Abstract
In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.39 at 3p26 and 1.42 at 11q14. The highest LOD scores were seen around markers D3S1270 and D3S4559 (α=0.89), covering approximately two megabases. The two known genes in this region CHL1 (cell adhesion molecule with homology to L1CAM) and CNTN6 (contactin 6) were screened for exonic mutations in the families showing the strongest linkage, but no disease-segregating sequence variants were observed. The recombination map pointed to a region proximal to the area of best linkage, suggesting that more genes may need to be investigated as candidates. These results provide strong evidence for the existence of a prostate cancer susceptibility gene at 3p26 in Finnish prostate cancer families. This locus has not been strongly linked with hereditary prostate cancer in other populations. However, the mildly positive 3p LOD scores in a recent GWL analysis of patients from the United States suggest that the locus may also be important in other populations.
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Acknowledgements
We thank Minna Sjöblom for skillful technical help and Riitta Vaalavuo for assistance. In addition, we thank all the patients with prostate cancer and their families for their participation. The present study was supported by grants from The Pirkanmaa Regional Fund of the Finnish Cultural Foundation, University of Tampere, Medical Research Fund of Tampere University Hospital, the Pirkanmaa Cancer Society, the Finnish Cancer Society, the Reino Lahtikari Foundation, the Academy of Finland (grant no. 201480) and the Sigrid Juselius Foundation. Agnes B. Baffoe-Bonnie received support from USPHS grant CA-06927 and an appropriation from the Commonwealth of Pennsylvania. Ascertainment of the families with HPC in Finland was supported by grant NO1-HG-55389 from the National Human Genome Research Institute, National Institutes of Health.
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Rökman, A., Baffoe-Bonnie, A.B., Gillanders, E. et al. Hereditary prostate cancer in Finland: fine-mapping validates 3p26 as a major predisposition locus. Hum Genet 116, 43–50 (2005). https://doi.org/10.1007/s00439-004-1214-7
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DOI: https://doi.org/10.1007/s00439-004-1214-7