Abstract
Prostate cancer is a complex disease with a substantial genetic contribution involved in the disease risk. Several genomewide linkage studies conducted so far have demonstrated a strong heterogeneity of susceptibility. In order to assess candidate regions that are particularly relevant for the German population, we performed a genomewide linkage search on 139 prostate cancer families. A nonparametric method (Zlr scores), using GENEHUNTERPLUS, was applied at 500 markers (panel P1400, deCODE), with an average spacing of 7.25 cM. In the entire family collection, linkage was most evident at 8p22 (Zlr=2.47, P=0.0068), close to the previously identified susceptibility gene MSR1. Further local maxima with Zlr>2 (P<0.025) were observed at 1q, 5q and 15q. In a subgroup of 47 families, which matched the Johns Hopkins criteria of hereditary prostate cancer, suggestive linkage was found on 1p31 (Zlr=3.37, P=0.00038), a previously not described candidate region. The remaining 92 pedigrees, with no strong disease history, revealed a maximum Zlr=3.15 (P=0.00082) at 8q13, possibly indicating a gene with reduced penetrance or recessive inheritance. Our results suggest pronounced locus heterogeneity of prostate cancer susceptibility in Germany. In the present study population, the MSR1 gene could play a significant role. Other conspicuous loci, like 1p31 and 8q13, need further investigation in order to verify their relevance and to identify candidate genes.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Lichtenstein P, Holm NV, Verkasalo PK et al: Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78–85.
Easton DF, Schaid DJ, Whittemore AS et al: Where are the prostate cancer genes? A summary of eight genome wide searches. Prostate 2003; 57: 261–269.
Schaid DJ : The complex genetic epidemiology of prostate cancer. Hum Mol Genet 2004; 13 (Spec No 1): R103–R121.
Smith JR, Freije D, Carpten JD et al: Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996; 274: 1371–1374.
Carpten J, Nupponen N, Isaacs S et al: Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet 2002; 30: 181–184.
Tavtigian SV, Simard J, Teng DH et al: A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 2001; 27: 172–180.
Xu J, Zheng SL, Hawkins GA et al: Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22–23. Am J Hum Genet 2001; 69: 341–350.
Xu J, Zheng SL, Komiya A et al: Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet 2002; 32: 321–325.
Berthon P, Valeri A, Cohen-Akenine A et al: Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. Am J Hum Genet 1998; 62: 1416–1424.
Gibbs M, Stanford JL, McIndoe RA et al: Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet 1999; 64: 776–787.
Berry R, Schroeder JJ, French AJ et al: Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 2000; 67: 82–91.
Xu J, Meyers D, Freije D et al: Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998; 20: 175–179.
Ostrander EA, Stanford JL : Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet 2000; 67: 1367–1375.
Carter BS, Beaty TH, Steinberg GD et al: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992; 89: 3367–3371.
Gronberg H, Damber L, Damber JE et al: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 1997; 146: 552–557.
Schaid DJ, McDonnell SK, Blute ML et al: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 1998; 62: 1425–1438.
Carter BS, Bova GS, Beaty TH et al: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 1993; 150: 797–802.
Cui J, Staples MP, Hopper JL et al: Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am J Hum Genet 2001; 68: 1207–1218.
Gong G, Oakley-Girvan I, Wu AH et al: Segregation analysis of prostate cancer in 1,719 white, African-American and Asian-American families in the United States and Canada. Cancer Causes Control 2002; 13: 471–482.
Kong A, Cox NJ : Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.
Kruglyak L, Daly MJ, Reeve-Daly MP et al: Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996; 58: 1347–1363.
Mirea L, Briollais L, Bull S : Tests for covariate-associated heterogeneity in IBD allele sharing of affected relatives. Genet Epidemiol 2004; 26: 44–60.
Xu J : Combined analysis of hereditary prostate cancer linkage to 1q24–25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am J Hum Genet 2000; 66: 945–957.
Lander E, Kruglyak L : Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Ott J : Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci USA 1989; 86: 4175–4178.
Paiss T, Herkommer K, Chab A et al: Familial prostate carcinoma in Germany. Urology A 2002; 41: 38–43.
Cui J, Hopper JL : Why are the majority of hereditary cases of early-onset breast cancer sporadic? A simulation study. Cancer Epidemiol Biomarkers Prev 2000; 9: 805–812.
Witte JS, Suarez BK, Thiel B et al: Genome-wide scan of brothers: replication and fine mapping of prostate cancer susceptibility and aggressiveness loci. Prostate 2003; 57: 298–308.
Gibbs M, Stanford JL, Jarvik GP et al: A genomic scan of families with prostate cancer identifies multiple regions of interest. Am J Hum Genet 2000; 67: 100–109.
Wiklund F, Gillanders EM, Albertus JA et al: Genome-wide scan of Swedish families with hereditary prostate cancer: suggestive evidence of linkage at 5q11.2 and 19p13.3. Prostate 2003; 57: 290–297.
Wiklund F, Jonsson BA, Goransson I et al: Linkage analysis of prostate cancer susceptibility: confirmation of linkage at 8p22–23. Hum Genet 2003; 112: 414–418.
Wang L, McDonnell SK, Cunningham JM et al: No association of germline alteration of MSR1 with prostate cancer risk. Nat Genet 2003; 35: 128–129.
Seppala EH, Ikonen T, Autio V et al: Germ-line alterations in MSR1 gene and prostate cancer risk. Clin Cancer Res 2003; 9: 5252–5256.
Lindmark F, Jonsson BA, Bergh A et al: Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer. Prostate 2004; 59: 132–140.
Acknowledgements
We want to thank all patients, their families and attending urologists for contributing to this study. We gratefully acknowledge Petra Reutter and Margot Brugger for technical assistance. This work was supported by the Deutsche Krebshilfe, grant number 70-3111-V03 and in part by NCI Grant #U01 CA89600-02.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Maier, C., Herkommer, K., Hoegel, J. et al. A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany. Eur J Hum Genet 13, 352–360 (2005). https://doi.org/10.1038/sj.ejhg.5201333
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201333
Keywords
This article is cited by
-
Association between DPYSL2 gene polymorphisms and alcohol dependence in Caucasian samples
Journal of Neural Transmission (2014)
-
Genome-wide linkage analyses of hereditary prostate cancer families with colon cancer provide further evidence for a susceptibility locus on 15q11–q14
European Journal of Human Genetics (2010)
-
Susceptibility loci in a molecular subtype of prostate cancer
Nature Reviews Urology (2009)
-
Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect
Human Genetics (2006)
-
Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene
British Journal of Cancer (2005)
