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A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region

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An Erratum to this article was published on 22 October 2005

Abstract

Background: Prostate cancer (PRCA) is the most common cancer in males in the western world. In Finland PRCA has an age-adjusted incidence of 81.5 per 100,000. We previously reported that in Finland, the late-onset cases in families with “no-male-to-male” (NMM) transmission of PRCA accounted for most of the linkage to the HPCX region (Xq27-28). The aim of the present study was to test for linkage disequilibrium (LD) and haplotype-sharing around marker DXS1205 between cases from hereditary prostate cancer (HPC) families and population controls. The initial allelic association was performed between 108 PRCA cases and 257 population controls genotyped for 23 markers in the Xq26-28 region. This resulted in a highly significant nominal one-sided Fisher’s exact P-value of 0.0003 for allele ″180″ of marker DXS1205. Subsequently, a similar level of significance was observed for the same allele for marker DXS1205 (P=0.0002) when comparing 60 NMM cases and 257 controls. These results were still significant after Bonferroni correction for multiple testing. Fine mapping efforts included the genotyping of four additional markers D3S2390, bG82i1.9, bG82i1.1, bG82i1.0 and four single nucleotide polymorphisms (SNPs) to augment the original markers around DXS1205. Results: Our major finding is that markers extending from ″D3S2390″ to ″bG82i1.0″ flank the critical locus, about 150 kb. Levin and Bertell’s LD measure (δ), a guide to localization of a possible variant, was 0.42 and 0.41 for alleles of markers bG82i1.9 and DXS1205, respectively. Conclusions: In this study, the most significant haplotype comprised the three tightly linked, contiguous markers: ″cen-bG82i1.9-SNP-Hap B-bG82i1.1-tel″ [″197-2-234″] among several possible haplotypes (nominal Fisher’s one-sided P=0.003). The two transcription units mapping within this interval are the LDOC1 and SPANXC genes. Positional cloning of the HPCX gene(s) is being facilitated by this exploration of the Xq26-28 region. This study represents the first report identifying a haplotype in the Xq27-28 region for an association between HPCX and X-linked prostate cancer with no-male-to-male transmission in the Finnish population.

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Acknowledgment

This work has greatly benefited from discussions with and comments from Dr. Alfred Knudson (Fox Chase Cancer Center) and Dr. Neil Risch (Stanford School of Medicine). The authors acknowledge Mark Ross of the Sanger Institute for his help with aligning the markers in the Xq27-28 region. We thank Ms. Pia Johnson of the Fox Chase Cancer Center for secretarial assistance. This study was supported in part by the Medical Research Fund of the Tampere University Hospital, the Reino Lahtikari Foundation, the Finnish Cancer Organizations, the Sigrid Juselius Foundation and the Academy of Finland, the National Human Genome Research Institute, National Institutes of Health, Contract Number N01-HG-55389, the Translational Genomics Research Institute, and by the Howard Hughes Medical Institute (HHMI) Undergraduate Training Award through the Fox Chase Cancer Center to S.D.S. A.B.B-B and A.B. also received support from USPHS grant CA-06927 and an appropriation from the Commonwealth of Pennsylvania.

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Authors and Affiliations

  1. Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA

    Agnes B. Baffoe-Bonnie, Andrew M. Balshem & Sheehan D. Scarborough

  2. Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive, Suite 2000, Baltimore, MD, 21224, USA

    Agnes B. Baffoe-Bonnie & Joan E. Bailey-Wilson

  3. Department of Medicine, VA Tennessee Valley Healthcare System, Medical Research Service, Vanderbilt University Medical Center, 535 Light Hall, 2215 Garland Avenue, Nashville, TN, 37232, USA

    Jeffrey R. Smith

  4. Translational Genomics Research Institution (TGEN), 400 North Fifth, Suite 1600, Phoenix, AZ, 85004, USA

    Dietrich A. Stephan, John D. Carpten & Jeffrey M. Trent

  5. Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Lenkkeilijänkatu 6, 33014 University of Tampere, Tampere, Finland

    Johanna Schleutker & Tommi Kainu

  6. National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bldg. 49-50, Bethesda, MD, 20892, USA

    Elizabeth M. Gillanders & Raman Sood

  7. Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland

    Mika Matikainen & Teuvo Tammela

  8. Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Jianfeng Xu

  9. Johns Hopkins School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    Tanya M. Teslovich & William B. Isaacs

  10. Medical Biotechnology Department, VTT Technical Research Center of Finland and University of Turku, Turku, Finland

    Olli-P. Kallioniemi

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  1. Agnes B. Baffoe-Bonnie
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  2. Jeffrey R. Smith
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  3. Dietrich A. Stephan
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  14. Jianfeng Xu
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  17. Olli-P. Kallioniemi
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  18. Joan E. Bailey-Wilson
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Correspondence to Joan E. Bailey-Wilson.

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An erratum to this article is available at http://dx.doi.org/10.1007/s00439-005-0050-8.

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Baffoe-Bonnie, A.B., Smith, J.R., Stephan, D.A. et al. A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region. Hum Genet 117, 307–316 (2005). https://doi.org/10.1007/s00439-005-1306-z

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