Abstract
The search for susceptibility loci in hereditary prostate cancer (HPC) is challenging because of locus and disease heterogeneity. One approach to reduce disease heterogeneity is to stratify families on the basis of the occurrence of multiple cancer types. This method may increase the power for detecting susceptibility loci, including those with pleiotropic effects. We have completed a genome-wide SNP linkage analysis of 96 HPC families, each of which has one or more first-degree relatives with colon cancer (CCa), and further analyzed the subset of families with two or more CCa cases (n=27). When only a prostate cancer (PCa) phenotype was considered to be affected, we observed suggestive evidence for linkage (LOD ≥1.86) at 15q14, 18q21 and 19q13 in all families, and at 1p32 and 15q11–q14 in families with two or more CCa cases. When both the PCa and CCa phenotypes were considered affected, suggestive evidence for linkage was observed at 11q25, 15q14 and 18q21 in all families, and at 1q31, 11q14 and 15q11–14 in families with two or more CCa cases. The strongest linkage signal was identified at 15q14 when both PCa and CCa phenotypes were considered to be affected in families with two or more CCa cases (recessive HLOD=3.88). These results provide further support for the presence of HPC susceptibility loci on chromosomes 11q14, 15q11–q14 and 19q13 and highlight loci at 1q31, 11q, 15q11–14 and 18q21 as having possible pleiotropic effects. This study shows the benefit of using a comprehensive family cancer history to create more genetically homogenous subsets of HPC families for linkage analyses.
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References
Ostrander EA, Markianos K, Stanford JL : Finding prostate cancer susceptibility genes. Annu Rev Genomics Hum Genet 2004; 5: 151–175.
Schaid DJ : The complex genetic epidemiology of prostate cancer. Hum Mol Genet 2004; 13 (Spec No 1): R103–R121.
Chang BL, Isaacs SD, Wiley KE et al: Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease. Prostate 2005; 64: 356–361.
Stanford JL, McDonnell SK, Friedrichsen DM et al: Prostate cancer and genetic susceptibility: a genome scan incorporating disease aggressiveness. Prostate 2006; 66: 317–325.
Fearon ER : Human cancer syndromes: clues to the origin and nature of cancer. Science 1997; 278: 1043–1050.
Damber L, Gronberg H, Damber JE : Familial prostate cancer and possible associated malignancies: nation-wide register cohort study in Sweden. Int J Cancer 1998; 78: 293–297.
Hall JM, Lee MK, Newman B et al: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990; 250: 1684–1689.
Miki Y, Swensen J, Shattuck-Eidens D et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994; 266: 66–71.
Thorlacius S, Tryggvadottir L, Olafsdottir GH et al: Linkage to BRCA2 region in hereditary male breast cancer. Lancet 1995; 346: 544–545.
Wooster R, Bignell G, Lancaster J et al: Identification of the breast cancer susceptibility gene BRCA2. Nature 1995; 378: 789–792.
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.
Matsui H, Suzuki K, Ohtake N et al: Genomewide linkage analysis of familial prostate cancer in the Japanese population. J Hum Genet 2004; 49: 9–15.
Badzioch M, Eeles R, Leblanc G et al: Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36. The CRC/BPG UK Familial Prostate Cancer Study Coordinators and Collaborators. The EU Biomed Collaborators. J Med Genet 2000; 37: 947–949.
Johanneson B, Deutsch K, McIntosh L et al: Suggestive genetic linkage to chromosome 11p11.2-q12.2 in hereditary prostate cancer families with primary kidney cancer. Prostate 2007; 67: 732–742.
Pierce BL, Friedrichsen-Karyadi DM, McIntosh L et al: Genomic scan of 12 hereditary prostate cancer families having an occurrence of pancreas cancer. Prostate 2007; 67: 410–415.
Suarez BK, Lin J, Burmester JK et al: A genome screen of multiplex sibships with prostate cancer. Am J Hum Genet 2000; 66: 933–944.
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.
Albright LA, Schwab A, Camp NJ, Farnham JS, Thomas A : Population-based risk assessment for other cancers in relatives of hereditary prostate cancer (HPC) cases. Prostate 2005; 64: 347–355.
Enblad P, Adami HO, Glimelius B, Krusemo U, Pahlman L : The risk of subsequent primary malignant diseases after cancers of the colon and rectum. A nationwide cohort study. Cancer 1990; 65: 2091–2100.
Haiman CA, Le Marchand L, Yamamato J et al: A common genetic risk factor for colorectal and prostate cancer. Nat Genet 2007; 39: 954–956.
Larson GP, Ding Y, Cheng LS et al: Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT. Cancer Res 2005; 65: 805–814.
Amundadottir LT, Sulem P, Gudmundsson J et al: A common variant associated with prostate cancer in European and African populations. Nat Genet 2006; 38: 652–658.
Maier C, Herkommer K, Hoegel J, Vogel W, Paiss T : A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany. Eur J Hum Genet 2005; 13: 352–360.
Stanford JL, FitzGerald LM, McDonnell SK et al: Dense genome-wide SNP linkage scan in 301 hereditary prostate cancer families identifies multiple regions with suggestive evidence for linkage. Hum Mol Genet 2009; 18: 1839–1848.
Daley D, Lewis S, Platzer P et al: Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study. Am J Hum Genet 2008; 82: 723–736.
Ohta M, Inoue H, Cotticelli MG et al: The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 1996; 84: 587–597.
Tomlinson I, Rahman N, Frayling I et al: Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. Gastroenterology 1999; 116: 789–795.
Janer M, Friedrichsen DM, Stanford JL et al: Genomic scan of 254 hereditary prostate cancer families. Prostate 2003; 57: 309–319.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR : Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
Kong A, Cox NJ : Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.
Abecasis GR, Wigginton JE : Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 2005; 77: 754–767.
Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA : Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004; 74: 106–120.
Lander E, Kruglyak L : Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Schaid DJ, McDonnell SK, Zarfas KE et al: Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics. Hum Genet 2006; 120: 471–485.
Schleutker J, Baffoe-Bonnie AB, Gillanders E et al: Genome-wide scan for linkage in Finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26. Prostate 2003; 57: 280–289.
Eeles RA, Kote-Jarai Z, Giles GG et al: Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 2008; 40: 316–321.
Slager SL, Schaid DJ, Cunningham JM et al: Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q. Am J Hum Genet 2003; 72: 759–762.
Xu J, Dimitrov L, Chang BL et al: A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am J Hum Genet 2005; 77: 219–229.
Ozden N, Saruc M, Smith LM, Sanjeevi A, Roy HK : Increased cumulative incidence of prostate malignancies in colorectal cancer patients. Int J Gastrointest Cancer 2003; 34: 49–54.
Burmester JK, Suarez BK, Lin JH et al: Analysis of candidate genes for prostate cancer. Hum Hered 2004; 57: 172–178.
Hirata H, Hinoda Y, Kawamoto K et al: Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer. J Urol 2008; 179: 2020–2024.
Curtin K, Lin WY, George R et al: Meta association of colorectal cancer confirms risk alleles at 8q24 and 18q21. Cancer Epidemiol Biomarkers Prev 2009; 18: 616–621.
Tomlinson I, Webb E, Carvajal-Carmona L et al: A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 2007; 39: 984–988.
Jaeger E, Webb E, Howarth K et al: Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 2008; 40: 26–28.
Wallar BJ, Alberts AS : The formins: active scaffolds that remodel the cytoskeleton. Trends Cell Biol 2003; 13: 435–446.
Zhou F, Leder P, Martin SS : Formin-1 protein associates with microtubules through a peptide domain encoded by exon-2. Exp Cell Res 2006; 312: 1119–1126.
Djureinovic T, Skoglund J, Vandrovcova J et al: A genome wide linkage analysis in Swedish families with hereditary non-familial adenomatous polyposis/non-hereditary non-polyposis colorectal cancer. Gut 2006; 55: 362–366.
Cui Y, Ying Y, van Hasselt A et al: OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation. PLoS ONE 2008; 3: e2990.
Frattini M, Balestra D, Suardi S et al: Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res 2004; 10: 4015–4021.
Ueda T, Komiya A, Emi M et al: Allelic losses on 18q21 are associated with progression and metastasis in human prostate cancer. Genes Chromosomes Cancer 1997; 20: 140–147.
Broderick P, Carvajal-Carmona L, Pittman AM et al: A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 2007; 39: 1315–1317.
Navarro C, Chirlaque MD, Tormo MJ et al: Validity of self reported diagnoses of cancer in a major Spanish prospective cohort study. J Epidemiol Community Health 2006; 60: 593–599.
Sijmons RH, Boonstra AE, Reefhuis J et al: Accuracy of family history of cancer: clinical genetic implications. Eur J Hum Genet 2000; 8: 181–186.
Chang ET, Smedby KE, Hjalgrim H, Glimelius B, Adami HO : Reliability of self-reported family history of cancer in a large case-control study of lymphoma. J Natl Cancer Inst 2006; 98: 61–68.
Theis B, Boyd N, Lockwood G, Tritchler D : Accuracy of family cancer history in breast cancer patients. Eur J Cancer Prev 1994; 3: 321–327.
Rapiti E, Fioretta G, Verkooijen HM et al: Increased risk of colon cancer after external radiation therapy for prostate cancer. Int J Cancer 2008; 123: 1141–1145.
Bostrom PJ, Soloway MS : Secondary cancer after radiotherapy for prostate cancer: should we be more aware of the risk? Eur Urol 2007; 52: 973–982.
Acknowledgements
We thank all the men and women who are participating in the PROGRESS study for their time, effort and cooperation. We also thank the study staff for help with ongoing data collection and processing. This work was supported by grants RO1-CA080122 and P50-CA097186 from the National Cancer Institute, with additional support from the Fred Hutchinson Cancer Research Center. Genotyping services were provided by the Center for Inherited Disease Research at Johns Hopkins University (contract N01-HG-65403 from the National Institutes of Health). We acknowledge the Prostate Cancer Foundation and the Intramural Program of the National Human Genome Research Institute.
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FitzGerald, L., McDonnell, S., Carlson, E. et al. Genome-wide linkage analyses of hereditary prostate cancer families with colon cancer provide further evidence for a susceptibility locus on 15q11–q14. Eur J Hum Genet 18, 1141–1147 (2010). https://doi.org/10.1038/ejhg.2010.49
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DOI: https://doi.org/10.1038/ejhg.2010.49
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