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Human Molecular Genetics Advance Access published online on January 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi459
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received October 7, 2005
Revised December 8, 2005
Accepted December 14, 2005

Article

Genome-wide linkage screen for testicular germ cell tumour susceptibility loci

Gillian P. Crockford 1, Rachel Linger 2, Sarah Hockley 2, Darshna Dudakia 2, Lola Johnson 2, Robert Huddart 3, Kathy Tucker 4, Michael Friedlander 4, Kelly-Anne Phillips 5, David Hogg 6, Michael A.S. Jewett 6, Radka Lohynska 7, Gedske Daugaard 8, Stéphane Richard 9, Agnes Chompret 10, Catherine Bonaïti-Pellié 11, Axel Heidenreich 12, Peter Albers 13, Edith Olah 14, Lajos Geczi 14, Istvan Bodrogi 14, Wilma J. Ormiston 15, Peter A. Daly 15, Parry Guilford 16, Sophie D. Fosså 17, Ketil Heimdal 17, Sergei A. Tjulandin 18, Ludmila Liubchenko 18, Hans Stoll 19, Walter Weber 19, David Forman 20, Timothy Oliver 21, Lawrence Einhorn 22, Mary McMaster 23, Joan Kramer 23, Mark H. Greene 23, Barbara L. Weber 24, Katherine L. Nathanson 24, Malcolm Pike 25, Duncan Thomas 25, Victoria Cortessis 25, Douglas F. Easton 26, D. Timothy Bishop 1, Michael R. Stratton 2, and Elizabeth A. Rapley 27 *

1 Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds, UK
2 Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK
3 Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, Surrey, UK
4 Department of Medical Oncology, Division of Medicine, University of New South Wales and Prince of Wales Hospital Randwick, Sydney Australia
5 Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
6 Princess Margaret Hospital and University of Toronto, Toronto, ON, Canada
7 University Hospital, Dept of Radiotherapy and Oncology, Prague, Czech Republic
8 Department of Oncology, Rigshospitalet, Copenhagen, Denmark
9 Génétique Oncologique EPHE-UMR 8125 Faculté de Médecine Paris-Sud and Service d'Urologie, CHU, Le Kremlin-Bicêtre, France
10 Génétique Oncologique, Institut Gustave Roussy, Villejuif, France
11 INSERM U535, Hôpital Paul Brousse, Villejuif, France
12 Department of Urological Oncology, Phillips University, Marburg, Germany
13 Department of Urology, Klinikum Kassel GmbH, Moenchebergstr. 41-43, D-34125 Kassel, Germany
14 Department of Molecular Genetics and Department of Chemotherapy, National Institute of Oncology, Budapest, Hungary
15 Department of Medical Oncology, St James's Hospital, Dublin, Ireland
16 Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand
17 Departments of Clinical Cancer Research and genetics, Rikshospitalet-Radiumhospitalet Trust, Oslo, Norway
18 Laboratory of Clinical Genetics, Institute of Clinical Oncology, N.N.Blokhin Russian Cancer Research Center, Moscow, Russian Federation
19 Medical Oncology, University Hospital, Basel, Switzerland
20 Cancer Epidemiology, University of Leeds, Cookridge Hospital, Leeds, LS16 6QB, UK
21 Department of Medical Oncology, Barts and The London Queen Mary's School of Medicine, London, UK
22 Department of Medicine, Indiana University School of Medicine, Indianapolis, USA
23 Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute National Institutes of Health, Rockville, MD, USA
24 Departments of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
25 Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, California, USA
26 Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, UK
27 Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK

* To whom correspondence should be addressed.
Elizabeth A. Rapley, E-mail: liz.rapley{at}icr.ac.uk


  Abstract

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. 179 pedigrees were evaluated genome-wide with an average inter-marker distance of 10cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease.


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