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

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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.

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Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).

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Author and article information

Contributors

Joan E Bailey-Wilson

Erica J Childs

Cheryl D Cropp

Daniel J Schaid

Jianfeng Xu

Nicola J Camp

Lisa A Cannon-Albright

James M Farnham

Asha George

Isaac Powell

John D Carpten

Graham G Giles

John L Hopper

Gianluca Severi

Dallas R English

William D Foulkes

Lovise Mæhle

Pål Møller

Rosalind Eeles

Douglas Easton

Michelle Guy

Steve Edwards

Michael D Badzioch

Alice S Whittemore

Ingrid Oakley-Girvan

Chih-Lin Hsieh

Latchezar Dimitrov

Janet L Stanford

Danielle M Karyadi

Kerry Deutsch

Laura McIntosh

Elaine A Ostrander

Kathleen E Wiley

Sarah D Isaacs

Patrick C Walsh

Stephen N Thibodeau

Shannon K McDonnell

Scott Hebbring

Ethan M Lange

Kathleen A Cooney

Teuvo LJ Tammela

Johanna Schleutker

Christiane Maier

Sylvia Bochum

Josef Hoegel

Henrik Grönberg

Fredrik Wiklund

Monica Emanuelsson

Geraldine Cancel-Tassin

Antoine Valeri

Olivier Cussenot

William B Isaacs

Journal

Journal ID (nlm-ta): BMC Med Genet

Journal ID (iso-abbrev): BMC Med. Genet

Title: BMC Medical Genetics

Publisher: BioMed Central

ISSN (Electronic): 1471-2350

Publication date Collection: 2012

Publication date (Electronic): 19 June 2012

Volume: 13

Page: 46

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

Article

Publisher ID: 1471-2350-13-46

DOI: 10.1186/1471-2350-13-46

PMC ID: 3495053

PubMed ID: 22712434

SO-VID: 15893e0e-94c4-46e8-907d-4e962a9cbddf

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 26 July 2011

Date accepted : 30 April 2012

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