gulietta M GM Newman Beth B Chenevix-Trench Georgia G Szabo Csilla C Southey Melissa M Renard Hélène H Odefrey Fabrice F Lynch Henry H Stoppa-Lyonnet Dominique D Couch Fergus F Hopper John L JL Giles Graham G GG McCredie Margaret R E MR Buys Saundra S Andrulis Irene I Senie Ruby R Goldgar David E DE Oldenburg Rogier R Kroeze-Jansema Karin K Kraan Jaennelle J Meijers-Heijboer Hanne H Klijn Jan G M JG van Asperen Christi C van Leeuwen Inge I Vasen Hans F A HF Cornelisse Cees J CJ Devilee Peter P Baskcomb Linda L Seal Sheila S Barfoot Rita R Mangion Jon J Hall Anita A Edkins Sarah S Rapley Elizabeth E Wooster Richard R Chang-Claude Jenny J Eccles Diana D Evans D Gareth DG Futreal P Andrew P Nathanson Katherine L KL Weber Barbara L BL Rahman Nazneen N Stratton Michael R MR

Genes, chromosomes & cancer 20060701 7

Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Eviden ...[more]

PMID: 16575876

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Project description:IntroductionA significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers.MethodsGWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene.ResultsThe three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer.ConclusionsChromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.

Dataset Information

A genome wide linkage search for breast cancer susceptibility genes.

Publications

A genome wide linkage search for breast cancer susceptibility genes.

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