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Open Access Research article

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Joan E Bailey-Wilson1327*, Erica J Childs12, Cheryl D Cropp1, Daniel J Schaid3, Jianfeng Xu4, Nicola J Camp5, Lisa A Cannon-Albright56, James M Farnham5, Asha George178, Isaac Powell79, John D Carpten107, Graham G Giles111213, John L Hopper1113, Gianluca Severi111213, Dallas R English111213, William D Foulkes1114, Lovise Mæhle1115, Pål Møller1115, Rosalind Eeles1116, Douglas Easton1117, Michelle Guy1116, Steve Edwards1116, Michael D Badzioch1118, Alice S Whittemore192021, Ingrid Oakley-Girvan19202142, Chih-Lin Hsieh1922, Latchezar Dimitrov4, Janet L Stanford2324, Danielle M Karyadi2325, Kerry Deutsch2326, Laura McIntosh2324, Elaine A Ostrander2325, Kathleen E Wiley27, Sarah D Isaacs27, Patrick C Walsh27, Stephen N Thibodeau28, Shannon K McDonnell28, Scott Hebbring28, Ethan M Lange2930, Kathleen A Cooney2931, Teuvo LJ Tammela323334, Johanna Schleutker323334, Christiane Maier353637, Sylvia Bochum3537, Josef Hoegel3537, Henrik Grönberg38, Fredrik Wiklund38, Monica Emanuelsson39, Geraldine Cancel-Tassin40, Antoine Valeri40, Olivier Cussenot4041, William B Isaacs27 and and the International Consortium for Prostate Cancer Genetics

Author Affiliations

1 Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, 21224, USA

2 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

3 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA

4 Data Coordinating Center for the ICPCG and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

5 University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA

6 George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA

7 African American Hereditary Prostate Cancer ICPCG Group, Phoenix, AZ, USA

8 Fox Chase Cancer Center, Philadelphia, PA, USA

9 Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

10 Translational Genomics Research Institute, Genetic Basis of Human Disease Research Division, Phoenix, AZ, USA

11 ACTANE consortium

12 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia

13 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia

14 Program in Cancer Genetics, McGill University, Montreal, QC, Canada

15 Department of Medical Genetics, Oslo University Hospital, The Norwegian Radium Hospital, Oslo,Norway

16 Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey, UK

17 Cancer Research UK Genetic Epidemiology Unit, Cambridge, UK

18 Division of Medical Genetics, University of Washington Medical Center, Seattle, WA, USA

19 BC/CA/HI ICPCG Group, Stanford, CA, USA

20 Department of Health Research and Policy, Stanford School of Medicine, Stanford, CA, USA

21 Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA

22 Department of Urology and Department of Biochemistry and Molecular Biology, University of Southern California, Los Ageles, CA, USA

23 FHCRC ICPCG Group, Seattle, WA, USA

24 Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA

25 Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

26 Institute for Systems Biology, Seattle, WA, USA

27 Johns Hopkins University ICPCG Group and Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

28 Mayo Clinic, Rochester, MN, USA

29 University of Michigan ICPCG Group, Ann Arbor, MI, USA

30 Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

31 University of Michigan, Ann Arbor, MI, USA

32 University of Tampere ICPCG Group, Tampere, Finland

33 Institute of Biomedical Technology, University of Tampere, Tampere, Finland

34 Centre for Laboratory Medicine and Department of Urology, Tampere University Hospital, Tampere, Finland

35 University of Ulm ICPCG Group, Ulm, Germany

36 Dept of Urology, University of Ulm, Ulm, Germany

37 Institute of Human Genetics, University of Ulm, Ulm, Germany

38 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

39 Oncologic Centre, Umeå University, Umeå, Sweden

40 CeRePP ICPCG Group, 75020, Paris, France

41 Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020, Paris, France

42 Cancer Prevention Institute of California

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BMC Medical Genetics 2012, 13:46  doi:10.1186/1471-2350-13-46

Published: 19 June 2012

Abstract

Background

Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.

Methods

Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.

Results

Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2–3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.

Conclusions

Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2–3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.