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1. Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease

Author

Teerlink, Craig C., Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., Rinckleb, Antje, Maier, Christiane, Vogel, Walther, Cancel-Tassin, Geraldine, Egrot, Christophe, Cussenot, Olivier, Foulkes, William D., Giles, Graham G., Hopper, John L., Severi, Gianluca, Eeles, Ros, Easton, Douglas, Kote-Jarai, Zsofia, Guy, Michelle, Cooney, Kathleen A., Ray, Anna M., Zuhlke, Kimberly A., Lange, Ethan M., FitzGerald, Liesel M., Stanford, Janet L., Ostrander, Elaine A., Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Wahlfors, Tiina, Tammela, Teuvo, Schleutker, Johanna, Wiklund, Fredrik, Grönberg, Henrik, Emanuelsson, Monica, Carpten, John, Bailey-Wilson, Joan, Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Catalona, William J., Zheng, S. Lilly, Jin, Guangfu, Lu, Lingyi, Xu, Jianfeng, Camp, Nicola J., Cannon-Albright, Lisa A., Teerlink, Craig C., Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., Rinckleb, Antje, Maier, Christiane, Vogel, Walther, Cancel-Tassin, Geraldine, Egrot, Christophe, Cussenot, Olivier, Foulkes, William D., Giles, Graham G., Hopper, John L., Severi, Gianluca, Eeles, Ros, Easton, Douglas, Kote-Jarai, Zsofia, Guy, Michelle, Cooney, Kathleen A., Ray, Anna M., Zuhlke, Kimberly A., Lange, Ethan M., FitzGerald, Liesel M., Stanford, Janet L., Ostrander, Elaine A., Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Wahlfors, Tiina, Tammela, Teuvo, Schleutker, Johanna, Wiklund, Fredrik, Grönberg, Henrik, Emanuelsson, Monica, Carpten, John, Bailey-Wilson, Joan, Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Catalona, William J., Zheng, S. Lilly, Jin, Guangfu, Lu, Lingyi, Xu, Jianfeng, Camp, Nicola J., and Cannon-Albright, Lisa A.

Abstract

Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p a parts per thousand currency sign 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.

Published
2014
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2. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Author

Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Isaacs, William B, Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, and Isaacs, William B

Abstract

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. O

Published
2012
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3. Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG

Author

Lu, Lingyi, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Lange, Ethan M., Cooney, Kathleen A., Farnham, James M., Camp, Nicola J., Cannon-Albright, Lisa A., Tammela, Teuvo L. J., Schleutker, Johanna, Hoegel, Josef, Herkommer, Kathleen, Maier, Christiane, Vogel, Walther, Wiklund, Fredrik, Emanuelsson, Monica, Groenberg, Henrik, Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Helfand, Brian T., Kan, Donghui, Catalona, William J., Stanford, Janet L., FitzGerald, Liesel M., Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A., Thibodeau, Stephen N., McDonnell, Shannon K., Hebbring, Scott, Schaid, Daniel J., Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Powell, Isaac, Bailey-Wilson, Joan E., Cropp, Cheryl D., Simpson, Claire, Carpten, John D., Seminara, Daniela, Zheng, S. Lilly, Xu, Jianfen, Giles, Graham G., Severi, Gianluca, Hopper, John L., English, Dallas R., Foulkes, William D., Maehle, Lovise, Moller, Pal, Badzioch, Michael D., Edwards, Steve, Guy, Michelle, Eeles, Ros, Easton, Douglas, Isaacs, William B., Lu, Lingyi, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Lange, Ethan M., Cooney, Kathleen A., Farnham, James M., Camp, Nicola J., Cannon-Albright, Lisa A., Tammela, Teuvo L. J., Schleutker, Johanna, Hoegel, Josef, Herkommer, Kathleen, Maier, Christiane, Vogel, Walther, Wiklund, Fredrik, Emanuelsson, Monica, Groenberg, Henrik, Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Helfand, Brian T., Kan, Donghui, Catalona, William J., Stanford, Janet L., FitzGerald, Liesel M., Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A., Thibodeau, Stephen N., McDonnell, Shannon K., Hebbring, Scott, Schaid, Daniel J., Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Powell, Isaac, Bailey-Wilson, Joan E., Cropp, Cheryl D., Simpson, Claire, Carpten, John D., Seminara, Daniela, Zheng, S. Lilly, Xu, Jianfen, Giles, Graham G., Severi, Gianluca, Hopper, John L., English, Dallas R., Foulkes, William D., Maehle, Lovise, Moller, Pal, Badzioch, Michael D., Edwards, Steve, Guy, Michelle, Eeles, Ros, Easton, Douglas, and Isaacs, William B.

Abstract

BACKGROUND In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 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 International Consortium for Prostate Cancer Genetics (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, 37cM 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 cores 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 thiscommon cancer. Prostate 72: 410-426, 2012. (C) 2011 Wiley Periodicals, Inc.

Published
2012
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4. 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)

Author

Jin, Guangfu, Lu, Lingyi, Cooney, Kathleen A, Ray, Anna M, Zuhlke, Kimberly A, Lange, Ethan M, Cannon-Albright, Lisa A, Camp, Nicola J, Teerlink, Craig C, Fitzgerald, Liesel M, Stanford, Janet L, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Foulkes, William D, Giles, Graham G, Hopper, John L, Severi, Gianluca, Eeles, Ros, Easton, Doug, Kote-Jarai, Zsofia, Guy, Michelle, Rinckleb, Antje, Maier, Christiane, Vogel, Walther, Cancel-Tassin, Geraldine, Egrot, Christophe, Cussenot, Olivier, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Wiklund, Fredrik, Grönberg, Henrik, Emanuelsson, Monica, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Wahlfors, Tiina, Tammela, Teuvo, Schleutker, Johanna, Catalona, William J, Zheng, S Lilly, Ostrander, Elaine A, Isaacs, William B, Xu, Jianfeng, Jin, Guangfu, Lu, Lingyi, Cooney, Kathleen A, Ray, Anna M, Zuhlke, Kimberly A, Lange, Ethan M, Cannon-Albright, Lisa A, Camp, Nicola J, Teerlink, Craig C, Fitzgerald, Liesel M, Stanford, Janet L, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Foulkes, William D, Giles, Graham G, Hopper, John L, Severi, Gianluca, Eeles, Ros, Easton, Doug, Kote-Jarai, Zsofia, Guy, Michelle, Rinckleb, Antje, Maier, Christiane, Vogel, Walther, Cancel-Tassin, Geraldine, Egrot, Christophe, Cussenot, Olivier, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Wiklund, Fredrik, Grönberg, Henrik, Emanuelsson, Monica, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Wahlfors, Tiina, Tammela, Teuvo, Schleutker, Johanna, Catalona, William J, Zheng, S Lilly, Ostrander, Elaine A, Isaacs, William B, and Xu, Jianfeng

Abstract

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.

Published
2012
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5. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Author

Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Isaacs, William B, Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, and Isaacs, William B

Abstract

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. O

Published
2012
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6. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Author

Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Isaacs, William B, Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, and Isaacs, William B

Abstract

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. O

Published
2012
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7. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Author

Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Isaacs, William B, Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, and Isaacs, William B

Abstract

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. O

Published
2012
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8. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Author

Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Isaacs, William B, Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Gronberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, and Isaacs, William B

Abstract

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. O

Published
2012
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9. Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.

Author

Christensen, G Bryce, Baffoe-Bonnie, Agnes B, George, Asha, Powell, Isaac, Bailey-Wilson, Joan E, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L, Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Isaacs, William B, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Schaid, Daniel J, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo L J, Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Grönberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Farnham, James M, Cannon-Albright, Lisa A, Camp, Nicola J, Christensen, G Bryce, Baffoe-Bonnie, Agnes B, George, Asha, Powell, Isaac, Bailey-Wilson, Joan E, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L, Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Isaacs, William B, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Schaid, Daniel J, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo L J, Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Grönberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Farnham, James M, Cannon-Albright, Lisa A, and Camp, Nicola J

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 (c) 2010 Wiley-Liss, Inc.

Published
2010
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10. Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.

Author

Xu, Jianfeng, Zheng, Siqun Lilly, Isaacs, Sarah D, Wiley, Kathleen E, Wiklund, Fredrik, Sun, Jielin, Kader, A Karim, Li, Ge, Purcell, Lina D, Kim, Seong-Tae, Hsu, Fang-Chi, Stattin, Pär, Hugosson, Jonas, Adolfsson, Jan, Walsh, Patrick C, Trent, Jeffrey M, Duggan, David, Carpten, John, Grönberg, Henrik, Isaacs, William B, Xu, Jianfeng, Zheng, Siqun Lilly, Isaacs, Sarah D, Wiley, Kathleen E, Wiklund, Fredrik, Sun, Jielin, Kader, A Karim, Li, Ge, Purcell, Lina D, Kim, Seong-Tae, Hsu, Fang-Chi, Stattin, Pär, Hugosson, Jonas, Adolfsson, Jan, Walsh, Patrick C, Trent, Jeffrey M, Duggan, David, Carpten, John, Grönberg, Henrik, and Isaacs, William B

Abstract

Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.

Published
2010
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11. Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses

Author

University of Michigan ICPCG Group ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, University of Michigan ICPCG Group ; University of Michigan, Ann Arbor, Michigan, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah ; Division of Genetic Epidemiology, University of Utah School of Medicine, 391, Chipeta Way, Suite D, Salt Lake City, UT 84108., African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania, African American Hereditary Prostate Cancer ICPCG Group ; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, African American Hereditary Prostate Cancer ICPCG Group ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Translational Genomics Research Institute, Genetic Basis of Human Disease Research Division, Phoenix, Arizona, ACTANE Consortium ICPCG Group ; Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Department of Oncology, McGill University, Montreal, Quebec, Canada, ACTANE Consortium ICPCG Group ; The Norwegian Radium Hospital, Oslo, Norway, ACTANE Consortium ICPCG Group ; Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Surrey, UK, ACTANE Consortium ICPCG Group ; Cancer Research UK Genetic Epidemiology Unit, Cambridge, UK, ACTANE Consortium ICPCG Group ; Division of Medical Genetics, University of Washington Medical Center, Seattle, Washington, BC/CA/HI ICPCG Group ; Department of Health Research and Policy, Stanford School of Medicine, Stanford, California ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Department of Urology and Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, Data Coordinating Center for the ICPCG and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, FHCRC ICPCG Group ; Fred Hutchinson Cancer Research Center, Divisions of Public Health Sciences, Seattle, Washington, FHCRC ICPCG Group ; Cancer Genetics Branch, National Institutes of Health, Bethesda, Maryland, FHCRC ICPCG Group ; Institute for Systems Biology, Seattle, Washington, Johns Hopkins University ICPCG Group and Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, Mayo Clinic ICPCG Group and Mayo Clinic, Rochester, Minnesota, University of Tampere ICPCG Group, University of Tampere and Tampere University Hospital, Tampere, Finland, University of Ulm ICPCG Group ; Department of Urology, University of Ulm, Ulm, Germany, University of Ulm ICPCG Group ; Institute of Human Genetics, University of Ulm, Ulm, Germany, University of Ume?? ICPCG Group ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, University of Ume?? ICPCG Group ; Oncologic Centre, Ume?? University, Ume??, Sweden, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah, Christensen, G. Bryce, Baffoe-Bonnie, Agnes B., George, Asha, Powell, Isaac, Bailey-Wilson, Joan E., Carpten, John D., Giles, Graham G., Hopper, John L., Severi, Gianluca, English, Dallas R., Foulkes, William D., Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D., Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L., Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A., Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Thibodeau, Stephen N., McDonnell, Shannon K., Hebbring, Scott, Schaid, Daniel J., Lange, Ethan M., Cooney, Kathleen A., Tammela, Teuvo L. J., Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Gr??nberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Farnham, James M., Cannon-Albright, Lisa A., Camp, Nicola J., University of Michigan ICPCG Group ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, University of Michigan ICPCG Group ; University of Michigan, Ann Arbor, Michigan, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah ; Division of Genetic Epidemiology, University of Utah School of Medicine, 391, Chipeta Way, Suite D, Salt Lake City, UT 84108., African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania, African American Hereditary Prostate Cancer ICPCG Group ; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, African American Hereditary Prostate Cancer ICPCG Group ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Translational Genomics Research Institute, Genetic Basis of Human Disease Research Division, Phoenix, Arizona, ACTANE Consortium ICPCG Group ; Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Department of Oncology, McGill University, Montreal, Quebec, Canada, ACTANE Consortium ICPCG Group ; The Norwegian Radium Hospital, Oslo, Norway, ACTANE Consortium ICPCG Group ; Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Surrey, UK, ACTANE Consortium ICPCG Group ; Cancer Research UK Genetic Epidemiology Unit, Cambridge, UK, ACTANE Consortium ICPCG Group ; Division of Medical Genetics, University of Washington Medical Center, Seattle, Washington, BC/CA/HI ICPCG Group ; Department of Health Research and Policy, Stanford School of Medicine, Stanford, California ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Department of Urology and Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, Data Coordinating Center for the ICPCG and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, FHCRC ICPCG Group ; Fred Hutchinson Cancer Research Center, Divisions of Public Health Sciences, Seattle, Washington, FHCRC ICPCG Group ; Cancer Genetics Branch, National Institutes of Health, Bethesda, Maryland, FHCRC ICPCG Group ; Institute for Systems Biology, Seattle, Washington, Johns Hopkins University ICPCG Group and Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, Mayo Clinic ICPCG Group and Mayo Clinic, Rochester, Minnesota, University of Tampere ICPCG Group, University of Tampere and Tampere University Hospital, Tampere, Finland, University of Ulm ICPCG Group ; Department of Urology, University of Ulm, Ulm, Germany, University of Ulm ICPCG Group ; Institute of Human Genetics, University of Ulm, Ulm, Germany, University of Ume?? ICPCG Group ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, University of Ume?? ICPCG Group ; Oncologic Centre, Ume?? University, Ume??, Sweden, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah, Christensen, G. Bryce, Baffoe-Bonnie, Agnes B., George, Asha, Powell, Isaac, Bailey-Wilson, Joan E., Carpten, John D., Giles, Graham G., Hopper, John L., Severi, Gianluca, English, Dallas R., Foulkes, William D., Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D., Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L., Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A., Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Thibodeau, Stephen N., McDonnell, Shannon K., Hebbring, Scott, Schaid, Daniel J., Lange, Ethan M., Cooney, Kathleen A., Tammela, Teuvo L. J., Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Gr??nberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Farnham, James M., Cannon-Albright, Lisa A., and Camp, Nicola J.

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. ?? 2010 Wiley-Liss, Inc.

Published
2010

12. Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.

Author

Liu, Wennuan, Sun, Jishan, Li, Ge, Zhu, Yi, Zhang, Scott, Kim, Seong-Tae, Sun, Jielin, Wiklund, Fredrik, Wiley, Kathleen, Isaacs, Sarah D, Stattin, Pär, Xu, Jianfeng, Duggan, David, Carpten, John D, Isaacs, William B, Grönberg, Henrik, Zheng, S Lilly, Chang, Bao-Li, Liu, Wennuan, Sun, Jishan, Li, Ge, Zhu, Yi, Zhang, Scott, Kim, Seong-Tae, Sun, Jielin, Wiklund, Fredrik, Wiley, Kathleen, Isaacs, Sarah D, Stattin, Pär, Xu, Jianfeng, Duggan, David, Carpten, John D, Isaacs, William B, Grönberg, Henrik, Zheng, S Lilly, and Chang, Bao-Li

Abstract

We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.

Published
2009
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13. A novel prostate cancer susceptibility locus at 19q13.

Author

Hsu, Fang-Chi, Sun, Jielin, Wiklund, Fredrik, Isaacs, Sarah D, Wiley, Kathleen E, Purcell, Lina D, Gao, Zhengrong, Stattin, Pär, Zhu, Yi, Kim, Seong-Tae, Zhang, Zheng, Liu, Wennuan, Chang, Bao-Li, Walsh, Patrick C, Duggan, David, Carpten, John D, Isaacs, William B, Grönberg, Henrik, Xu, Jianfeng, Zheng, S Lilly, Hsu, Fang-Chi, Sun, Jielin, Wiklund, Fredrik, Isaacs, Sarah D, Wiley, Kathleen E, Purcell, Lina D, Gao, Zhengrong, Stattin, Pär, Zhu, Yi, Kim, Seong-Tae, Zhang, Zheng, Liu, Wennuan, Chang, Bao-Li, Walsh, Patrick C, Duggan, David, Carpten, John D, Isaacs, William B, Grönberg, Henrik, Xu, Jianfeng, and Zheng, S Lilly

Abstract

A two-stage genome-wide association study (GWAS) of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative identified single nucleotide polymorphisms (SNP) in 150 regions across the genome that may be associated with prostate cancer (PCa) risk. We filtered these results to identify 43 independent SNPs where the frequency of the risk allele was consistently higher in cases than in controls in each of the five CGEMS study populations. Genotype information for 22 of these 43 SNPs was obtained either directly by genotyping or indirectly by imputation in our PCa GWAS of 500 cases and 500 controls selected from a population-based case-control study in Sweden [Cancer of the Prostate in Sweden (CAPS)]. Two of these 22 SNPs were significantly associated with PCa risk (P<0.05). We then genotyped these two SNPs in the remaining cases (n=2,393) and controls (n=1,222) from CAPS and found that rs887391 at 19q13 was highly associated with PCa risk (P=9.4 x 10(-4)). A similar trend of association was found for this SNP in a case-control study from Johns Hopkins Hospital (JHH), albeit the result was not statistically significant. Altogether, the frequency of the risk allele of rs887391 was consistently higher in cases than controls among each of seven study populations examined, with an overall P=3.2 x 10(-7) from a combined allelic test. A fine-mapping study in a 110-kb region at 19q13 among CAPS and JHH study populations revealed that rs887391 was the most strongly associated SNP in the region. Additional confirmation studies of this region are warranted.

Published
2009
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14. Sequence variants at 22q13 are associated with prostate cancer risk.

Author

Sun, Jielin, Zheng, Siqun Lilly, Wiklund, Fredrik, Isaacs, Sarah D, Li, Ge, Wiley, Kathleen E, Kim, Seong-Tae, Zhu, Yi, Zhang, Zheng, Hsu, Fang-Chi, Turner, Aubrey R, Stattin, Pär, Liu, Wennuan, Kim, Jin Woo, Duggan, David, Carpten, John, Isaacs, William, Grönberg, Henrik, Xu, Jianfeng, Chang, Bao-Li, Sun, Jielin, Zheng, Siqun Lilly, Wiklund, Fredrik, Isaacs, Sarah D, Li, Ge, Wiley, Kathleen E, Kim, Seong-Tae, Zhu, Yi, Zhang, Zheng, Hsu, Fang-Chi, Turner, Aubrey R, Stattin, Pär, Liu, Wennuan, Kim, Jin Woo, Duggan, David, Carpten, John, Isaacs, William, Grönberg, Henrik, Xu, Jianfeng, and Chang, Bao-Li

Abstract

To search for genetic variants that are associated with prostate cancer risk in the genome, we combined the data from our genome-wide association study (GWAS) in a population-based case-control study in Sweden with publicly available GWAS data from the Cancer Genetic Markers of Susceptibility (CGEMS) study. We limited the cases to those with aggressive disease in an attempt to identify risk variants that are associated with this most clinically relevant form of the disease. Among the most likely candidate single nucleotide polymorphisms (SNP) identified from the two GWAS, we sequentially confirmed one SNP at 22q13 in two independent study populations: the remaining subjects in Cancer of the Prostate in Sweden and a hospital-based case-control study at Johns Hopkins Hospital. Association of aggressive prostate cancer with the SNP at 22q13 was also observed in the publicly available data of four additional study populations from the second stage of the CGEMS study. In all seven study populations examined, the frequency of allele "C" of rs9623117 at 22q13 was consistently higher in aggressive cases than in controls. The combined allelic test was highly significant, with P = 5.0 x 10(-7). The odds ratio (OR) of allele C for aggressive prostate cancer was estimated to be 1.18 [95% confidence interval (95% CI), 1.11-1.26]. However, the SNP was also associated with nonaggressive prostate cancer, with an estimated OR of 1.11 (95% CI, 1.04-1.19; P = 0.004). The risk-associated variants are located within the genomic region of TNRC6B, a gene involved in miRNA-mediated mRNA degradation. Additional studies are warranted to further confirm the association.

Published
2009
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15. Two independent prostate cancer risk-associated Loci at 11q13

Author

Zheng, S. Lilly, Stevens, Victoria L., Wiklund, Fredrik, Isaacs, Sarah D., Sun, Jielin, Smith, Shelly, Pruett, Kristen, Wiley, Kathleen E., Kim, Seong-Tae, Zhu, Yi, Zhang, Zheng, Hsu, Fang-Chi, Turner, Aubrey R., Johansson, Jan-Erik, Liu, Wennuan, Kim, Jin Woo, Chang, Bao-Li, Duggan, David, Carpten, John, Rodriguez, Carmen, Isaacs, William, Grönberg, Henrik, Xu, Jianfeng, Zheng, S. Lilly, Stevens, Victoria L., Wiklund, Fredrik, Isaacs, Sarah D., Sun, Jielin, Smith, Shelly, Pruett, Kristen, Wiley, Kathleen E., Kim, Seong-Tae, Zhu, Yi, Zhang, Zheng, Hsu, Fang-Chi, Turner, Aubrey R., Johansson, Jan-Erik, Liu, Wennuan, Kim, Jin Woo, Chang, Bao-Li, Duggan, David, Carpten, John, Rodriguez, Carmen, Isaacs, William, Grönberg, Henrik, and Xu, Jianfeng

Abstract

Single nucleotide polymorphisms (SNP) at 11q13 were recently implicated in prostate cancer risk by two genome-wide association studies and were consistently replicated in multiple study populations. To explore prostate cancer association in the regions flanking these SNPs, we genotyped 31 tagging SNPs in a approximately 110 kb region at 11q13 in a Swedish case-control study (Cancer of the Prostate in Sweden), including 2,899 cases and 1,722 controls. We found evidence of prostate cancer association for the previously implicated SNPs including rs10896449, which we termed locus 1. In addition, multiple SNPs on the centromeric side of the region, including rs12418451, were also significantly associated with prostate cancer risk (termed locus 2). The two groups of SNPs were separated by a recombination hotspot. We then evaluated these two representative SNPs in an additional approximately 4,000 cases and approximately 3,000 controls from three study populations and confirmed both loci at 11q13. In the combined allelic test of all four populations, P = 4.0 x 10(-11) for rs10896449 at locus 1 and P = 1.2 x 10(-6) for rs12418451 at locus 2, and both remained significant after adjusting for the other locus and study population. The prostate cancer association at these two 11q13 loci was unlikely confounded by prostate-specific antigen (PSA) detection bias because neither SNP was associated with PSA levels in controls. Unlike locus 1, in which no known gene is located, several putative mRNAs are in close proximity to locus 2. Additional confirmation studies at locus 2 and functional studies for both loci are needed to advance our knowledge on the etiology of prostate cancer.

Published
2009
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16. Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12.

Author

Sun, Jielin, Zheng, Siqun Lilly, Wiklund, Fredrik, Isaacs, Sarah D, Purcell, Lina D, Gao, Zhengrong, Hsu, Fang-Chi, Kim, Seong-Tae, Liu, Wennuan, Zhu, Yi, Stattin, Pär, Adami, Hans-Olov, Wiley, Kathleen E, Dimitrov, Latchezar, Sun, Jishan, Li, Tao, Turner, Aubrey R, Adams, Tamara S, Adolfsson, Jan, Johansson, Jan-Erik, Lowey, James, Trock, Bruce J, Partin, Alan W, Walsh, Patrick C, Trent, Jeffrey M, Duggan, David, Carpten, John, Chang, Bao-Li, Grönberg, Henrik, Isaacs, William B, Xu, Jianfeng, Sun, Jielin, Zheng, Siqun Lilly, Wiklund, Fredrik, Isaacs, Sarah D, Purcell, Lina D, Gao, Zhengrong, Hsu, Fang-Chi, Kim, Seong-Tae, Liu, Wennuan, Zhu, Yi, Stattin, Pär, Adami, Hans-Olov, Wiley, Kathleen E, Dimitrov, Latchezar, Sun, Jishan, Li, Tao, Turner, Aubrey R, Adams, Tamara S, Adolfsson, Jan, Johansson, Jan-Erik, Lowey, James, Trock, Bruce J, Partin, Alan W, Walsh, Patrick C, Trent, Jeffrey M, Duggan, David, Carpten, John, Chang, Bao-Li, Grönberg, Henrik, Isaacs, William B, and Xu, Jianfeng

Published
2008

17. Cumulative effect of five genetic variants on prostate cancer risk in multiple study populations.

Author

Sun, Jielin, Chang, Bao-Li, Isaacs, Sarah D, Wiley, Kathleen E, Wiklund, Fredrik, Stattin, Pär, Duggan, David, Carpten, John D, Trock, Bruce J, Partin, Alan W, Walsh, Patrick C, Grönberg, Henrik, Xu, Jianfeng, Isaacs, William B, Zheng, S Lilly, Sun, Jielin, Chang, Bao-Li, Isaacs, Sarah D, Wiley, Kathleen E, Wiklund, Fredrik, Stattin, Pär, Duggan, David, Carpten, John D, Trock, Bruce J, Partin, Alan W, Walsh, Patrick C, Grönberg, Henrik, Xu, Jianfeng, Isaacs, William B, and Zheng, S Lilly

Published
2008

18. Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12

Author

Sun, Jielin, Zheng, Siqun Lilly, Wiklund, Fredrik, Isaacs, Sarah D., Purcell, Lina D., Gao, Zhengrong, Hsu, Fang-Chi, Kim, Seong-Tae, Liu, Wennuan, Zhu, Yi, Stattin, Pär, Adami, Hans-Olov, Wiley, Kathleen E., Dimitrov, Latchezar, Sun, Jishan, Li, Tao, Turner, Aubrey R., Adams, Tamara S., Adolfsson, Jan, Johansson, Jan-Erik, Lowey, James, Trock, Bruce J., Partin, Alan W., Walsh, Patrick C., Trent, Jeffrey M., Duggan, David, Carpten, John, Chang, Bao-Li, Grönberg, Henrik, Isaacs, William B., Xu, Jianfeng, Sun, Jielin, Zheng, Siqun Lilly, Wiklund, Fredrik, Isaacs, Sarah D., Purcell, Lina D., Gao, Zhengrong, Hsu, Fang-Chi, Kim, Seong-Tae, Liu, Wennuan, Zhu, Yi, Stattin, Pär, Adami, Hans-Olov, Wiley, Kathleen E., Dimitrov, Latchezar, Sun, Jishan, Li, Tao, Turner, Aubrey R., Adams, Tamara S., Adolfsson, Jan, Johansson, Jan-Erik, Lowey, James, Trock, Bruce J., Partin, Alan W., Walsh, Patrick C., Trent, Jeffrey M., Duggan, David, Carpten, John, Chang, Bao-Li, Grönberg, Henrik, Isaacs, William B., and Xu, Jianfeng

Abstract

We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 10-9 for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.

Published
2008
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19. Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP.

Author

Duggan, David, Zheng, Siqun L, Knowlton, Michele, Benitez, Debbie, Dimitrov, Latchezar, Wiklund, Fredrik, Robbins, Christiane, Isaacs, Sarah D, Cheng, Yu, Li, Ge, Sun, Jielin, Chang, Bao-Li, Marovich, Leslie, Wiley, Kathleen E, Bälter, Katarina, Stattin, Pär, Adami, Hans-Olov, Gielzak, Marta, Yan, Guifang, Sauvageot, Jurga, Liu, Wennuan, Kim, Jin Woo, Bleecker, Eugene R, Meyers, Deborah A, Trock, Bruce J, Partin, Alan W, Walsh, Patrick C, Isaacs, William B, Grönberg, Henrik, Xu, Jianfeng, Carpten, John D, Duggan, David, Zheng, Siqun L, Knowlton, Michele, Benitez, Debbie, Dimitrov, Latchezar, Wiklund, Fredrik, Robbins, Christiane, Isaacs, Sarah D, Cheng, Yu, Li, Ge, Sun, Jielin, Chang, Bao-Li, Marovich, Leslie, Wiley, Kathleen E, Bälter, Katarina, Stattin, Pär, Adami, Hans-Olov, Gielzak, Marta, Yan, Guifang, Sauvageot, Jurga, Liu, Wennuan, Kim, Jin Woo, Bleecker, Eugene R, Meyers, Deborah A, Trock, Bruce J, Partin, Alan W, Walsh, Patrick C, Isaacs, William B, Grönberg, Henrik, Xu, Jianfeng, and Carpten, John D

Published
2007

20. Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics.

Author

Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, Baffoe-Bonnie, Agnes B, George, Asha, Powell, Isaac, Bailey-Wilson, Joan E, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L, Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Schaid, Daniel J, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo L J, Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Grönberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Isaacs, William B, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, Baffoe-Bonnie, Agnes B, George, Asha, Powell, Isaac, Bailey-Wilson, Joan E, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L, Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Schaid, Daniel J, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo L J, Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Grönberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, and Isaacs, William B

Published
2007
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21. Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect

Author

Chang, Bao-Li, Lange, Ethan M, Dimitrov, Latchezar, Valis, Christopher J, Gillanders, Elizabeth M, Lange, Leslie A, Wiley, Kathleen E, Isaacs, Sarah D, Wiklund, Fredrik, Baffoe-Bonnie, Agnes, Langefeld, Carl D, Zheng, S Lilly, Matikainen, Mika P, Ikonen, Tarja, Fredriksson, Henna, Tammela, Teuvo, Walsh, Patrick C, Bailey-Wilson, Joan E, Schleutker, Johanna, Grönberg, Henrik, Cooney, Kathleen A, Isaacs, William B, Suh, Edward, Trent, Jeffrey M, Xu, Jianfeng, Chang, Bao-Li, Lange, Ethan M, Dimitrov, Latchezar, Valis, Christopher J, Gillanders, Elizabeth M, Lange, Leslie A, Wiley, Kathleen E, Isaacs, Sarah D, Wiklund, Fredrik, Baffoe-Bonnie, Agnes, Langefeld, Carl D, Zheng, S Lilly, Matikainen, Mika P, Ikonen, Tarja, Fredriksson, Henna, Tammela, Teuvo, Walsh, Patrick C, Bailey-Wilson, Joan E, Schleutker, Johanna, Grönberg, Henrik, Cooney, Kathleen A, Isaacs, William B, Suh, Edward, Trent, Jeffrey M, and Xu, Jianfeng

Published
2006
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22. Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect

Author

Department of Internal Medicine and Urology, University of Michigan, Ann Arbor, MI, USA, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA, Department of Genetics, University of North Carolina, Chapel Hill, NC, USA, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA, Department of Genetics, University of North Carolina, Chapel Hill, NC, USA, ; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA, ; Translational Genomics Research Institute (TGen), Phoenix, AZ, USA, ; Medical Center Blvd, Winston-Salem, NC, 27157, USA, ; Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland, Department of Urology, University of Tampere and Tampere University Hospital, Tampere, Finland, Department of Radiation Sciences, Oncology, University of Ume??, Ume??, Sweden, Department of Urology, University of Tampere and Tampere University Hospital, Tampere, Finland, ; Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA, Ann Arbor, Isaacs, William B., Cooney, Kathleen A., Wiley, Kathleen E., Trent, Jeffrey M., Dimitrov, Latchezar, Chang, Bao-Li, Lange, Ethan M., Suh, Edward, Gillanders, Elizabeth M., Lange, Leslie A., Xu, Jianfeng, Valis, Christopher J., Baffoe-Bonnie, Agnes, Zheng, S. Lilly, Fredriksson, Henna, Matikainen, Mika P., Gronberg, Henrik, Tammela, Teuvo, Bailey-Wilson, Joan E., Walsh, Patrick C., Schleutker, Johanna, Ikonen, Tarja, Langefeld, Carl D., Isaacs, Sarah D., Wiklund, Fredrik, Department of Internal Medicine and Urology, University of Michigan, Ann Arbor, MI, USA, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA, Department of Genetics, University of North Carolina, Chapel Hill, NC, USA, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA, Department of Genetics, University of North Carolina, Chapel Hill, NC, USA, ; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA, ; Translational Genomics Research Institute (TGen), Phoenix, AZ, USA, ; Medical Center Blvd, Winston-Salem, NC, 27157, USA, ; Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland, Department of Urology, University of Tampere and Tampere University Hospital, Tampere, Finland, Department of Radiation Sciences, Oncology, University of Ume??, Ume??, Sweden, Department of Urology, University of Tampere and Tampere University Hospital, Tampere, Finland, ; Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA, Ann Arbor, Isaacs, William B., Cooney, Kathleen A., Wiley, Kathleen E., Trent, Jeffrey M., Dimitrov, Latchezar, Chang, Bao-Li, Lange, Ethan M., Suh, Edward, Gillanders, Elizabeth M., Lange, Leslie A., Xu, Jianfeng, Valis, Christopher J., Baffoe-Bonnie, Agnes, Zheng, S. Lilly, Fredriksson, Henna, Matikainen, Mika P., Gronberg, Henrik, Tammela, Teuvo, Bailey-Wilson, Joan E., Walsh, Patrick C., Schleutker, Johanna, Ikonen, Tarja, Langefeld, Carl D., Isaacs, Sarah D., and Wiklund, Fredrik

Abstract

Prostate cancer represents a significant worldwide public health burden. Epidemiological and genetic epidemiological studies have consistently provided data supporting the existence of inherited prostate cancer susceptibility genes. Segregation analyses of prostate cancer suggest that a multigene model may best explain familial clustering of this disease. Therefore, modeling gene???gene interactions in linkage analysis may improve the power to detect chromosomal regions harboring these disease susceptibility genes. In this study, we systematically screened for prostate cancer linkage by modeling two-locus gene???gene interactions for all possible pairs of loci across the genome in 426 prostate cancer families from Johns Hopkins Hospital, University of Michigan, University of Ume??, and University of Tampere. We found suggestive evidence for an epistatic interaction for six sets of loci (target chromosome-wide/reference marker-specific P???0.0001). Evidence for these interactions was found in two independent subsets from within the 426 families. While the validity of these results requires confirmation from independent studies and the identification of the specific genes underlying this linkage evidence, our approach of systematically assessing gene???gene interactions across the entire genome represents a promising alternative approach for gene identification for prostate cancer.

Published
2006

23. A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics

Author

Xu, Jianfeng, Dimitrov, Latchezar, Chang, Bao-Li, Adams, Tamara S, Turner, Aubrey R, Meyers, Deborah A, Eeles, Rosalind A, Easton, Douglas F, Foulkes, William D, Simard, Jacques, Giles, Graham G, Hopper, John L, Mahle, Lovise, Moller, Pal, Bishop, Tim, Evans, Chris, Edwards, Steve, Meitz, Julia, Bullock, Sarah, Hope, Questa, Hsieh, Chih-Lin, Halpern, Jerry, Balise, Raymond N, Oakley-Girvan, Ingrid, Whittemore, Alice S, Ewing, Charles M, Gielzak, Marta, Isaacs, Sarah D, Walsh, Patrick C, Wiley, Kathleen E, Isaacs, William B, Thibodeau, Stephen N, McDonnell, Shannon K, Cunningham, Julie M, Zarfas, Katherine E, Hebbring, Scott, Schaid, Daniel J, Friedrichsen, Danielle M, Deutsch, Kerry, Kolb, Suzanne, Badzioch, Michael, Jarvik, Gail P, Janer, Marta, Hood, Leroy, Ostrander, Elaine A, Stanford, Janet L, Lange, Ethan M, Beebe-Dimmer, Jennifer L, Mohai, Caroline E, Cooney, Kathleen A, Ikonen, Tarja, Baffoe-Bonnie, Agnes, Fredriksson, Henna, Matikainen, Mika P, Tammela, Teuvo Lj, Bailey-Wilson, Joan, Schleutker, Johanna, Maier, Christiane, Herkommer, Kathleen, Hoegel, Josef J, Vogel, Walther, Paiss, Thomas, Wiklund, Fredrik, Emanuelsson, Monica, Stenman, Elisabeth, Jonsson, Björn-Anders, Grönberg, Henrik, Camp, Nicola J, Farnham, James, Cannon-Albright, Lisa A, Seminara, Daniela, Xu, Jianfeng, Dimitrov, Latchezar, Chang, Bao-Li, Adams, Tamara S, Turner, Aubrey R, Meyers, Deborah A, Eeles, Rosalind A, Easton, Douglas F, Foulkes, William D, Simard, Jacques, Giles, Graham G, Hopper, John L, Mahle, Lovise, Moller, Pal, Bishop, Tim, Evans, Chris, Edwards, Steve, Meitz, Julia, Bullock, Sarah, Hope, Questa, Hsieh, Chih-Lin, Halpern, Jerry, Balise, Raymond N, Oakley-Girvan, Ingrid, Whittemore, Alice S, Ewing, Charles M, Gielzak, Marta, Isaacs, Sarah D, Walsh, Patrick C, Wiley, Kathleen E, Isaacs, William B, Thibodeau, Stephen N, McDonnell, Shannon K, Cunningham, Julie M, Zarfas, Katherine E, Hebbring, Scott, Schaid, Daniel J, Friedrichsen, Danielle M, Deutsch, Kerry, Kolb, Suzanne, Badzioch, Michael, Jarvik, Gail P, Janer, Marta, Hood, Leroy, Ostrander, Elaine A, Stanford, Janet L, Lange, Ethan M, Beebe-Dimmer, Jennifer L, Mohai, Caroline E, Cooney, Kathleen A, Ikonen, Tarja, Baffoe-Bonnie, Agnes, Fredriksson, Henna, Matikainen, Mika P, Tammela, Teuvo Lj, Bailey-Wilson, Joan, Schleutker, Johanna, Maier, Christiane, Herkommer, Kathleen, Hoegel, Josef J, Vogel, Walther, Paiss, Thomas, Wiklund, Fredrik, Emanuelsson, Monica, Stenman, Elisabeth, Jonsson, Björn-Anders, Grönberg, Henrik, Camp, Nicola J, Farnham, James, Cannon-Albright, Lisa A, and Seminara, Daniela

Published
2005

24. Combined genome-wide scan for prostate cancer susceptibility genes

Author

Gillanders, Elizabeth M, Xu, Jianfeng, Chang, Bao-li, Lange, Ethan M, Wiklund, Fredrik, Bailey-Wilson, Joan E, Baffoe-Bonnie, Agnes, Jones, MaryPat, Gildea, Derek, Riedesel, Erica, Albertus, Julie, Isaacs, Sarah D, Wiley, Kathleen E, Mohai, Caroline E, Matikainen, Mika P, Tammela, Teuvo L J, Zheng, S Lilly, Brown, W Mark, Rökman, Annika, Carpten, John D, Meyers, Deborah A, Walsh, Patrick C, Schleutker, Johanna, Grönberg, Henrik, Cooney, Kathleen A, Isaacs, William B, Trent, Jeffrey M, Gillanders, Elizabeth M, Xu, Jianfeng, Chang, Bao-li, Lange, Ethan M, Wiklund, Fredrik, Bailey-Wilson, Joan E, Baffoe-Bonnie, Agnes, Jones, MaryPat, Gildea, Derek, Riedesel, Erica, Albertus, Julie, Isaacs, Sarah D, Wiley, Kathleen E, Mohai, Caroline E, Matikainen, Mika P, Tammela, Teuvo L J, Zheng, S Lilly, Brown, W Mark, Rökman, Annika, Carpten, John D, Meyers, Deborah A, Walsh, Patrick C, Schleutker, Johanna, Grönberg, Henrik, Cooney, Kathleen A, Isaacs, William B, and Trent, Jeffrey M

Published
2004
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