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1.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression 
Kote-Jarai, Zsofia | Saunders, Edward J. | Leongamornlert, Daniel A. | Tymrakiewicz, Malgorzata | Dadaev, Tokhir | Jugurnauth-Little, Sarah | Ross-Adams, Helen | Al Olama, Ali Amin | Benlloch, Sara | Halim, Silvia | Russell, Roslin | Dunning, Alison M. | Luccarini, Craig | Dennis, Joe | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Muir, Ken | Giles, Graham G. | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J. | Gapstur, Susan | Chanock, Stephen | Berndt, Sonja I. | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J. | Travis, Ruth C. | Campa, Daniele | Ingles, Sue A. | John, Esther M. | Hayes, Richard B. | Pharoah, Paul | Khaw, Kay-Tee | Stanford, Janet L. | Ostrander, Elaine A. | Signorello, Lisa B. | Thibodeau, Stephen N. | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S. | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright, Lisa | Brenner, Hermann | Park, Jong Y. | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda | Clements, Judith A. | Teixeira, Manuel R. | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A. | Sawyer, Emma J. | Morgan, Angela | Dicks, Ed | Baynes, Caroline | Conroy, Don | Bojensen, Stig E. | Kaaks, Rudolf | Vincent, Daniel | Bacot, François | Tessier, Daniel C. | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2013;22(20):4239.
doi:10.1093/hmg/ddt334
PMCID: PMC3871151
2.  Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality 
Aging cell  2010;9(6):1057-1064.
Summary
Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease, chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine if serum MIC-1/GDF15 estimation is a predictor of all-cause mortality we examined a cohort of 876 male subjects aged 35 to 80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C reactive protein (CRP) available. Patients were followed for up to 14 years and had cause specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio of death of 3.38 (95%CI 1.38–8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality.
doi:10.1111/j.1474-9726.2010.00629.x
PMCID: PMC4139960  PMID: 20854422
MIC-1/GDF15; all-cause mortality; serum marker; cytokine; prospective observational cohort; environmental toxicity
4.  Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer 
PLoS Genetics  2014;10(2):e1004129.
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Author Summary
Genome-wide association studies (GWAS) have identified numerous low penetrance disease susceptibility variants, yet few causal alleles have been unambiguously identified. The underlying causal variants are expected to be predominantly common; however synthetic associations with rare, higher penetrance variants have been hypothesised though not yet observed. Here, we report detection of a novel common, low penetrance prostate cancer association at the HOXB locus at ch17q and show that this signal can actually be attributed to a previously identified rare, moderate penetrance coding variant (G84E) in HOXB13. This study therefore provides the first experimental evidence for the existence of synthetic associations in cancer and shows that where GWAS signals arise through this phenomenon, risk predictions derived using the tag SNP would substantially underestimate the relative risk conferred and overestimate the number of carriers of the causal variant. Synthetic associations at GWAS signals could therefore account for a proportion of the missing heritability of complex diseases.
doi:10.1371/journal.pgen.1004129
PMCID: PMC3923678  PMID: 24550738
5.  A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease 
Amin Al Olama, Ali | Kote-Jarai, Zsofia | Schumacher, Fredrick R. | Wiklund, Fredrik | Berndt, Sonja I. | Benlloch, Sara | Giles, Graham G. | Severi, Gianluca | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Hunter, David J. | Henderson, Brian E. | Thun, Michael J. | Gaziano, Michael | Giovannucci, Edward L. | Siddiq, Afshan | Travis, Ruth C. | Cox, David G. | Canzian, Federico | Riboli, Elio | Key, Timothy J. | Andriole, Gerald | Albanes, Demetrius | Hayes, Richard B. | Schleutker, Johanna | Auvinen, Anssi | Tammela, Teuvo L.J. | Weischer, Maren | Stanford, Janet L. | Ostrander, Elaine A. | Cybulski, Cezary | Lubinski, Jan | Thibodeau, Stephen N. | Schaid, Daniel J. | Sorensen, Karina D. | Batra, Jyotsna | Clements, Judith A. | Chambers, Suzanne | Aitken, Joanne | Gardiner, Robert A. | Maier, Christiane | Vogel, Walther | Dörk, Thilo | Brenner, Hermann | Habuchi, Tomonori | Ingles, Sue | John, Esther M. | Dickinson, Joanne L. | Cannon-Albright, Lisa | Teixeira, Manuel R. | Kaneva, Radka | Zhang, Hong-Wei | Lu, Yong-Jie | Park, Jong Y. | Cooney, Kathleen A. | Muir, Kenneth R. | Leongamornlert, Daniel A. | Saunders, Edward | Tymrakiewicz, Malgorzata | Mahmud, Nadiya | Guy, Michelle | Govindasami, Koveela | O'Brien, Lynne T. | Wilkinson, Rosemary A. | Hall, Amanda L. | Sawyer, Emma J. | Dadaev, Tokhir | Morrison, Jonathan | Dearnaley, David P. | Horwich, Alan | Huddart, Robert A. | Khoo, Vincent S. | Parker, Christopher C. | Van As, Nicholas | Woodhouse, Christopher J. | Thompson, Alan | Dudderidge, Tim | Ogden, Chris | Cooper, Colin S. | Lophatonanon, Artitaya | Southey, Melissa C. | Hopper, John L. | English, Dallas | Virtamo, Jarmo | Le Marchand, Loic | Campa, Daniele | Kaaks, Rudolf | Lindstrom, Sara | Diver, W. Ryan | Gapstur, Susan | Yeager, Meredith | Cox, Angela | Stern, Mariana C. | Corral, Roman | Aly, Markus | Isaacs, William | Adolfsson, Jan | Xu, Jianfeng | Zheng, S. Lilly | Wahlfors, Tiina | Taari, Kimmo | Kujala, Paula | Klarskov, Peter | Nordestgaard, Børge G. | Røder, M. Andreas | Frikke-Schmidt, Ruth | Bojesen, Stig E. | FitzGerald, Liesel M. | Kolb, Suzanne | Kwon, Erika M. | Karyadi, Danielle M. | Orntoft, Torben Falck | Borre, Michael | Rinckleb, Antje | Luedeke, Manuel | Herkommer, Kathleen | Meyer, Andreas | Serth, Jürgen | Marthick, James R. | Patterson, Briony | Wokolorczyk, Dominika | Spurdle, Amanda | Lose, Felicity | McDonnell, Shannon K. | Joshi, Amit D. | Shahabi, Ahva | Pinto, Pedro | Santos, Joana | Ray, Ana | Sellers, Thomas A. | Lin, Hui-Yi | Stephenson, Robert A. | Teerlink, Craig | Muller, Heiko | Rothenbacher, Dietrich | Tsuchiya, Norihiko | Narita, Shintaro | Cao, Guang-Wen | Slavov, Chavdar | Mitev, Vanio | Chanock, Stephen | Gronberg, Henrik | Haiman, Christopher A. | Kraft, Peter | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2012;22(2):408-415.
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03–1.21), P = 1.4 × 10−8]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
doi:10.1093/hmg/dds425
PMCID: PMC3526158  PMID: 23065704
6.  Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array 
Eeles, Rosalind A | Olama, Ali Amin Al | Benlloch, Sara | Saunders, Edward J | Leongamornlert, Daniel A | Tymrakiewicz, Malgorzata | Ghoussaini, Maya | Luccarini, Craig | Dennis, Joe | Jugurnauth-Little, Sarah | Dadaev, Tokhir | Neal, David E | Hamdy, Freddie C | Donovan, Jenny L | Muir, Ken | Giles, Graham G | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A | Schumacher, Fredrick | Henderson, Brian | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J | Gapstur, Susan | Chanock, Stephen J | Berndt, Sonja I | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J | Travis, Ruth | Campa, Daniele | Ingles, Sue A | John, Esther M | Hayes, Richard B | Pharoah, Paul DP | Pashayan, Nora | Khaw, Kay-Tee | Stanford, Janet | Ostrander, Elaine A | Signorello, Lisa B | Thibodeau, Stephen N | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright,  | Brenner, Hermann | Park, Jong Y | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda B | Clements, Judith A | Teixeira, Manuel R | Dicks, Ed | Lee, Andrew | Dunning, Alison | Baynes, Caroline | Conroy, Don | Maranian, Melanie J | Ahmed, Shahana | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A | Sawyer, Emma J | Morgan, Angela | Dearnaley, David P | Horwich, Alan | Huddart, Robert A | Khoo, Vincent S | Parker, Christopher C | Van As, Nicholas J | Woodhouse, J | Thompson, Alan | Dudderidge, Tim | Ogden, Chris | Cooper, Colin | Lophatananon, Artitaya | Cox, Angela | Southey, Melissa | Hopper, John L | English, Dallas R | Aly, Markus | Adolfsson, Jan | Xu, Jiangfeng | Zheng, Siqun | Yeager, Meredith | Kaaks, Rudolf | Diver, W Ryan | Gaudet, Mia M | Stern, Mariana | Corral, Roman | Joshi, Amit D | Shahabi, Ahva | Wahlfors, Tiina | Tammela, Teuvo J | Auvinen, Anssi | Virtamo, Jarmo | Klarskov, Peter | Nordestgaard, Børge G | Røder, Andreas | Nielsen, Sune F | Bojesen, Stig E | Siddiq, Afshan | FitzGerald, Liesel | Kolb, Suzanne | Kwon, Erika | Karyadi, Danielle | Blot, William J | Zheng, Wei | Cai, Qiuyin | McDonnell, Shannon K | Rinckleb, Antje | Drake, Bettina | Colditz, Graham | Wokolorczyk, Dominika | Stephenson, Robert A | Teerlink, Craig | Muller, Heiko | Rothenbacher, Dietrich | Sellers, Thomas A | Lin, Hui-Yi | Slavov, Chavdar | Mitev, Vanio | Lose, Felicity | Srinivasan, Srilakshmi | Maia, Sofia | Paulo, Paula | Lange, Ethan | Cooney, Kathleen A | Antoniou, Antonis | Vincent, Daniel | Bacot, François | Tessier,  | Kote-Jarai, Zsofia | Easton, Douglas F
Nature genetics  2013;45(4):10.1038/ng.2560.
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
doi:10.1038/ng.2560
PMCID: PMC3832790  PMID: 23535732
7.  Genetic variation in the upstream region of ERG and prostate cancer 
Cancer causes & control : CCC  2009;20(7):1173-1180.
Objective
A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival.
Methods
We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5′UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case–control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival.
Results
One haplotype—′CTCGTATG′ located 100 kb upstream of ERG—was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2–1.9, p = 0.006). Carriers of the variant ‘T’ allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1–1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk.
Conclusions
Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.
doi:10.1007/s10552-009-9305-3
PMCID: PMC3755494  PMID: 19205910
Prostate cancer; ERG; Haplotype; Polymorphism; Survival
8.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression 
Kote-Jarai, Zsofia | Saunders, Edward J. | Leongamornlert, Daniel A. | Tymrakiewicz, Malgorzata | Dadaev, Tokhir | Jugurnauth-Little, Sarah | Ross-Adams, Helen | Al Olama, Ali Amin | Benlloch, Sara | Halim, Silvia | Russel, Roslin | Dunning, Alison M. | Luccarini, Craig | Dennis, Joe | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Muir, Ken | Giles, Graham G. | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J. | Gapstur, Susan | Chanock, Stephen | Berndt, Sonja I. | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J. | Travis, Ruth C. | Campa, Daniele | Ingles, Sue A. | John, Esther M. | Hayes, Richard B. | Pharoah, Paul | Khaw, Kay-Tee | Stanford, Janet L. | Ostrander, Elaine A. | Signorello, Lisa B. | Thibodeau, Stephen N. | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S. | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright, Lisa | Brenner, Hermann | Park, Jong Y. | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda | Clements, Judith A. | Teixeira, Manuel R. | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A. | Sawyer, Emma J. | Morgan, Angela | Dicks, Ed | Baynes, Caroline | Conroy, Don | Bojesen, Stig E. | Kaaks, Rudolf | Vincent, Daniel | Bacot, François | Tessier, Daniel C. | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2013;22(12):2520-2528.
Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
doi:10.1093/hmg/ddt086
PMCID: PMC3658165  PMID: 23535824
9.  Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer 
Gudmundsson, Julius | Sulem, Patrick | Rafnar, Thorunn | Bergthorsson, Jon T | Manolescu, Andrei | Gudbjartsson, Daniel | Agnarsson, Bjarni A | Sigurdsson, Asgeir | Benediktsdottir, Kristrun R | Blondal, Thorarinn | Jakobsdottir, Margret | Stacey, Simon N | Kostic, Jelena | Kristinsson, Kari T | Birgisdottir, Birgitta | Ghosh, Shyamali | Magnusdottir, Droplaug N | Thorlacius, Steinunn | Thorleifsson, Gudmar | Zheng, S Lilly | Sun, Jielin | Chang, Bao-Li | Elmore, J Bradford | Breyer, Joan P | McReynolds, Kate M | Bradley, Kevin M | Yaspan, Brian L | Wiklund, Fredrik | Stattin, Par | Lindström, Sara | Adami, Hans-Olov | McDonnell, Shannon K | Schaid, Daniel J | Cunningham, Julie M | Wang, Liang | Cerhan, James R | St Sauver, Jennifer L | Isaacs, Sara D | Wiley, Kathleen E | Partin, Alan W | Walsh, Patrick C | Polo, Sonia | Ruiz-Echarri, Manuel | Navarrete, Sebastian | Fuertes, Fernando | Saez, Berta | Godino, Javier | Weijerman, Philip C | Swinkels, Dorine W | Aben, Katja K | Witjes, J Alfred | Suarez, Brian K | Helfand, Brian T | Frigge, Michael L | Kristjansson, Kristleifur | Ober, Carole | Jonsson, Eirikur | Einarsson, Gudmundur V | Xu, Jianfeng | Gronberg, Henrik | Smith, Jeffrey R | Thibodeau, Stephen N | Isaacs, William B | Catalona, William J | Mayordomo, Jose I | Kiemeney, Lambertus A | Barkardottir, Rosa B | Gulcher, Jeffrey R | Thorsteinsdottir, Unnur | Kong, Augustine | Stefansson, Kari
Nature genetics  2008;40(3):281-283.
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 × 10−13 and 7.7 × 10−9, respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.
doi:10.1038/ng.89
PMCID: PMC3598012  PMID: 18264098
10.  Chromosomes 4 and 8 Implicated in a Genome Wide SNP Linkage Scan of 762 Prostate Cancer Families Collected by the ICPCG 
The Prostate  2011;72(4):410-426.
Background
In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer remains largely incomplete. In a previous microsatellite-based linkage scan of 1233 prostate cancer (PC) families, we identified suggestive evidence for linkage (i.e. LOD≥1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members.
Methods
In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 ICPCG groups.
Results
Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology.
Conclusions
These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.
doi:10.1002/pros.21443
PMCID: PMC3568777  PMID: 21748754
11.  Macrophage Inhibitory Cytokine 1: A New Prognostic Marker in Prostate Cancer 
Purpose
High serum levels of macrophage inhibitory cytokine 1 (MIC-1) are strongly associated with metastatic prostate cancer, suggesting MIC-1 is a biomarker for prostate cancer prognosis.
Experimental Design
We conducted a prospective cohort study of 1,442 Swedish men with a pathologically verified diagnosis of prostate cancer between 2001 and 2003. Blood was drawn either pretreatment (n = 431) or posttreatment (n = 1,011) and cases were followed for a mean time of 4.9 years (range, 0.1–6.8 years).
Results
MIC-1 serum levels independently predicted poor cancer-specific survival with an almost 3-fold higher cancer death rate in patients with serum levels in the highest quartile compared with men with serum levels in the lowest quartile (adjusted hazard ratio, 2.98; 95% confidence interval, 1.82–4.68). Pretreatment MIC-1 levels revealed an even stronger association with disease outcome with an 8-fold higher death rate in the highest compared with the lowest category (adjusted hazard ratio, 7.98; 95% confidence interval, 1.73–36.86). Among patients considered to have localized disease, MIC-1 significantly increased the discriminative capacity between indolent and lethal prostate cancer compared with the established prognostic markers clinical stage, pathologic grade, and prostate-specific antigen level (P = 0.016). A sequence variant in the MIC-1 gene was associated with decreased MIC-1 serum levels (P = 0.002) and decreased prostate cancer mortality (P = 0.003), suggesting a causative role of MIC-1 in prostate cancer prognosis.
Conclusions
Serum MIC-1 concentration is a novel biomarker capable of predicting prostate cancer prognosis.
doi:10.1158/1078-0432.CCR-08-3126
PMCID: PMC3557964  PMID: 19843661
12.  Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG) 
Human genetics  2011;131(7):1095-1103.
Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case–control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case–control GWAS are also associated with disease risk in HPC families.
doi:10.1007/s00439-011-1136-0
PMCID: PMC3535428  PMID: 22198737
13.  Genome-wide Association Study Identifies Loci at ATF7IP and KLK2 Associated with Percentage of Circulating Free PSA1 2 
Neoplasia (New York, N.Y.)  2013;15(1):95-101.
Background
Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy.
Materials/Methods
To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10-5 were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml.
Results
We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10-8). The first associated SNP was rs3213764 (P = 6.45 x 10-10), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10-12), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness.
Conclusions
These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.
PMCID: PMC3556942  PMID: 23359319
14.  HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG) 
Human Genetics  2012;132(1):5-14.
Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10−8 [odds ratio 4.42 (95 % confidence interval 2.56–7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10−6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-012-1229-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-012-1229-4
PMCID: PMC3535370  PMID: 23064873
15.  Genome-wide association study identifies new prostate cancer susceptibility loci 
Human Molecular Genetics  2011;20(19):3867-3875.
Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10−8). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10−9). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.
doi:10.1093/hmg/ddr295
PMCID: PMC3168287  PMID: 21743057
17.  Genetic Variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF Genes Are Prognostic Markers of Prostate Cancer-Specific Mortality 
Background
Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for over 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer.
Methods
In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P ≤0.01, FDR ≤0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients.
Results
Five SNPs were validated (P ≤0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared to patients with 0–2 of the at-risk genotypes those with 4–5 at-risk genotypes had a 50% (95% CI, 1.2–1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (Ptrend = 0.001), adjusting for clinicopathological factors known to influence prognosis.
Conclusion
Five genetic markers were validated to be associated with lethal prostate cancer.
Impact
This is the first population-based study to demonstrate that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated.
doi:10.1158/1055-9965.EPI-11-0236
PMCID: PMC3169727  PMID: 21846818
Prostate cancer-specific mortality; survival; genetic variants; single nucleotide polymorphisms; hazard ratio
18.  Identification of a novel prostate cancer susceptibility locus on chromosome 8q24 
Nature genetics  2009;41(10):1055-1057.
We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry, in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative, identifying a new association with prostate cancer risk on chromosome 8q24 (rs620861, p=1.3×10-10, heterozygote OR = 1.17, 95% CI 1.10 – 1.24; homozygote OR = 1.33; 95% CI 1.21 – 1.45). This defines a new prostate locus on 8q24, Region 4, previously associated with breast cancer.
doi:10.1038/ng.444
PMCID: PMC3430510  PMID: 19767755
19.  Genome-wide linkage analysis of 1233 prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics using novel sumLINK and sumLOD analyses 
The Prostate  2010;70(7):735-744.
Background
Prostate cancer 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 1233 prostate cancer 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 genomewide 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 prostate cancer (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 prostate cancer pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify prostate cancer predisposition genes.
doi:10.1002/pros.21106
PMCID: PMC3428045  PMID: 20333727
20.  Large-scale fine mapping of the HNF1B locus and prostate cancer risk 
Human Molecular Genetics  2011;20(16):3322-3329.
Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case–control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10−8 with the most significant association with rs4430796 (P = 1.62 × 10−24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10−23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10−8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10−10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.
doi:10.1093/hmg/ddr213
PMCID: PMC3140817  PMID: 21576123
21.  Seven novel prostate cancer susceptibility loci identified by a multi-stage genome-wide association study 
Kote-Jarai, Zsofia | Olama, Ali Amin Al | Giles, Graham G. | Severi, Gianluca | Schleutker, Johanna | Weischer, Maren | Canzian, Frederico | Riboli, Elio | Key, Tim | Gronberg, Henrik | Hunter, David J. | Kraft, Peter | Thun, Michael J | Ingles, Sue | Chanock, Stephen | Albanes, Demetrius | Hayes, Richard B | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Pharoah, Paul | Schumacher, Fredrick | Henderson, Brian E. | Stanford, Janet L. | Ostrander, Elaine A. | Sorensen, Karina Dalsgaard | Dörk, Thilo | Andriole, Gerald | Dickinson, Joanne L. | Cybulski, Cezary | Lubinski, Jan | Spurdle, Amanda | Clements, Judith A. | Chambers, Suzanne | Aitken, Joanne | Frank Gardiner, R. A. | Thibodeau, Stephen N. | Schaid, Dan | John, Esther M. | Maier, Christiane | Vogel, Walther | Cooney, Kathleen A. | Park, Jong Y. | Cannon-Albright, Lisa | Brenner, Hermann | Habuchi, Tomonori | Zhang, Hong-Wei | Lu, Yong-Jie | Kaneva, Radka | Muir, Ken | Benlloch, Sara | Leongamornlert, Daniel A. | Saunders, Edward J. | Tymrakiewicz, Malgorzata | Mahmud, Nadiya | Guy, Michelle | O’Brien, Lynne T. | Wilkinson, Rosemary A. | Hall, Amanda L. | Sawyer, Emma J. | Dadaev, Tokhir | Morrison, Jonathan | Dearnaley, David P. | Horwich, Alan | Huddart, Robert A. | Khoo, Vincent S. | Parker, Christopher C. | Van As, Nicholas | Woodhouse, Christopher J. | Thompson, Alan | Christmas, Tim | Ogden, Chris | Cooper, Colin S. | Lophatonanon, Aritaya | Southey, Melissa C. | Hopper, John L. | English, Dallas | Wahlfors, Tiina | Tammela, Teuvo LJ | Klarskov, Peter | Nordestgaard, Børge G. | Røder, M. Andreas | Tybjærg-Hansen, Anne | Bojesen, Stig E. | Travis, Ruth | Campa, Daniele | Kaaks, Rudolf | Wiklund, Fredrik | Aly, Markus | Lindstrom, Sara | Diver, W Ryan | Gapstur, Susan | Stern, Mariana C | Corral, Roman | Virtamo, Jarmo | Cox, Angela | Haiman, Christopher A. | Le Marchand, Loic | FitzGerald, Liesel | Kolb, Suzanne | Kwon, Erika M. | Karyadi, Danielle M. | Orntoft, Torben Falck | Borre, Michael | Meyer, Andreas | Serth, Jürgen | Yeager, Meredith | Berndt, Sonja I. | Marthick, James R | Patterson, Briony | Wokolorczyk, Dominika | Batra, Jyotsna | Lose, Felicity | McDonnell, Shannon K | Joshi, Amit D. | Shahabi, Ahva | Rinckleb, Antje E. | Ray, Ana | Sellers, Thomas A. | Lin, Huo-Yi | Stephenson, Robert A | Farnham, James | Muller, Heiko | Rothenbacher, Dietrich | Tsuchiya, Norihiko | Narita, Shintaro | Cao, Guang-Wen | Slavov, Chavdar | Mitev, Vanio | Easton, Douglas F. | Eeles, Rosalind A.
Nature Genetics  2011;43(8):785-791.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (P=4.0 ×10−8 to P=2.7 ×10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified.
doi:10.1038/ng.882
PMCID: PMC3396006  PMID: 21743467
22.  Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer 
Human Molecular Genetics  2011;20(14):2869-2878.
Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10−8) with rs10896449 the most significant (P= 7.94 × 10−19). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10−5, adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r2= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10−3, adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449–rs12793759, r2= 0.17; rs10896449–rs10896438, r2= 0.10; rs12793759–rs10896438, r2= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
doi:10.1093/hmg/ddr189
PMCID: PMC3118760  PMID: 21531787
23.  Genome-wide copy-number variation analysis identifies common genetic variants at 20p13 associated with aggressiveness of prostate cancer 
Carcinogenesis  2011;32(7):1057-1062.
The genetic determinants for aggressiveness of prostate cancer (PCa) are poorly understood. Copy-number variations (CNVs) are one of the major sources for genetic diversity and critically modulate cellular biology and human diseases. We hypothesized that CNVs may be associated with PCa aggressiveness. To test this hypothesis, we conducted a genome-wide common CNVs analysis in 448 aggressive and 500 nonaggressive PCa cases recruited from Johns Hopkins Hospital (JHH1) using Affymetrix 6.0 arrays. Suggestive associations were further confirmed using single-nucleotide polymorphisms (SNPs) that tagged the CNVs of interest in an additional 2895 aggressive and 3094 nonaggressive cases, including those from the remaining case subjects of the JHH study (JHH2), the NCI Cancer Genetic Markers of Susceptibility (CGEMS) Study, and the CAncer of the Prostate in Sweden (CAPS) Study. We found that CNP2454, a 32.3 kb deletion polymorphism at 20p13, was significantly associated with aggressiveness of PCa in JHH1 [odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.01–1.68; P = 0.045]. The best-tagging SNP for CNP2454, rs2209313, was used to confirm this finding in both JHH1 (P = 0.045) and all confirmation study populations combined (P = 1.77 × 10−3). Pooled analysis using all 3353 aggressive and 3584 nonaggressive cases showed the T allele of rs2209313 was significantly associated with an increased risk of aggressive PCa (OR = 1.17, 95% CI: 1.07–1.27; P = 2.75 × 10−4). Our results indicate that genetic variations at 20p13 may be responsible for the progression of PCa.
doi:10.1093/carcin/bgr082
PMCID: PMC3128563  PMID: 21551127
24.  Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families 
BMC Medical Genetics  2012;13:46.
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.
doi:10.1186/1471-2350-13-46
PMCID: PMC3495053  PMID: 22712434
25.  Established Prostate Cancer Susceptibility Variants are not Associated with Disease Outcome 
Recent genome-wide association studies have been successful in identifying common sequence variants associated with prostate cancer risk; however, their importance in prostate cancer prognosis remains unknown. To assess confirmed prostate cancer susceptibility variants with prostate cancer prognosis, we genotyped 16 established susceptibility variants in a Swedish cohort of 2,875 prostate cancer cases, ascertained between 2001 and 2003, with complete follow-up regarding vital status through January 2008. Cox regression models, adjusted for age, clinical stage, pathologic grade, nodal or distant metastases, and diagnostic serum levels of prostate-specific antigen level, were used to assess association between risk variants and prostate cancer–specific survival. During follow-up, 626 men died, and of those, 440 had prostate cancer classified as their underlying cause of death. We found no association between any of the explored sequence variants and prostate cancer–specific mortality, either in exploring individual variants or in assessing the cumulative effect of all variants. We conclude that hitherto established prostate cancer susceptibility variants are not associated with the lethal potential of prostate cancer.
doi:10.1158/1055-9965.EPI-08-1148
PMCID: PMC3353269  PMID: 19423541

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