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Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance

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Abstract

Prostate cancer (PCa) is the most frequently diagnosed cancer in men worldwide and is likely to be caused by a number of genes with different modes of inheritance, population frequencies and penetrance. The objective of this study was to assess the familial aggregation of PCa in a sample of 1,546 nuclear families ascertained through an affected father and diagnosed during 1988–1993, from the unique, founder population-based resource of the Finnish Cancer Registry. Segregation analysis was performed for two cohorts of 557 early-onset and 989 late-onset families evaluating residual paternal effects and assuming that age at diagnosis followed a logistic distribution after log-transformation. The results did not support an autosomal dominant inheritance as has been reported in many of the hospital-based prostatectomy series. Instead, it confirmed the existence of hereditary PCa in the Finnish population under a complex model that included a major susceptibility locus with Mendelian recessive inheritance and a significant paternal regressive coefficient that is indicative of a polygenic/multifactorial component. The strengths of our study are the homogenous Finnish population, large epidemiological population-based data, histologically confirmed cancer diagnosis done before the PSA-era in Finland and registry based approach. Our results support the evidence that the inheritance of PCa is controlled by major genes and are in line with the previous linkage studies. Moreover, this is the first time a recessive inheritance is suggested to fit PCa in all data even when divided to early and late-onset cohorts.

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References

  • Akaike H (1974) A new look at the statistical model identification. IEEE Trans 19:716–723

    Google Scholar 

  • Baffoe-Bonnie AB, Kiemeney LA, Beaty TH, Bailey-Wilson JE, Schnell AH, Sigvaldsson H, Olafsdottir G, Tryggvadottir L, Tulinius H (2002) Segregation analysis of 389 Icelandic pedigrees with breast and prostate cancer. Genet Epidemiol 23:349–363

    Article  PubMed  Google Scholar 

  • Baffoe-Bonnie AB, Smith JR, Stephan DA, Schleutker J, Carpten JD, Kainu T, Gillanders EM, Matikainen M, Teslovich TM, Tammela T, Sood R, Balshem AM, Scarborough SD, Xu J, Isaacs WB, Trent JM, Kallioniemi OP, Bailey-Wilson E (2005). A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region. Hum Genet 117(4):307–316

    Article  PubMed  CAS  Google Scholar 

  • Bonney GE (1986) Regressive logistic models for familial disease and other binary traits. Biometrics 42:611–625

    Article  PubMed  CAS  Google Scholar 

  • Cannings C, Thompson EA (1977) Ascertainment in the sequential sampling of pedigrees. Clin Genet 12:208–212

    Article  PubMed  CAS  Google Scholar 

  • Cannings C, Thompson E, Skolnick M (1978) Probability functions on complex pedigrees. Adv Appl Probl 10:26–26–61

    Article  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 30:181–184

    Article  PubMed  CAS  Google Scholar 

  • Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC (1992) Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 89:3367–3371

    Article  PubMed  CAS  Google Scholar 

  • Conlon EM, Goode EL, Gibbs M, Stanford JL, Badzioch M, Janer M, Kolb S, Hood L, Ostrander EA, Jarvik GP, Wijsman EM (2003) Oligogenic segregation analysis of hereditary prostate cancer pedigrees: Evidence for multiple loci affecting age at onset. Int J Cancer 105:630–635

    Article  PubMed  CAS  Google Scholar 

  • Cui J, Staples MP, Hopper JL, English DR, McCredie MR, Giles GG (2001) Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am J Hum Genet 68:1207–1218

    Article  PubMed  CAS  Google Scholar 

  • De la Chapelle A (1993) Disease gene mapping in isolated human populations: the example of Finland. J Med Genet 30:857–865

    Article  Google Scholar 

  • Elston RC (1981) Segregation analysis. Adv Hum Genet 11:63–120, 372–373

  • Elston RC, George VT (1989) Age of onset, age at examination, and other covariates in the analysis of family data. Genet Epidemiol 6:217–220

    Article  PubMed  CAS  Google Scholar 

  • Elston RC, Sobel E (1979) Sampling considerations in the gathering and analysis of pedigree data. Am J Hum Genet 31:62–69

    PubMed  CAS  Google Scholar 

  • Elston RC, Stewart J (1971) A general model for the genetic analysis of pedigree data. Hum Hered 21:523–542

    PubMed  CAS  Google Scholar 

  • Elston RC, Yelverton KC (1975) General models for segregation analysis. Am J Hum Genet 27:31–45

    PubMed  CAS  Google Scholar 

  • Finnish Cancer Registry (2006) Cancer incidence in Finland 1995 and 2004. Cancer statistics at http://www.cancerregistry.fi last updated on 7 June 2006

  • Gianferrari L, Arrigoni G, Cresseri A, Lovati G, Morganti G (1956) Genetic and clinico-statistical research on neoplasms of the prostate. Acta Gerontol Milano 5:224–233

    PubMed  CAS  Google Scholar 

  • Gong G, Oakley-Girvan I, Wu AH, Kolonel LN, John EM, West DW, Felberg A, Gallagher RP, Whittemore AS (2002) Segregation analysis of prostate cancer in 1,719 white, African–American and Asian–American families in the United States and Canada. Cancer Causes Control 13:471–482

    Article  PubMed  Google Scholar 

  • Grönberg H, Damber L, Damber JE, Iselius L (1997) Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146:552–557

    PubMed  Google Scholar 

  • Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85

    Article  PubMed  CAS  Google Scholar 

  • Mäkinen T, Tammela TLJ, Stenman U-H, Määttänen L, Rannikko S, Aro J, Juusela H, Hakama M, Auvinen A (2002). Family history and prostate cancer screening with prostate-specific antigen. J Clin Oncol 20(11):2658–2663

    Article  PubMed  Google Scholar 

  • Mäkinen T, Tammela TLJ, Hakama M, Stenman U-H, Rannikko S, Aro J, Juusela H, Määttänen L, Auvinen A (2003) Tumor characteristics in a population-based prostate cancer screening trial with prostate-specific antigen. Clin Cancer Res 9:2435–2439

    PubMed  Google Scholar 

  • Matikainen MP, Pukkala E, Schleutker J, Tammela TL, Koivisto P, Sankila R, Kallioniemi OP (2001) Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland. Cancer Causes Control 12:223–230

    Article  Google Scholar 

  • Monroe KR, Yu MC, Kolonel LN, Coetzee GA, Wilkens LR, Ross RK, Henderson BE (1995) Evidence of an X-linked or recessive genetic component to prostate cancer risk. Nat Med 1:827–829

    Article  PubMed  CAS  Google Scholar 

  • Narod SA, Dupont A, Cusan L, Diamond P, Gomez JL, Suburu R, Labrie F (1995) The impact of family history on early detection of prostate cancer. Nat Med 1:99–101

    Article  PubMed  CAS  Google Scholar 

  • Peltonen L (1997) Molecular background of the Finnish disease heritage. Ann Med 29:553–556

    PubMed  CAS  Google Scholar 

  • Rebbeck TR, Walker AH, Zeigler-Johnson C, Weisburg S, Martin AM, Nathanson KL, Wein AJ, Malkowicz SB (2000) Association of HPC2/ELAC2 genotypes and prostate cancer. Am J Hum Genet 67:1014–1019

    Article  PubMed  CAS  Google Scholar 

  • Rökman A, Ikonen T, Mononen N, Autio V, Matikainen M.P, Koivisto PA, Tammela TL, Kallioniemi OP, Schleutker J (2001) ELAC2/HPC2 involvement in hereditary and sporadic prostate caner. Cancer Res 61:6038–6041

    PubMed  Google Scholar 

  • Rökman A, Ikonen T, Seppälä EH, Nupponen N, Autio V, Mononen N, Bailey-Wilson J, Trent J, Carpten J, Matikainen MP, Koivisto PA, Tammela TL, Kallioniemi OP, Schleutker J (2002) Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. Am J Hum Genet 70 (5):1299–1304

    Article  PubMed  Google Scholar 

  • SAGE 3.1. (1997) Statistical analysis for genetic epidemiology, release 3.1. Computer program package available from the Department of Epidemiology and Biostatistics, Rammelcamp Center for Education and Research, MetroHealth campus, Case Western Reserve University, Cleveland

  • Schaid DJ (2004) The complex genetic epidemiology of prostate cancer. Hum Mol Genet 13 Spec no. 1, pp R103–R121

  • Schaid DJ, McDonnell SK, Blute ML, Thibodeau SN (1998) Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62:1425–1438

    Article  PubMed  CAS  Google Scholar 

  • Schleutker J, Matikainen M, Smith J, Koivisto P, Baffoe-Bonnie A, Kainu T, Gillanders E, Sankila R, Pukkala E, Carpten J, Stephan D, Tammela T, Brownstein M, Bailey-Wilson J, Trent J, Kallioniemi OP (2000) A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease. Clin Cancer Res 6(12):4810–4815

    PubMed  CAS  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 57:280–289

    Article  PubMed  CAS  Google Scholar 

  • Seppälä EH, Ikonen T, Autio V, Rökman A, Mononen N, Matikainen MP, Tammela TL, Schleutker J (2003a) Germ-line alterations in MSR1 gene and prostate cancer risk. Clin Cancer Res 9:5252–5256

    Google Scholar 

  • Seppälä EH, Ikonen T, Mononen N, Autio V, Rökman A, Matikainen MP, Tammela TL, Schleutker J (2003b) CHEK2 variants associate with hereditary prostate cancer. Br J Cancer 89:1966–1970

    Article  CAS  Google Scholar 

  • Smith JR, Freije D, Carpten JD, Gronberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky 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 274:1371–1374

    Article  PubMed  CAS  Google Scholar 

  • Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ et al (2001) A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 27:172–180

    Article  PubMed  CAS  Google Scholar 

  • Teppo L, Pukkala E, Lehtonen M (1994) Data quality and quality control of a population-based cancer registry, experience in Finland. Acta Oncol 33:365–369

    PubMed  CAS  Google Scholar 

  • Valeri A, Briollais L, Azzouzi R, Fournier G, Mangin P, Berthon P, Cussenot O, Demenais F (2003) Segregation analysis of prostate cancer in France: evidence for autosomal dominant inheritance and residual brother–brother dependence. Ann Hum Genet 67:125–137

    Article  PubMed  CAS  Google Scholar 

  • Verhage BA, Baffoe-Bonnie AB, Baglietto L, Smith DS, Bailey-Wilson JE, Beaty TH, Catalona WJ, Kiemeney LA (2001) Autosomal dominant inheritance of prostate cancer: a confirmatory study. Urology 57:97–101

    Article  PubMed  CAS  Google Scholar 

  • World Health Organization (2003) Global cancer rates could increase by 50% to 15 million by 2020 http://www.who.int/mediacentre/news/releases/2003/pr27/en/

  • Xu J, Meyers D, Freije D, Isaacs S, Wiley K, Nusskern D, Ewing C, Wilkens E, Bujnovszky P, Bova GS, Walsh P, Isaacs W, Schleutker J, Matikainen M, Tammela T, Visakorpi T, Kallioniemi OP, Berry R, Schaid D, French A, McDonnell S, Schroeder J, Blute M, Thibodeau S, Trent J (1998) Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 20:175–179

    Article  PubMed  CAS  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 32:321–325

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Dimitrov L, Chang BL, Adams TS, Turner AR, Meyers DA, Eeles RA et al (2005) A Combined genome-wide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the International Consortium for Prostate Cancer Genetics. Am J Hum Genet 77:219–229

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Riitta Vaalavuo for her excellent assistance. Dr. Erica Golemis of the Fox Chase Cancer Center provided beneficial comments on this manuscript. This study was financially supported by the Medical Research Fund of Tampere University Hospital, the Reino Lahtikari Foundation, the Finnish Cancer Organizations, the Sigrid Juselius Foundation and the Academy of Finland (grant no. 211123). The program package SAGE supported by the US Public Health Service Resource Grant RR03655 from Division of Research Resources, was used for the complex segregation analyses. This work was partially supported by the Intramural Research Program of the National Human Genome Research Institute, the National Institutes of Health (Contract Number N01-HG-55389). A.B.B-B, S.D. and L.O also received support from USPHS grant CA-06927 and an appropriation from the Commonwealth of Pennsylvania.

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Authors and Affiliations

  1. Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Biokatu 8, 33014, Tampere, Finland

    Sanna Pakkanen, Pasi A. Koivisto & Johanna Schleutker

  2. Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    Agnes B. Baffoe-Bonnie, Snehal Deshmukh & Liang Ou

  3. National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, 21131, USA

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

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

    Mika P. Matikainen & Teuvo L. J. Tammela

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  1. Sanna Pakkanen
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  2. Agnes B. Baffoe-Bonnie
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  3. Mika P. Matikainen
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Correspondence to Johanna Schleutker.

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Sanna Pakkanen and Agnes B Baffoe-Bonnie equally contributed to this work.

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Pakkanen, S., Baffoe-Bonnie, A.B., Matikainen, M.P. et al. Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance. Hum Genet 121, 257–267 (2007). https://doi.org/10.1007/s00439-006-0310-2

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