Christensen, G. B., Baffoe-Bonnie, A. B., George, A., Powell, I., Bailey-Wilson, J. E., Carpten, J. D., Giles, G. G., Hopper, J. L., Seven, G., English, D. R., Foulkes, W. D., Maehle, L., Moller, P., Eeles, R., Easton, D., Badzioch, M. D., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Dimitrov, L., Xu, J., Stanford, J. L., Johanneson, B., Deutsch, K., McIntosh, L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Isaacs, W. B., Thibodeau, S. N., McDonnell, S. K., Hebbring, S., Schaid, D. J., Lange, E. M., Cooney, K. A., Tammela, T. L. J., Schleutker, J., Paiss, T., Maier, C., Gronberg, H., Wiklund, F., Emanuelsson, M., Farnham, J. M., Cannon-Albright, L. A., Camp, N. J., Int Consortium Prostate Canc Genet, [Group Author] (2010) Genome-Wide Linkage Analysis of 1,233 Prostate Cancer Pedigrees From the International Consortium for Prostate Cancer Genetics Using Novel sum LINK and sum LOD Analyses. PROSTATE, 70 (7). pp. 735-744. ISSN 0270-4137

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Abstract

BACKGROUND. Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS. We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS. Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS. Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate 70: 735-744, 2010. (C) 2010 Wiley-Liss, Inc.

Item Type:	Article
Authors (ICR Faculty only):	Eeles, Rosalind
All Authors:	Christensen, G. B., Baffoe-Bonnie, A. B., George, A., Powell, I., Bailey-Wilson, J. E., Carpten, J. D., Giles, G. G., Hopper, J. L., Seven, G., English, D. R., Foulkes, W. D., Maehle, L., Moller, P., Eeles, R., Easton, D., Badzioch, M. D., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Dimitrov, L., Xu, J., Stanford, J. L., Johanneson, B., Deutsch, K., McIntosh, L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Isaacs, W. B., Thibodeau, S. N., McDonnell, S. K., Hebbring, S., Schaid, D. J., Lange, E. M., Cooney, K. A., Tammela, T. L. J., Schleutker, J., Paiss, T., Maier, C., Gronberg, H., Wiklund, F., Emanuelsson, M., Farnham, J. M., Cannon-Albright, L. A., Camp, N. J., Int Consortium Prostate Canc Genet, [Group Author]
Uncontrolled Keywords:	genetic epidemiology; meta analysis; susceptibility; predisposition; cancer;SUSCEPTIBILITY; FAMILIES; LOCI; AGGRESSIVENESS; GENES; SCAN; ASSOCIATION; 22Q12.3; RISK
Funding Acknowledgement:	National Institutes of Health [U01 CA89600]; National Library of Medicine [T15 LM07124]; USPHS [CA98364, CA-06927, CA67044, CA80122, CA78836, CA72818, CA079596, CA90752, CA106523, CA95052]; National Human Genome Research Institute (NHGRI) ; NIH Center for Minority and Health Disparities [1-HG-75418]; NIH (NHGRI) ; National Center for Research Institute [RR03048]; National Center for Research Resources [RR03048, M01-RR00064]; Cancer Research UK (CR-UK) ; The Prostate Cancer Research Foundation ; The Times Christmas Appeal ; Institute of Cancer Research ; BREAKTHROUGH Breast Cancer-Charity [328323]; The Cancer Council Victoria ; The National Health and Medical Research Council [940934, 251533, 209057, 126402, 396407]; Tattersall's ; The Whitten Foundation ; NCI [R25]; Pirkanmaa Hospital District ; Reino Lahtikari Foundation ; Finnish Cancer Organisations ; Sigrid Juselius Foundation ; Academy of Finland [211123]; Deutsche Krebshilfe [70-3111-V03]; Umea University Hospital, Umea, Sweden ; National Cancer Institute [N01-PC-35141]; Utah State Department of Heath ; University of Utah ; University of Utah Huntsman Cancer Institute ; Center for Inherited Disease Research [N01-HG-65403]; Department of Defense [PC051264]
Funding Text:	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.). G.B.C. was supported by National Library of Medicine training grant NLM T15 LM07124. N.J.C. was supported in part by USPHS CA98364 (to N.J.C.). Additional support to participating groups, or members within groups, is as follows: AAHPC Group: The authors would like to express their gratitude to the African-American Hereditary Prostate Cancer Study (AAHPC) families and study participants for their continued involvement in this research. We specifically name, C. Ahaghotu, J. Bennett, W. Boykin, G. Hoke, T. Mason, C. Pettaway, S. Vijayakumar, S. Weinrich, M. Franklin, P. Roberson, J. Frost, E. Johnson, L. Faison-Smith, C. Meegan, M. Johnson, L. Kososki, C. Jones, and R. Mejia. We would also like to thank members of the National Human Genome Center (NHGC) at Howard University namely R. Kitties, G.M. Dunston, P. Furbert-Harris, and C. Royal. We would also like to acknowledge the contribution of the National Human Genome Research Institute (NHGRI) and TGen genotyping staff including E. Gillanders and C. Robbins. The AAHPC study would not have been possible without F. Collins (Director of NHGRI) and J. Trent (Director of TGen). This research was funded primarily through the NIH Center for Minority and Health Disparities (1-HG-75418). A.B.B.-B. and A.G. also received support from USPHS CA-06927 and an appropriation from the Commonwealth of Pennsylvania. This research was also supported in part by the Intramural Research Program of the NIH (NHGRI) and USPHS RR03048 from the National Center for Research Institute and USPHS RR03048 from the National Center for Research Resources. ACTANE Group: Genotyping and statistical analysis for this study, and recruitment of UK families, was supported by Cancer Research UK (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). We would also like to specifically thank the following members of ACTANE: S. Edwards, M. Guy, Q. Hope, S. Bullock, S. Bryant, S. Mulholland, S. Jugurnauth, N. Garcia, A. Ardern-Jones, A. Hall, L. O'Brien, B. Gehr-Swain, R. Wilkinson, D. Dearnaley, The UKGPCS Collaborators, British Association of tiro logical Surgeons' Section of Oncology (UK Sutton); Chris Evans (UK Camridge); M. Southey (Australia); N. Hamel, S. Narod, J. Simard (Canada); C. Amos (USA Texas); N. Wessel, T. Andersen (Norway); D.T. Bishop (EU Biomed). BC/CA/HI Group: USPHS CA67044. FHCRC Group: USPHS CA80122 (to J.L.S.) which supports the family collection; USPHS CA78836 (to E.A.O.). E.A.O. was supported in part by the NHGRI. JHU Group: Genotyping for the JHU, University of Michigan, University of Tampere, and University of Umea Groups' pedigrees was provided by NHGRI and TGen genotyping staff including E. Gillanders, M.P. Jones, D. Gildea, E. Riedesel, J. Albertus, 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 211123. 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 Umea University Hospital, Umea, 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 #N01-PC-35141 from the National Cancer Institute's Surveillance, Epidemiology, and End-Results Program with additional support from the Utah State Department of Heath 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). 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.).
Research teams:	ICR divisions > Genetics and Epidemiology > Oncogenetics ICR divisions > Radiotherapy and Imaging > Oncogenetics
Depositing User:	Users 10 not found.
Date Deposited:	25 May 2010 11:34
Last Modified:	25 May 2010 11:34
URI:	http://publications.icr.ac.uk/id/eprint/9584

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