TY - JOUR
T1 - Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families
AU - Bailey-Wilson, Joan E.
AU - Childs, Erica J.
AU - Cropp, Cheryl D.
AU - Schaid, Daniel J.
AU - Xu, Jianfeng
AU - Camp, Nicola J.
AU - Cannon-Albright, Lisa A.
AU - Farnham, James M.
AU - George, Asha
AU - Powell, Isaac
AU - Carpten, John D.
AU - Giles, Graham G.
AU - Hopper, John L.
AU - Severi, Gianluca
AU - English, Dallas R.
AU - Foulkes, William D.
AU - Mæhle, Lovise
AU - Møller, Pål
AU - Eeles, Rosalind
AU - Easton, Douglas
AU - Guy, Michelle
AU - Edwards, Steve
AU - Badzioch, Michael D.
AU - Whittemore, Alice S.
AU - Oakley-Girvan, Ingrid
AU - Hsieh, Chih Lin
AU - Dimitrov, Latchezar
AU - Stanford, Janet L.
AU - Karyadi, Danielle M.
AU - Deutsch, Kerry
AU - McIntosh, Laura
AU - Ostrander, Elaine A.
AU - Wiley, Kathleen E.
AU - Isaacs, Sarah D.
AU - Walsh, Patrick C.
AU - Thibodeau, Stephen N.
AU - McDonnell, Shannon K.
AU - Hebbring, Scott
AU - Lange, Ethan M.
AU - Cooney, Kathleen A.
AU - Tammela, Teuvo L.J.
AU - Schleutker, Johanna
AU - Maier, Christiane
AU - Bochum, Sylvia
AU - Hoegel, Josef
AU - Grönberg, Henrik
AU - Wiklund, Fredrik
AU - Emanuelsson, Monica
AU - Cancel-Tassin, Geraldine
AU - Valeri, Antoine
AU - Cussenot, Olivier
AU - Isaacs, William B.
N1 - Funding Information:
We would like to express our gratitude to the many families who participated in the many studies involved in the International Consortium for Prostate Cancer Genetics (ICPCG). The ICPCG, including the consortium’s Data Coordinating Center (DCC), is made possible by a grant from the National Institutes of Health U01 CA89600 (to W.B.I.). This project was supported in part by the Intramural Research Programs of the National Human Genome Research Institute and the National Cancer Institute, National Institutes of Health (J.E.B-W, E.L.C., C.D.C., E.A.O., D.M.K.). 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 (CR-UK). Additional support was provided by The 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 No. 328323. The funds for the ABI 377 used in this study were generously provided by the legacy of the late Marion Silcock. We thank S. Seal and A. Hall for kindly storing and logging the samples that were provided. D.F.E is a Principal Research Fellow of CR-UK. Funding in Australia was obtained from The Cancer Council Victoria, The National Health and Medical Research Council (grants 940934, 251533, 209057, 126402, 396407), Tattersall’s and The Whitten Foundation. We would like to acknowledge the work of the study coordinator M. Staples and the Research Team B. McCudden, J. Connal, R. Thorowgood, C. Costa, M. Kevan, and S. Palmer, and to J. Karpowicz for DNA extractions. The Texas study of familial prostate cancer was initiated by the Department of Epidemiology, M.D. Anderson Cancer Center. M.B. was supported by an NCI Post-doctoral Fellowship in Cancer Prevention (R25). BC/CA/HI Group: USPHS CA67044. Research carried out by WDF was supported by the Department of Defense. Fred Hutchingson Cancer Research Center Group: USPHS CA80122 (to J.L. S.) which supports the family collection; USPHS CA78836 (to E.A.O), with additional support from the Fred Hutchinson Cancer Research Center. JHU Group: Genotyping for the JHU, University of Michigan, University of Tampere, and University of Umeå groups’ pedigrees was provided by NHGRI genotyping staff including E. Gillanders, MP Jones, D. Gildea, D. Freas-Lutz, C. Markey, J. Carpten and J. Trent. Mayo Clinic Group: USPHS CA72818. Michigan Group: USPHS CA079596. University of Tampere Group: The Competitive Research Funding of the Pirkanmaa Hospital District, Reino Lahtikari Foundation, Finnish Cancer Organisations, Sigrid Juselius Foundation, and Academy of Finland grant 118413. University of Ulm Group: Deutsche Krebshilfe, grant number 70-3111-V03. University of Umea Group: Work was supported by the Swedish Cancer Society and a Spear grant from the Umeå University Hospital, Umeå, Sweden. University of Utah Group: Data collection was supported by USPHS CA90752 (to L.A.C.-A.) and by the Utah Cancer Registry, which is funded by Contract HHSN261201000026C from the National Cancer Institute's Surveillance, Epidemiology, and End-Results Program with additional support from the Utah State Department of Health and the University of Utah. Partial support for all datasets within the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute and also by the USPHS M01-RR00064 from the National Center for Research Resources. Genotyping services were provided by the Center for Inherited Disease Research (N01-HG-65403). CeRePP Group: work was supported by the Association pour la Recherche sur le Cancer, grant number 5441. DCC: The study is partially supported by USPHS CA106523 (to J.X.), USPHS CA95052 (to J.X.), and Department of Defense grant PC051264 (to J.X.). The funding bodies did not play a role in study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript or in the decision to submit the manuscript for publication.
PY - 2012/6/19
Y1 - 2012/6/19
N2 - 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.
AB - 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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U2 - 10.1186/1471-2350-13-46
DO - 10.1186/1471-2350-13-46
M3 - Article
C2 - 22712434
AN - SCOPUS:84862273373
SN - 1471-2350
VL - 13
JO - BMC medical genetics
JF - BMC medical genetics
M1 - 46
ER -