A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.
Journal: 2005/September - American Journal of Human Genetics
ISSN: 0002-9297
Abstract:
Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.
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Am J Hum Genet 77(2): 219-229

A Combined Genomewide Linkage Scan of 1,233 Families for Prostate Cancer–Susceptibility Genes Conducted by the International Consortium for Prostate Cancer Genetics

+63 authors
Data Coordinating Center, ACTANE, BC/CA/HI, Johns Hopkins University, Mayo Clinic, PROGRESS, University of Michigan, University of Tampere and Tampere University Hospital, University of Ulm, University of Umeå, University of Utah, and National Cancer Institute
Address for correspondence and reprints: Dr. William B. Isaacs, Marburg 115, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: ude.imhj@scaasiw
The authors' affiliations can be found in the Acknowledgments.
Address for correspondence and reprints: Dr. William B. Isaacs, Marburg 115, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: ude.imhj@scaasiw
Received 2005 Mar 22; Accepted 2005 May 27.

Abstract

Evidence of the existence of major prostate cancer (PC)–susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with “suggestive” linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a “significant” linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of ⩽65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Abstract

Acknowledgments

We express our gratitude to the many families who participated in this study and to the many urologists who kindly assisted us by providing information and access to their patients. The ICPCG is supported by U.S. Public Health Service (USPHS) National Institutes of Health (NIH) grant CA89600. Additional support to participating groups or members within groups is as follows. ACTANE Group: Genotyping and statistical analysis for this study and recruitment of U.K. families was supported by Cancer Research U.K. Additional support was provided by the Prostate Cancer Charitable Trust (now Prostate Cancer Research Foundation), The Times Christmas Appeal, and the Institute of Cancer Research. Genotyping was conducted in the Jean Rook Gene Cloning Laboratory, which is supported by BREAKTHROUGH Breast Cancer–Charity 328323. The funds for the ABI 377 used in this study were generously provided by the legacy of the late Marion Silcock. We thank Mrs. Sheila Seal and Mrs. Anita Hall for kindly storing and logging the samples that were provided. D.F.E. is a principal research fellow of Cancer Research U.K. Recruitment of Australian PC-affected families was funded by National Health and Medical Research Council grant 940934 and was further supported by Tattersall’s and the Whitten Foundation; infrastructure was provided by the Cancer Council Victoria. We acknowledge the work of study coordinator Margaret Staples; the research team of Bernadette McCudden, John Connal, Richard Thorowgood, Chris Costa, Melodie Kevan, and Sue Palmer; and Jolanta Karpowicz, for DNA extractions. The Texas study of familial PC was initiated by the Department of Epidemiology, M. D. Anderson Cancer Center. M.B. was supported by NCI post-doctoral fellowship in Cancer Prevention R25. BC/CA/HI Group: USPHS grant CA67044. JHU Group: USPHS grants CA58236 (to W.B.I.), CA95052-01 (to J.X.), and CA106523-01A1 (to J.X.). Mayo Clinic Group: USPHS grant CA72818. Michigan Group: USPHS grant CA079596. PROGRESS Group: USPHS grants CA78835 (to E.A.O.) and {"type":"entrez-nucleotide","attrs":{"text":"CA080122","term_id":"34932698","term_text":"CA080122"}}CA080122 (to J.L.S.) and support from the Prostate Cancer Foundation and the Fred Hutchinson Cancer Research Center (University of Washington Markey Center). Tampere Group: Medical Research Fund of Tampere University Hospital, Reino Lahtikari Foundation, Finnish Cancer Organizations, Sigrid Juselius Foundation, and Academy of Finland grant 201480. Ulm Group: Deutsche Krebshilfe grant 70–3111-V03. Umeå Group: Grants from the Swedish Cancer Society (Cancerfonden) and Stiftelsen för Strategisk Forskning. Utah Group: NIH NCI grant R01 CA90752 (to L.C.A.), a subcontract from JHU with funds provided by NIH NCI grant R01 CA89600 (to L.C.A.), and NIH grant K07 CA98364 (to N.C.). Data collection for this publication was assisted by the Utah Cancer Registry, supported by NIH Contract NO1-PC-35141 and Surveillance, Epidemiology and End Results Program, with additional support from the Utah Department of Health, the University of Utah, and Public Health Services research grant M01-RR00064 from the National Center for Research Resources. Partial support for all data sets within the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through federal NIH contract N01-HG-65403 (to J.H.U.). Genotyping for the JHU, Michigan, Tampere, and Umeå groups was performed by Elizabeth Gillanders, MaryPat Jones, Derk Gildea, Erica Riedesel, Julie Albertus, Diana Freas-Lutz, Carol Markey, John Carpten, and Jeff Trent at the National Human Genome Research Institute, NIH. Other investigators who contributed to this work: ACTANE:United Kingdom (Sutton): Rifat Hamoudi, Audrey Ardern-Jones, Christine Southgate, Anna Dowe, Kim Coleman, David Dearnaley, The Cancer Research U.K./British Prostate Group U.K. Familial Prostate Cancer Study Collaborators, British Association of Urological Surgeons’ Section of Oncology, Translational Cancer Genetics Team, Molecular Genetics Team, Section of Cancer Genetics; Institute of Cancer Research, Royal Marsden NHS Trust Foundation Hospital. United Kingdom (Cambridge): M. Dawn Teare, Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Labs. Australia: Dallas English, Gianluca Severi, Melissa Southey, Cancer Epidemiology Centre, The Cancer Council Victoria; University of Melbourne, Centre for Genetic Epidemiology. Canada: Nancy Hamel, Division of Medical Genetics, Research Institute of the McGill University Health Centre, Montreal; Steven Narod, Centre for Research in Women’s Health, University of Toronto, Toronto. Texas: Chris Amos, M. D. Anderson Cancer Centre, Houston. Norway (Oslo): Ketil Heimdal Unit of Medical Genetics, Norwegian Radium Hospital, Oslo. Norway (Ullevaal): Nicolai Wessel, Tone Andersen, Department of Oncology, Ullevaal University Hospital, Oslo. EU Biomed: The EU Biomed Prostate Cancer Linkage Consortium, Cancer Research U.K. Genetic Epidemiology Laboratory, St. James’ University Hospital, Leeds. JHU: Piroska Bujnovszky, Tanya Ray, Vivian Bailey, Mary Buedel, and Dawn Steinberg. Utah: Alan Thomas, Lewis Ershler, and Kim Nguyen.

Author affiliations.—Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC (J.X., L.D., B.-L.C., T.S.A., A.R.T., and D.A.M.); Institute of Cancer Research and Royal Marsden National Health Service Trust Foundation Hospital, Sutton, United Kingdom (R.A.E., S.E., J.M., S.B., and Q.H.); Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Labs, Cambridge, United Kingdom (D.F.E. and C.E.); Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal (W.D.F.); Cancer Genomics Laboratory, Centre hospitalier de l'Universite Laval Research Centre, Sainte-Foy, Quebec (J. Simard); University of Washington Medical Center (M.B. and G.P.J.) and Department of Medical Genetics, School of Public Health and Community Medicine, University of Washington (M.B. and G.P.J.), Divisions of Human Biology (D.M.F. and E.A.O.) and Public Health Sciences, Fred Hutchinson Cancer Center (S.K. and J.L.S.), and Institute for System Biology (K.D., M.J., and L.H.), Seattle; Cancer Epidemiology Centre, Cancer Council Victoria (G.G.G.), and Centre for Genetic Epidemiology, University of Melbourne (J.L.H.), Carlton, Australia; Unit of Medical Genetics, Norwegian Radium Hospital, Oslo (L.M. and P.M.); Cancer Research U.K. Genetic Epidemiology Laboratory, St. James’ University Hospital, Leeds (T.B.); University of Southern California, Los Angeles (C.-l.H.); Stanford University School of Medicine, Stanford (J.H., R.N.B., and A.S.W.); Northern California Cancer Center, Union City and Stanford (I.O.-G.); Department of Urology, Johns Hopkins Medical Institutions (C.M.E., M.G., S.D.I. P.C.W., K.E.W., and W.B.I), and Inherited Disease Research Branch, National Human Genome Research Institute, NIH (J.B.-W.), Baltimore; Mayo Clinic, Rochester, MN (S.N.T., S.K.M., J.M.C., K.E.Z., S.H., and D.J.S.); Cancer Genetics Branch, National Human Genome Research Institute, (E.A.O.), and National Cancer Institute (NCI) (D.S.), NIH, Bethesda; Department of Genetics, University of North Carolina, Chapel Hill (E.M.L.); University of Michigan, Ann Arbor (J.L.B.-D., C.E.M., and K.A.C.); University of Tampere and Tampere University Hospital, Tampere, Finland (T.I., H.F., M.P.M. T.L.T., and J. Schleutker); Fox Chase Cancer Center, Division of Population Science, Philadelphia (A.B.-B.); Abteilung Humangenetik, Universität Ulm (C.M., J.J.H., and W.V.), and Urologische Universitätsklinik und Poliklinik, Abteilung für Urologie und Kinderurologie (K.H. and T.P.), Ulm, Germany; Department of Radiation Sciences, Oncology, University of Umeå, Umeå, Sweden (F.W., M.E., E.S., B.-A.J., and H.G.); Division of Genetic Epidemiology, University of Utah, Salt Lake City (N.J.C., J.F., and L.C.A).

Acknowledgments

Web Resource

Web Resource
Camp NJ, Farnham JM (2001) Correcting for multiple analyses in genomewide linkage studies. Ann Hum Genet 65:577–58210.1046/j.1469-1809.2001.6560577.x [PubMed] [CrossRef] [Google Scholar]
Camp NJ, Farnham JM, Cannon-Albright LA. Genome search for prostate cancer predisposition loci in Utah pedigrees. Prostate (in press) [PubMed] [Google Scholar]
Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, et al (2002) Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet 30:181–18410.1038/ng823 [PubMed] [CrossRef] [Google Scholar]
Clerget-Darpoux F, Bonaiti-Pellie C, Hochez J (1986a) Effects of misspecifying genetic parameters in lod score analysis. Biometrics 42:393–399 [PubMed] [Google Scholar]
Clerget-Darpoux F, Dizier MH, Bonaiti-Pellie C, Babron MC, Hochez J, Martinez M (1986b) Discrimination between genetic models for insulin dependent diabetes mellitus. Genet Epidemiol Suppl 1:313–31810.1002/gepi.1370030747 [PubMed] [CrossRef] [Google Scholar]
Cunningham JM, McDonnell SK, Marks A, Hebbring S, Anderson SA, Peterson BJ, Slager S, French A, Blute ML, Schaid DJ, Thibodeau SN (2003) Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study. Prostate 57:335–34610.1002/pros.10308 [PubMed] [CrossRef] [Google Scholar]
Easton DF, Bishop DT, Ford D, Crockford GP (1993) Breast Cancer Linkage Consortium: genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 52:678–701 [PMC free article] [PubMed] [Google Scholar]
Easton DF, Schaid DJ, Whittemore AS, Isaacs WJ (2003) Where are the prostate cancer genes? A summary of eight genome wide searches. Prostate 57:261–26910.1002/pros.10300 [PubMed] [CrossRef] [Google Scholar]
Edwards SM, Eeles RA (2004) Unravelling the genetics of prostate cancer. Am J Med Genet C Semin Med Genet 129:65–7310.1002/ajmg.c.30027 [PubMed] [CrossRef] [Google Scholar]
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–1689 [PubMed] [Google Scholar]
Hsieh C-l, Oakley-Girvan I, Balise RR, Halpern J, Gallagher RP, Wu AH, Kolonel LN, O’Brien LE, Lin IG, Van Den Berg DJ, Teh C-Z, West DW, Whittemore AS (2001) A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity. Am J Hum Genet 69:148–158 [PMC free article] [PubMed] [Google Scholar]
Isaacs WB, Xu J (2002) Prostate cancer. In: King RA, Totter JI, Motulsky AG (eds) The genetic basis of common diseases. Oxford University Press, New York [Google Scholar]
International ACTANE Consortium (2003) Results of a genome-wide linkage analysis in prostate cancer families ascertained through the ACTANE consortium. Prostate 57:270–27910.1002/pros.10301 [PubMed] [CrossRef] [Google Scholar]
Janer M, Friedrichsen DM, Stanford JL, Badzioch MD, Kolb S, Deutsch K, Peters MA, Goode EL, Welti R, DeFrance HB, Iwasaki L, Li S, Hood L, Ostrander EA, Jarvik GP (2003) Genomic scan of 254 hereditary prostate cancer families. Prostate 57:309–31910.1002/pros.10305 [PubMed] [CrossRef] [Google Scholar]
Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61:1179–1188 [PMC free article] [PubMed] [Google Scholar]
Kong A, Gudbjartsson D, Sainz J, Jonsdottir G, Gudjonsson S, Richardsson B, Sigurdardottir S, Barnard B, Hallbeck B, Masson M, Shlien A, Palsson S, Frigge M, Thorgeirsson T, Gulcher J, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247 [PubMed] [Google Scholar]
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363 [PMC free article] [PubMed] [Google Scholar]
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–24710.1038/ng1195-241 [PubMed] [CrossRef] [Google Scholar]
Lange EM, Gillanders EM, Davis CC, Brown WM, Campbell JK, Jones M, Gildea D, Riedesel E, Albertus J, Freas-Lutz D, Markey C, Giri V, Dimmer JB, Montie JE, Trent JM, Cooney KA (2003) Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1. Prostate 57:326–33410.1002/pros.10307 [PubMed] [CrossRef] [Google Scholar]
Lio P, Morton NE (1997) Comparison of parametric and nonparametric methods to map oligogenes by linkage. Proc Natl Acad Sci USA 94:5344–534810.1073/pnas.94.10.5344 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Maier C, Herkommer K, Hoegel J, Vogel W, Paiss T (2005) A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany. Eur J Hum Genet 13:352–36010.1038/sj.ejhg.5201333 [PubMed] [CrossRef] [Google Scholar]
Ostrander EA, Markianos K, Stanford JL (2004) Finding prostate cancer susceptibility genes. Annu Rev Genomics Hum Genet 5:151–17510.1146/annurev.genom.5.061903.180044 [PubMed] [CrossRef] [Google Scholar]
Ott J (1999) Analysis of human genetic linkage. The Johns Hopkins University Press, Baltimore [Google Scholar]
Schaid D (2004) The complex genetic epidemiology of prostate cancer. Hum Mol Genet 13:R103–R12110.1093/hmg/ddh072 [PubMed] [CrossRef] [Google Scholar]
Schaid DJ, Chang BL, International Consortium for Prostate Cancer Genetics (2005) Description of the international consortium for prostate cancer genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13. Prostate 63:276–29010.1002/pros.20198 [PubMed] [CrossRef] [Google Scholar]
Schleutker J, Baffoe-Bonnie AB, Gillanders E, Kainu T, Jones MP, Freas-Lutz D, Markey C, Gildea D, Riedesel E, Albertus J, Gibbs KD Jr, Matikainen M, Koivisto PA, Tammela T, Bailey-Wilson JE, Trent JM, Kallioniemi OP (2003) Genome-wide scan for linkage in Finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26. Prostate 57:280–28910.1002/pros.10302 [PubMed] [CrossRef] [Google Scholar]
Smith JR, Freije D, Carpten JD, Grönberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujinovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB (1996) Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274:1371–137410.1126/science.274.5291.1371 [PubMed] [CrossRef] [Google Scholar]
Tavtigian S, Simard J, Teng D, Abtin V, Baumgard M, Beck A, Camp N, et al (2001) A strong candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 27:172–18010.1038/84808 [PubMed] [CrossRef] [Google Scholar]
Whittemore AS, Halpern J (1994) A class of tests for linkage using affected pedigree members. Biometrics 50:118–127 [PubMed] [Google Scholar]
Wiklund F, Gillanders EM, Albertus JA, Bergh A, Damber JE, Emanuelsson M, Freas-Lutz DL, Gildea DE, Goransson I, Jones MS, Jonsson BA, Lindmark F, Markey CJ, Riedesel EL, Stenman E, Trent JM, Grönberg H (2003) Genome-wide scan of Swedish families with hereditary prostate cancer: suggestive evidence of linkage at 5q11.2 and 19p13.3. Prostate 57:290–29710.1002/pros.10303 [PubMed] [CrossRef] [Google Scholar]
Xu J, Gillanders EM, Isaacs SD, Chang BL, Wiley KE, Zheng SL, Jones M, Gildea D, Riedesel E, Albertus J, Freas-Lutz D, Markey C, Meyers DA, Walsh PC, Trent JM, Isaacs WB (2003) Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families. Prostate 57:320–32510.1002/pros.10306 [PubMed] [CrossRef] [Google Scholar]
Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu JJ, Sterling D, et al (2002) Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet 32:321–32510.1038/ng994 [PubMed] [CrossRef] [Google Scholar]

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