Background
Prostate cancer (PC) is the most common male cancer in developed countries [
1]. In the United States, each year there are over 200,000 newly diagnosed cases and over 30,000 deaths attributable to prostate cancer [
2]. Family history, along with older age and African-American ancestry, are the most important risk factors established to date. Inherited genetic factors might account for a proportion of the familial risk, but it has been very difficult to discover the actual genetic basis of prostate cancer probably due to the large number of loci involved, the incomplete and possibly low penetrance associated with these loci, and the likely clinical and genetic heterogeneity of this disease.
In 1996, the first prostate cancer linkage report implicated chromosome 1q23-25 [
3], but subsequent linkage studies have found contradictory conclusions. In this same year the International Consortium for Prostate Cancer Genetics (ICPCG), consisting of researchers from 11 groups around the world, was formed. With the initial aim of examining linkage and trying to replicate previous linkage findings the ICPCG pooled 1,323 pedigrees with clinically- (but not genetically-) defined “hereditary prostate cancer” (HPC). Given the large number of families in this dataset, it was hoped that this would provide increased power to confirm or exclude linkage, and to allow for informative linkage analyses of large homogeneous subsets in an attempt to control for some of the likely heterogeneity that would otherwise weaken the ability to detect linkage. The ICPCG analysis of 775 families supported the finding of a prostate cancer–susceptibility gene linked to 1q24-25 in a defined subset of prostate cancer families with early age at onset, at least 5 affected relatives and evidence of male-to-male transmission [
4]. The
RNASEL gene was later implicated as harboring rare variant alleles that increase risk of prostate cancer and may account for this linkage signal [
5]. Evidence has been accumulating in support of
RNASEL as a prostate cancer risk locus, with several recent large case–control and cohort studies and a very large meta-analysis all showing significant associations of prostate cancer risk with polymorphisms in this locus [
6‐
10].
Several other susceptibility loci presumed to contain rare variants of large effect on individual risk of prostate cancer have been suggested [
3,
4,
11‐
42] and reviewed elsewhere [
30,
41,
42]. In addition, recent genome-wide association studies (GWAS) have implicated multiple loci at which there are common variants (single nucleotide polymorphisms; SNPs) that are not necessarily functional but are associated with small effects on individual risk of prostate cancer [
43‐
49]. For a review see Varghese and Easton [
50]. Work is proceeding to try to identify more susceptibility loci, by GWAS using common SNP risk alleles, by conventional linkage analyses aimed at detecting genes with rare, high-penetrance risk alleles and by whole exome and whole genome sequencing analyses that can be used in conjunction with linkage and GWAS results.
In 1998, a study of 360 multiple-case families found evidence for a prostate cancer susceptibility locus on chromosome X in the region Xq27-q28 (
HPCX) [
38]. A subset of 52 Finnish families from this study was used to examine whether phenotypic subsets of families exhibited different evidence for linkage to this region. This study showed that families with no male-to-male (NMM) transmission and late age of onset of prostate cancer (> 65 years) exhibited stronger evidence of linkage to the Xq27-28 region than did the complete set of families [
33]. There have been five replication studies, four of which supported linkage of prostate cancer susceptibility to this region [
6,
21,
51‐
53] with the study of large Utah pedigrees yielding independent genome-wide significant evidence of linkage [
21], and one which did not support linkage to this region [
12]. A fine-mapping study in the Finnish population examined association of prostate cancer to microsatellite markers in the
HPCX Xq27-28 region using 108 independent prostate cancer patients selected from families with multiple affected men (55 were from the linkage study above) and 257 controls (anonymous, healthy male blood donors) from the same Finnish population. Significant association was observed for two markers in the region, DXS1205 (p = 0.0003) and bG82i1.1 (p = 0.0006), with stronger association observed at DXS1205 in the subset of 60 cases from families with no evidence of male-to-male transmission (p = 0.0002) [
11]. Association of these two markers with prostate cancer risk has been replicated in an Ashkenazi Jewish founder population [
6]. Positive associations were observed for allele 135 of the bG82i1.1 marker (OR = 1.77, P = 0.01) and allele 188 of DXS1205 (OR = 1.65, P = 0.02) in 979 prostate cancer cases and 1,251 controls.
Under the Xq27-q28 linkage peak is a region of ~750 kb containing five
SPANX genes (
SPANX-A1, -A2, -B, -C, and
-D). The
SPANX genes encode nucleus-associated sperm proteins and their expression has been detected in a variety of cancers. While they were originally suggested as candidate genes for the
HPCX susceptibility locus [
54], more recent work has found no association between prostate cancer and mutations in any of these genes [
55]. However, a more complex involvement of these genes is possible. Putative candidate genes for association with prostate cancer have been found on other regions of the X chromosome.
Gudmundsson
et al. conducted a genome-wide SNP association study of prostate cancer in over 23,000 Icelanders followed by a separate replication study. Of the two novel SNPs identified by this study, one, rs5945572, was found on XP11.22 (odds ratio (OR) = 1.23) [
56]. Eeles
et al. also found association to this region in a large GWAS [
47]. However, the odds ratios for the risk genotypes at this putative locus are quite small and not likely to be responsible for the linkage signal observed on Xq in highly aggregated pedigrees.
The aims of this study were to examine the evidence for linkage of prostate cancer to chromosome X using 1,323 multiple-case prostate cancer families from the ICPCG and genotyping a consensus map of 25 microsatellite markers and using both parametric and non-parametric allele-sharing linkage analyses. The pedigree subsets evaluated were presence/absence of male-to-male disease transmission (a surrogate for X-linked inheritance), Carter criteria of HPC [
57,
58], average age at onset of affected men in the family (<65 years of age or ≥ 65 years), and number of men in a family with confirmed PC. Determining whether any of these subsets show stronger evidence of linkage to the region may guide the selection of cases for future mutational analysis in this region.
The members of the International Consortium for Prostate Cancer Genetics are as follows:
ACTANE Group: + Principal Investigators
UK, Sutton: S. Bullock, Q. Hope, S. Edwards, S. Bryant, S. Mulholland, S. Jugurnauth, N. Garcia, M. Guy, L. O'Brien, B. Gehr-Swain, A. Hall, R. Wilkinson, A. Ardern-Jones, D. Dearnaley, The UKGPCS Collaborators, British Association of Urological Surgeons' Section of Oncology, R. Eeles +
UK, Cambridge: Chris Evans, M. Dawn Teare, Doug Easton + (Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Labs, Cambridge)
Australia: John Hopper+, Graham Giles+, Dallas English, Gianluca Severi
(The Cancer Council of Victoria and The University of Melbourne, Carlton, Australia)
Canada: William D. Foulkes+, Nancy Hamel, Steven Narod, Jaques Simard+
(Department of Medical Genetics, Research Institute of the McGill University Health Centre, Montreal, Quebec; Women's College Hospital Research Institute, University of Toronto; Laboratoire de génomique des cancers, Centre de Recherche du CHUQ, Laval University, Quebec City)
Texas: Mike Badzioch+, Chris Amos (MD Anderson Cancer Centre, Houston, TX and Division of Medical Genetics, University of Washington Medical Centre, Seattle, WA)
Norway, Oslo: Ketil Heimdal, Lovise Mæhle, Pål Møller + (Unit of Medical Genetics, Norwegian Radium Hospital, Oslo)
Norway, Ullevaal: Nicolai Wessel, Tone Andersen + (Dept of Oncology, Ullevaal University Hospital, Oslo)
EU Biomed: Tim Bishop+, The EU Biomed Prostate Cancer Linkage Consortium
(Cancer Research UKGenetic Epidemiology Laboratory, St James’ University Hospital, Leeds, UK)
BC/CA/HI Group: Raymond N. Balise1, Richard Gallagher2, Jerry Halpern1, Chih-lin Hsieh3, Laurence Kolonel4, Ingrid Oakley5, Dee West1,5, Alice S. Whittemore1 and Anna Wu3 (1Stanford University School of Medicine, Stanford, CA; 2British Columbia Cancer Center, Vancouver; 3University of Southern California, Los Angeles, CA; 4University of Hawaii, Honolulu, HI; 5Northern California Cancer Center, Union City, CA, Stanford, CA;)
CeRePP Group: Géraldine Cancel-Tassin, Antoine Valéri, Philippe Mangin, Olivier Cussenot (Centre de Recherche pour les Pathologies Prostatiques, Paris, France)
JHU Group: Kathleen E. Wiley, Sarah D. Isaacs, Marta Gielzak, Charles M. Ewing, Patrick C. Walsh, William B. Isaacs (Johns Hopkins Medical Institutions, Baltimore, MD)
Mayo Group: Daniel J. Schaid, Shannon K. McDonnell, Gerald B. Christensen, Julie M. Cunningham, Scott Hebbring, Jennifer C. Guenther, Stephen N. Thibodeau (Mayo Clinic, Rochester, MN)
Michigan Group: Ethan M. Lange1, Cralen C. Davis1, W. Mark Brown1, Cathryn H. Bock2, Kathleen A. Cooney2 (1Wake Forest University, Winston-Salem, NC; 2University of Michigan, Ann Arbor, MI)
Fred Hutchinson Cancer Research Center Group (PROGRESS): Kerry Deutsch1, Danielle M. Friedrichsen2, Suzanne Kolb3, Elaine A. Ostrander2, Lee Hood1, Janet L. Stanford3 (1Institute for Systems Biology, Seattle, WA; 2National Human Genome Research Institute, NIH, Bethesda, MD; 3Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA)
Tampere Group:Tiina Wahlfors1, Henna Mattila1, Virpi Laitinen1, Riikka Nurminen1, Daniel Fischer1, Teuvo L.J. Tammela1, Asha George2, Joan Bailey-Wilson3, Johanna Schleutker1 (1University of Tampere and Tampere University Hospital, Tampere, Finland; 2Fox Chase Cancer Center, Division of Population Science, Philadelphia, PA; 3Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD)
Ulm Group: Ulm Group: Sylvia Bochum1, Thomas Paiss2, Josef Hoegel1, Florian Kurtz1,3, Manuel Luedeke1,2, Antje Rinckleb1,2, Kathleen Herkommer2,3, Walther Vogel1, Mark Schrader2, Christiane Maier1,2 (1Institut fuer Humangenetik, Universitätsklinikum Ulm, Ulm, Germany 2Urologische Klinik, Universitaetsklinik Ulm, Ulm, Germany, 3Urologische Klinik rechts der Isar, Technische Universitaet Muenchen, Munich, Germany)
Umeå/Karolinska Group: Fredrik Wiklund, Anders Bergh, Monica Emanuelsson, Ingela Göransson, Björn-Anders Jonsson, Fredrik Lindmark, Elisabeth Stenman, Henrik Grönberg(Umeå University, Umeå, Sweden and Karolinska Institutet, Stockholm, Sweden)
Utah Group: Lisa A. Cannon-Albright, Nicola J. Camp, James M. Farnham (University of Utah, Salt Lake City, UT)
Data Coordinating Center: Jianfeng Xu, Deborah A. Meyers, Bao-Li Chang, Aubrey R. Turner, Latchezar Dimitrov, Tamara S. Adams (Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC)
Daniella Seminara (National Cancer Institute, Division of Cancer Control and Population Sciences, Bethesda, Maryland)
Acknowledgements
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.
Authors’ contributions
JEB-W, ELC, DJS, RE, DE, DJS, JLS, EAO, DK, LM, GGG, JLH, GS, HG, FW, ME, OC, GC-T, KAC, NJC, LAC-A, ASW, WBI and JX contributed to the design of the study. JEB-W, ELC, DJS and JX contributed to the performance of the meta-analyses. JEB-W, ELC, and CDC wrote the manuscript. DJS, SJM, RE, DE, JLS, EAO, GGG, WDF, JLH, GS, JS, TLT, GC-T, KAC, NJC, LAC-A, ASW, IO-G and WBI contributed to critical revision of the manuscript. MG, SE, JLS, EAO, DK, LM, GGG, WDF, JLH, GS, JS, TLT, OC, LM, PM, AV, KAC, LAC-A, KEW, SDI, PCW and WBI collected and maintained samples and data. EAO, DMK, SNT, SH, SB, GC-T, AV, KAC and CH performed or oversaw laboratory-based studies of samples. JLS, EAO, DMK, LM, SKM, CM, JH, HG, FW, GC-T, EML, NJC, JF, ASW, IO-G and MDB contributed to the linkage analyses at an ICPCG site. KD built and maintains a genotyping database at an ICPCG site. JX and LD coordinated and stored the linkage results from the contributing sites and harmonized the data. All authors have read and approved the final manuscript.