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Open Access Research article

Pairwise shared genomic segment analysis in three Utah high-risk breast cancer pedigrees

Zheng Cai1, Alun Thomas2, Craig Teerlink2, James M Farnham2, Lisa A Cannon-Albright23 and Nicola J Camp2*

Author Affiliations

1 Department of Biomedical Informatics, University of Utah Medical School, Health Sciences Education Building, Salt Lake City, UT, 84112, USA

2 Division of Genetic Epidemiology, University of Utah Medical School, 391 Chipeta Way Suite D, Salt Lake City, UT, 84108, USA

3 George E. Wahlen Department of Veterans Affairs Medical Center, 500 Foothill Drive, Salt Lake City, UT, 84148, USA

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BMC Genomics 2012, 13:676  doi:10.1186/1471-2164-13-676

Published: 28 November 2012

Abstract

Background

We applied a new weighted pairwise shared genomic segment (pSGS) analysis for susceptibility gene localization to high-density genomewide SNP data in three extended high-risk breast cancer pedigrees.

Results

Using this method, four genomewide suggestive regions were identified on chromosomes 2, 4, 7 and 8, and a borderline suggestive region on chromosome 14. Seven additional regions with at least nominal evidence were observed. Of particular note among these total twelve regions were three regions that were identified in two pedigrees each; chromosomes 4, 7 and 14. Follow-up two-pedigree pSGS analyses further indicated excessive genomic sharing across the pedigrees in all three regions, suggesting that the underlying susceptibility alleles in those regions may be shared in common. In general, the pSGS regions identified were quite large (average 32.2 Mb), however, the range was wide (0.3 – 88.2 Mb). Several of the regions identified overlapped with loci and genes that have been previously implicated in breast cancer risk, including NBS1, BRCA1 and RAD51L1.

Conclusions

Our analyses have provided several loci of interest to pursue in these high-risk pedigrees and illustrate the utility of the weighted pSGS method and extended pedigrees for gene mapping in complex diseases. A focused sequencing effort across these loci in the sharing individuals is the natural next step to further map the critical underlying susceptibility variants in these regions.

Keywords:
Breast cancer; High-risk pedigrees; Susceptibility; Germline; Genomic sharing