Search

Your search keyword '"PRACTICAL consortium"' showing total 33 results
Start Over Descriptor "PRACTICAL consortium"
33 results on '"PRACTICAL consortium"'

1. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author

Huynh-Le, Minh-Phuong, Karunamuni, Roshan, Fan, Chun Chieh, Asona, Lui, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth R, Lophatananon, Artitaya, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Blot, William J, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Wiklund, Fredrik, Penney, Kathryn L, Huff, Chad D, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Ost, Piet, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Abraham, Aswin, Claessens, Frank, Castelao, Jose Esteban, Townsend, Paul A, Crawford, Dana C, Petrovics, Gyorgy, van Schaik, Ron HN, Parent, Marie-Élise, Hu, Jennifer J, Zheng, Wei, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Prostate Cancer, Cancer, Urologic Diseases, Prevention, Genetics, Good Health and Well Being, Male, Humans, Prostate-Specific Antigen, Prostatic Neoplasms, Early Detection of Cancer, Polymorphism, Single Nucleotide, Risk Factors, Risk Assessment, Genetic Predisposition to Disease, UKGPCS collaborators, APCB, NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Urology & Nephrology, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionsWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2022

2. A saturated map of common genetic variants associated with human height

Author

Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U, Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D, Graham, Sarah E, Mukamel, Ronen E, Spracklen, Cassandra N, Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H, Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E, Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S, Akiyama, Masato, Allison, Matthew A, Alvarez, Marcus, Andersen, Mette K, Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F, Bollepalli, Sailalitha, Bonnycastle, Lori L, Bork-Jensen, Jette, Bradfield, Jonathan P, Bradford, Yuki, Braund, Peter S, Brody, Jennifer A, Burgdorf, Kristoffer S, Cade, Brian E, Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E Warwick, Degenhard, Frauke, Delgado, Graciela E, Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B, Engmann, Jorgen E, Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D, Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E, Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P, Goel, Anuj, Gordon, Scott D, Gorski, Mathias, Grove, Jakob, and Guo, Xiuqing

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Humans, Body Height, Gene Frequency, Genome, Human, Genome-Wide Association Study, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Europe, Sample Size, Phenotype, Chromosome Mapping, 23andMe Research Team, VA Million Veteran Program, DiscovEHR, eMERGE, Lifelines Cohort Study, PRACTICAL Consortium, Understanding Society Scientific Group, General Science & Technology
Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022

3. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Lui, Asona, Martinez, Maria Elena, Rose, Brent S, Mahal, Brandon, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Lophatananon, Artitaya, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Blot, William J, Zheng, Wei, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Park, Jong Y, Lin, Hui-Yi, Taylor, Jack A, Bensen, Jeannette T, Mohler, James L, Fontham, Elizabeth TH, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Romana, Marc, Leach, Robin J, John, Esther M, Fowke, Jay H, Bush, William S, Aldrich, Melinda C, Crawford, Dana C, Cullen, Jennifer, Petrovics, Gyorgy, Parent, Marie-Élise, Hu, Jennifer J, Sanderson, Maureen, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Prevention, Genetics, Cancer, Urologic Diseases, Black People, Case-Control Studies, Chromosomes, Human, Pair 8, Genetic Predisposition to Disease, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Assessment, White People, UKGPCS Collaborators, PRACTICAL Consortium, Urology & Nephrology, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Published
2022

4. Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men

Author

Huynh-Le, Minh-Phuong, Karunamuni, Roshan, Fan, Chun Chieh, Thompson, Wesley K, Muir, Kenneth, Lophatananon, Artitaya, Tye, Karen, Wolk, Alicja, Håkansson, Niclas, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Urologic Diseases, Cancer, Prevention, Aging, Clinical Research, Prostate Cancer, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Aged, Aged, 80 and over, Biomarkers, Tumor, Case-Control Studies, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Male, Prognosis, Prostatic Neoplasms, Survival Rate, Sweden, PRACTICAL Consortium, Urology & Nephrology, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundClinical variables-age, family history, genetics-are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death.MethodsGenotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n = 3279; 2163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests.ResultsMedian age at last follow-up/prostate cancer death was 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p

Published
2021

5. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Lui, Asona, Martinez, Maria Elena, Rose, Brent S, Mahal, Brandon, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Lophatananon, Artitaya, UKGPCS Collaborators, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Blot, William J, Zheng, Wei, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Park, Jong Y, Lin, Hui-Yi, Taylor, Jack A, Bensen, Jeannette T, Mohler, James L, Fontham, Elizabeth TH, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Romana, Marc, Leach, Robin J, John, Esther M, Fowke, Jay H, Bush, William S, Aldrich, Melinda C, Crawford, Dana C, Cullen, Jennifer, Petrovics, Gyorgy, Parent, Marie-Élise, Hu, Jennifer J, Sanderson, Maureen, PRACTICAL Consortium, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
UKGPCS Collaborators, PRACTICAL Consortium, Urologic Diseases, Prevention, Genetics, Prostate Cancer, Cancer, Urology & Nephrology, Oncology and Carcinogenesis
Abstract

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Published
2021

6. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Lophatananon, Artitaya, UKGPCS collaborators, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, APCB BioResource (Australian Prostate Cancer BioResource), Grönberg, Henrik, Walsh, Eleanor I, Turner, Emma L, Lane, Athene, Martin, Richard M, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Wiklund, Fredrik, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Vega, Ana, IMPACT Study Steering Committee and Collaborators, Kogevinas, Manolis, Penney, Kathryn L, Teixeira, Manuel R, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, Razack, Azad, Newcomb, Lisa F, Canary PASS Investigators, Gamulin, Marija, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Townsend, Paul A, Roobol, Monique J, Zheng, Wei, Profile Study Steering Committee, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and PRACTICAL Consortium

Subjects
UKGPCS collaborators, APCB BioResource, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Prevention, Urologic Diseases, Cancer, Prostate Cancer, Aging, Urology & Nephrology, Oncology and Carcinogenesis
Abstract

BackgroundPolygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).Materials and method180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.Results166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.ConclusionsIncorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Published
2021

7. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Author

Huynh-Le, Minh-Phuong, Fan, Chun Chieh, Karunamuni, Roshan, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nielsen, Sune F, Nordestgaard, Børge G, Wiklund, Fredrik, Tangen, Catherine M, Giles, Graham G, Wolk, Alicja, Albanes, Demetrius, Travis, Ruth C, Blot, William J, Zheng, Wei, Sanderson, Maureen, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Khaw, Kay-Tee, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Thibodeau, Stephen N, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L, Huff, Chad, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Cannon-Albright, Lisa, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Pandha, Hardev, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Townsend, Paul A, Bush, William S, Roobol, Monique J, Parent, Marie-Élise, Hu, Jennifer J, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, UKGPCS collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, and PRACTICAL Consortium

Subjects
UKGPCS collaborators, APCB, NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Humans, Prostatic Neoplasms, Neoplasm Invasiveness, Multivariate Analysis, Multifactorial Inheritance, Aged, Middle Aged, Ethnic Groups, Male, Self Report, Aging, Urologic Diseases, Cancer, Prostate Cancer
Abstract

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p

Published
2021

8. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, UKGPCS Collaborators, Lophatananon, Artitaya, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Blot, William J, Zheng, Wei, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Park, Jong Y, Lin, Hui-Yi, Bensen, Jeannette T, Fontham, Elizabeth TH, Mohler, James L, Taylor, Jack A, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Romana, Marc, Leach, Robin J, John, Esther M, Fowke, Jay, Bush, William S, Aldrich, Melinda, Crawford, Dana C, Srivastava, Shiv, Cullen, Jennifer C, Petrovics, Gyorgy, Parent, Marie-Élise, Hu, Jennifer J, Sanderson, Maureen, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and PRACTICAL Consortium

Subjects
UKGPCS Collaborators, PRACTICAL Consortium, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Proportional Hazards Models, Case-Control Studies, Age Factors, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Models, Genetic, Middle Aged, African Continental Ancestry Group, Male, Genotyping Techniques, African, genome wide association study, genomics, genotypic ancestry, health disparities, polygenic risk, prostate cancer, Aging, Genetics, Urologic Diseases, Cancer, Prostate Cancer, Prevention, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

Published
2021

9. The effect of sample size on polygenic hazard models for prostate cancer

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, ZSofia, Amin Al Olama, Ali, Benlloch Garcia, Sara, Muir, Kenneth, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo LJ, Nordestgaard, Børge G, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Schöttker, Ben, Holleczek, Bernd, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Cancer, Aging, Urologic Diseases, Clinical Trials as Topic, Genome-Wide Association Study, Humans, Male, Models, Genetic, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prostatic Neoplasms, Sample Size, Australian Prostate Cancer BioResource, PRACTICAL Consortium, Genetics, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

Published
2020

10. A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data

Author

Huynh-Le, Minh-Phuong, Fan, Chun Chieh, Karunamuni, Roshan, Walsh, Eleanor I, Turner, Emma L, Lane, J Athene, Martin, Richard M, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Parsons, J Kellogg, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Garcia, Sara Benlloch, Muir, Kenneth, Grönberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo LJ, Nordestgaard, Børge Grønne, Key, Timothy J, Travis, Ruth C, Pharoah, Paul DP, Pashayan, Nora, Khaw, Kay-Tee, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa A, Brenner, Hermann, Schöttker, Ben, Holleczek, Bernd, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar Kroumov, Kaneva, Radka P, Mitev, Vanio I, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda B, BioResource, for the Australian Prostate Cancer, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and Consortium, for the PRACTICAL

Subjects
Biomedical and Clinical Sciences, Health Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Prostate Cancer, Cancer, Prevention, Urologic Diseases, Good Health and Well Being, Aged, Early Detection of Cancer, Humans, Male, Middle Aged, Neoplasm Grading, Population Control, Prostatic Neoplasms, Australian Prostate Cancer BioResource, PRACTICAL Consortium, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundA polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.ResultsThe expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.ImpactPersonalized genetic risk assessments could inform prostate cancer screening decisions.

Published
2020

11. Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Author

Matejcic, Marco, Saunders, Edward J, Dadaev, Tokhir, Brook, Mark N, Wang, Kan, Sheng, Xin, Olama, Ali Amin Al, Schumacher, Fredrick R, Ingles, Sue A, Govindasami, Koveela, Benlloch, Sara, Berndt, Sonja I, Albanes, Demetrius, Koutros, Stella, Muir, Kenneth, Stevens, Victoria L, Gapstur, Susan M, Tangen, Catherine M, Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Kraft, Peter, Cancel-Tassin, Géraldine, Sorensen, Karina D, Maehle, Lovise, Grindedal, Eli M, Strom, Sara S, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Travis, Ruth C, Hamilton, Robert J, Rosenstein, Barry, Lu, Yong-Jie, Giles, Graham G, Kibel, Adam S, Vega, Ana, Bensen, Jeanette T, Kogevinas, Manolis, Penney, Kathryn L, Park, Jong Y, Stanford, Janet L, Cybulski, Cezary, Nordestgaard, Børge G, Brenner, Hermann, Maier, Christiane, Kim, Jeri, Teixeira, Manuel R, Neuhausen, Susan L, De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F, Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A, Gago-Dominguez, Manuela, Roobol, Monique J, Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa A, Pandha, Hardev, Thibodeau, Stephen N, Schaid, Daniel J, PRACTICAL Consortium, Wiklund, Fredrik, Chanock, Stephen J, Easton, Douglas F, Eeles, Rosalind A, Kote-Jarai, Zsofia, Conti, David V, and Haiman, Christopher A

Subjects
PRACTICAL Consortium
Abstract

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

12. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Author

Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brüning, Thomas, Buring, Julie E, Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J, Cousminer, Diana L, Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eriksson, Johan G, Fasching, Peter A, Fernández-Rhodes, Lindsay, Ferrucci, Luigi, Flesch-Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Guénel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B, Hartman, Catharina A, Heiss, Gerardo, Hooning, Maartje J, Hopper, John L, Hu, Frank, Hunter, David J, Ikram, M Arfan, Im, Hae Kyung, Järvelin, Marjo-Riitta, Joshi, Peter K, Karasik, David, and Kellis, Manolis

Subjects
LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Humans, Neoplasms, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Ribonucleoproteins, Membrane Proteins, Body Mass Index, Risk Factors, Age Factors, Genomic Imprinting, Puberty, Menarche, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Databases, Genetic, Adolescent, Female, Male, Genome-Wide Association Study, Aging, Breast Cancer, Biotechnology, Cancer, Human Genome, Genetics, Prostate Cancer, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017

13. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Kar, Siddhartha P, Beesley, Jonathan, Olama, Ali Amin Al, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, Investigators, ABCTB, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, Study, AOCS Study Group amp Australian Cancer, BioResource, APCB, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, and Hopper, John L

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Aging, Urologic Diseases, Prostate Cancer, Ovarian Cancer, Rare Diseases, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Datasets as Topic, Enhancer Elements, Genetic, Female, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Organ Specificity, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Signal Transduction, ABCTB Investigators, AOCS Study Group & Australian Cancer Study, APCB BioResource, kConFab Investigators, NBCS Investigators, GENICA Network, PRACTICAL consortium, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledBreast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.SignificanceWe demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Published
2016

14. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Author

Gusev, Alexander, Shi, Huwenbo, Kichaev, Gleb, Pomerantz, Mark, Li, Fugen, Long, Henry W, Ingles, Sue A, Kittles, Rick A, Strom, Sara S, Rybicki, Benjamin A, Nemesure, Barbara, Isaacs, William B, Zheng, Wei, Pettaway, Curtis A, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P, John, Esther M, Murphy, Adam B, Signorello, Lisa B, Carpten, John, Leske, M Cristina, Wu, Suh-Yuh, Hennis, Anslem JM, Neslund-Dudas, Christine, Hsing, Ann W, Chu, Lisa, Goodman, Phyllis J, Klein, Eric A, Witte, John S, Casey, Graham, Kaggwa, Sam, Cook, Michael B, Stram, Daniel O, Blot, William J, Eeles, Rosalind A, Easton, Douglas, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G, Southey, Melissa C, Fitzgerald, Liesel M, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E, Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo LJ, Nordestgaard, Børge G, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Stanford, Janet L, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Teerlink, Craig, Brenner, Hermann, Dieffenbach, Aida K, Arndt, Volker, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Spurdle, Amanda, Clements, Judith A, Teixeira, Manuel R, Pandha, Hardev, Michael, Agnieszka, Paulo, Paula, Maia, Sofia, Kierzek, Andrzej, PRACTICAL consortium, Conti, David V, and Albanes, Demetrius

Subjects
PRACTICAL consortium, Cell Line, Tumor, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Histones, Epigenesis, Genetic, Acetylation, Inheritance Patterns, Linkage Disequilibrium, Polymorphism, Single Nucleotide, African Americans, European Continental Ancestry Group, Male, Atlases as Topic, Genome-Wide Association Study, Genetic Loci, Cell Line, Tumor, Epigenesis, Genetic, Polymorphism, Single Nucleotide
Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Published
2016

15. The contribution of rare variation to prostate cancer heritability

Author

Mancuso, Nicholas, Rohland, Nadin, Rand, Kristin A, Tandon, Arti, Allen, Alexander, Quinque, Dominique, Mallick, Swapan, Li, Heng, Stram, Alex, Sheng, Xin, Kote-Jarai, Zsofia, Easton, Douglas F, Eeles, Rosalind A, Le Marchand, Loic, Lubwama, Alex, Stram, Daniel, Watya, Stephen, Conti, David V, Henderson, Brian, Haiman, Christopher A, Pasaniuc, Bogdan, and Reich, David

Subjects
Biological Sciences, Genetics, Prevention, Urologic Diseases, Cancer, Aging, Prostate Cancer, 2.1 Biological and endogenous factors, Aetiology, Aged, Asian People, Black People, Case-Control Studies, Cohort Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Uganda, PRACTICAL consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We report targeted sequencing of 63 known prostate cancer risk regions in a multi-ancestry study of 9,237 men and use the data to explore the contribution of low-frequency variation to disease risk. We show that SNPs with minor allele frequencies (MAFs) of 0.1-1% explain a substantial fraction of prostate cancer risk in men of African ancestry. We estimate that these SNPs account for 0.12 (standard error (s.e.) = 0.05) of variance in risk (∼42% of the variance contributed by SNPs with MAF of 0.1-50%). This contribution is much larger than the fraction of neutral variation due to SNPs in this class, implying that natural selection has driven down the frequency of many prostate cancer risk alleles; we estimate the coupling between selection and allelic effects at 0.48 (95% confidence interval [0.19, 0.78]) under the Eyre-Walker model. Our results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits.

Published
2016

16. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Author

Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, McArdle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Goncalo, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, Caterina, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen-Dale, Anne-Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García-Closas, Montserrat, Giles, Graham G, Girotto, Giorgia G, Goldberg, Mark S, González-Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, and Hamann, Ute

Subjects
PRACTICAL consortium, kConFab Investigators, AOCS Investigators, Generation Scotland, EPIC-InterAct Consortium, LifeLines Cohort Study, Hypothalamus, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, Genomics, Age Factors, Signal Transduction, DNA Repair, Aging, Reproduction, Menopause, Genotype, Phenotype, Models, Genetic, Adult, Middle Aged, Female, Gene Regulatory Networks, Genetic Variation, Genome-Wide Association Study, Models, Genetic, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Published
2015

17. Generalizability of established prostate cancer risk variants in men of African ancestry

Author

Han, Ying, Signorello, Lisa B, Strom, Sara S, Kittles, Rick A, Rybicki, Benjamin A, Stanford, Janet L, Goodman, Phyllis J, Berndt, Sonja I, Carpten, John, Casey, Graham, Chu, Lisa, Conti, David V, Rand, Kristin A, Diver, W Ryan, Hennis, Anselm JM, John, Esther M, Kibel, Adam S, Klein, Eric A, Kolb, Suzanne, Le Marchand, Loic, Leske, M Cristina, Murphy, Adam B, Neslund‐Dudas, Christine, Park, Jong Y, Pettaway, Curtis, Rebbeck, Timothy R, Gapstur, Susan M, Zheng, S Lilly, Wu, Suh‐Yuh, Witte, John S, Xu, Jianfeng, Isaacs, William, Ingles, Sue A, Hsing, Ann, Consortium, The PRACTICAL, Consortium, The ELLIPSE GAME‐ON, Easton, Douglas F, Eeles, Rosalind A, Schumacher, Fredrick R, Chanock, Stephen, Nemesure, Barbara, Blot, William J, Stram, Daniel O, Henderson, Brian E, and Haiman, Christopher A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Prostate Cancer, Aging, Prevention, Genetics, Human Genome, Clinical Research, Urologic Diseases, Aetiology, 2.1 Biological and endogenous factors, Black People, Case-Control Studies, Cohort Studies, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Prognosis, Prostatic Neoplasms, Risk Factors, prostate cancer, genetic risk variant, generalizability, African ancestry, PRACTICAL Consortium, ELLIPSE GAME-ON Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Published
2015

18. Shared common variants in prostate cancer and blood lipids

Author

Andreassen, Ole A, Zuber, Verena, Thompson, Wesley K, Schork, Andrew J, Bettella, Francesco, Djurovic, Srdjan, Desikan, Rahul S, Mills, Ian G, and Dale, Anders M

Subjects
Epidemiology, Statistics, Health Sciences, Mathematical Sciences, Human Genome, Cancer, Aging, Prevention, Genetics, Urologic Diseases, Prostate Cancer, Heart Disease, Cardiovascular, Atherosclerosis, 2.1 Biological and endogenous factors, Aetiology, Blood Pressure, Body Mass Index, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Comorbidity, Diabetes Mellitus, Type 2, Dyslipidemias, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Molecular Epidemiology, Obesity, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Factors, Triglycerides, Waist-Hip Ratio, Prostate cancer, blood lipids, cholesterol, type 2 diabetes, genetic epidemiology, pleiotropy, PRACTICAL Consortium, CRUK GWAS, Public Health and Health Services, Public health
Abstract

BackgroundEpidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.MethodsWe applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.ResultsWe found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR

Published
2014

19. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author

Shen, Hui, Fridley, Brooke L, Song, Honglin, Lawrenson, Kate, Cunningham, Julie M, Ramus, Susan J, Cicek, Mine S, Tyrer, Jonathan, Stram, Douglas, Larson, Melissa C, Köbel, Martin, Ziogas, Argyrios, Zheng, Wei, Yang, Hannah P, Wu, Anna H, Wozniak, Eva L, Ling Woo, Yin, Winterhoff, Boris, Wik, Elisabeth, Whittemore, Alice S, Wentzensen, Nicolas, Palmieri Weber, Rachel, Vitonis, Allison F, Vincent, Daniel, Vierkant, Robert A, Vergote, Ignace, Van Den Berg, David, Van Altena, Anne M, Tworoger, Shelley S, Thompson, Pamela J, Tessier, Daniel C, Terry, Kathryn L, Teo, Soo-Hwang, Templeman, Claire, Stram, Daniel O, Southey, Melissa C, Sieh, Weiva, Siddiqui, Nadeem, Shvetsov, Yurii B, Shu, Xiao-Ou, Shridhar, Viji, Wang-Gohrke, Shan, Severi, Gianluca, Schwaab, Ira, Salvesen, Helga B, Rzepecka, Iwona K, Runnebaum, Ingo B, Anne Rossing, Mary, Rodriguez-Rodriguez, Lorna, Risch, Harvey A, Renner, Stefan P, Poole, Elizabeth M, Pike, Malcolm C, Phelan, Catherine M, Pelttari, Liisa M, Pejovic, Tanja, Paul, James, Orlow, Irene, Zawiah Omar, Siti, Olson, Sara H, Odunsi, Kunle, Nickels, Stefan, Nevanlinna, Heli, Ness, Roberta B, Narod, Steven A, Nakanishi, Toru, Moysich, Kirsten B, Monteiro, Alvaro NA, Moes-Sosnowska, Joanna, Modugno, Francesmary, Menon, Usha, McLaughlin, John R, McGuire, Valerie, Matsuo, Keitaro, Mat Adenan, Noor Azmi, Massuger, Leon FAG, Lurie, Galina, Lundvall, Lene, Lubiński, Jan, Lissowska, Jolanta, Levine, Douglas A, Leminen, Arto, Lee, Alice W, Le, Nhu D, Lambrechts, Sandrina, Lambrechts, Diether, Kupryjanczyk, Jolanta, Krakstad, Camilla, Konecny, Gottfried E, Krüger Kjaer, Susanne, Kiemeney, Lambertus A, Kelemen, Linda E, Keeney, Gary L, Karlan, Beth Y, Karevan, Rod, Kalli, Kimberly R, Kajiyama, Hiroaki, Ji, Bu-Tian, Jensen, Allan, and Jakubowska, Anna

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, Prevention, Aetiology, 2.1 Biological and endogenous factors, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-beta, Humans, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, PRACTICAL Consortium, Australian Ovarian Cancer Study Group, Australian Cancer Study
Abstract

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Published
2013

20. Assessing the causal role of epigenetic clocks in the development of multiple cancers:a Mendelian randomization study

Author

Morales Berstein, F, McCartney, DL, Lu, AT, Tsilidis, KK, Bouras, E, Haycock, P, Burrows, K, Phipps, AI, Buchanan, DD, Cheng, I, PRACTICAL consortium, Martin, RM, Davey Smith, G, Relton, CL, Horvath, S, Marioni, RE, Richardson, TG, Richmond, RC, and Urology

Subjects
epigenetic age acceleration, Male, medicine, epigenetic clocks, 0601 Biochemistry and Cell Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, PRACTICAL consortium, Epigenesis, Genetic, SDG 3 - Good Health and Well-being, Mendelian randomization, genomics, cancer, Humans, genetics, human, Colorectal Neoplasms/epidemiology, DNA methylation, General Immunology and Microbiology, General Neuroscience, General Medicine, Mendelian Randomization Analysis, Genome-Wide Association Study/methods, epidemiology, ICEP, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers.GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, EntrepreneurshipInnovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.Have you noticed that some people seem to get older faster than others? Scientists have previously found that a chemical tag on DNA known as DNA methylation can be used to predict an individual’s chronological age. However, age predicted using DNA methylation (also known as biological or epigenetic age) does not always perfectly correspond to chronological age. Indeed, some people’s biological age is higher than their years, while other people’s is lower. When an individual’s biological age is higher than their chronological age, they are said to be experiencing ‘epigenetic age acceleration’. This type of accelerated ageing, which can be measured with ‘epigenetic clocks’ based on DNA methylation, has been associated with several adverse health outcomes, including cancer. This means that epigenetic clocks may improve our ability to predict cancer risk and detect cancer early. However, it is still unclear whether accelerated biological ageing causes cancer, or whether it simply correlates with the disease. Morales-Berstein et al. wanted to investigate whether epigenetic age acceleration, as measured by epigenetic clocks, plays a role in the development of several cancers. To do so, they used an approach known as Mendelian randomization. Using genetic variants as natural experiments, they studied the effect of different measures of epigenetic age acceleration on cancer risk. Their work focused on five types of cancer: breast, colorectal, prostate, ovarian and lung cancer. They used genetic association data from people of European ancestry to determine whether genetic variants that are strongly associated with accelerated ageing are also strongly associated with cancer. The results showed that one of the DNA methylation markers used as an estimate of biological ageing could be directly related to the risk of developing colorectal cancer. This work provides new insights into the relationship between markers of biological ageing and cancer. Similar relationships should also be studied in other groups of people and for other cancer sites. The results suggest that reversing biological ageing by altering DNA methylation could prevent or delay the development of colorectal cancer.

Published
2022

21. Circulating inflammatory cytokines and risk of five cancers: a mendelian randomization analysis

Author

Tsilidis, K

Subjects
Inflammation, General & Internal Medicine, Cytokines, Mendelian randomisation, PRACTICAL consortium, 11 Medical and Health Sciences, Cancer
Abstract

Background: Epidemiological and experimental evidence has linked chronic inflammation to cancer etiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically-predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomization (MR) analysis. Methods: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian and prostate) and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12 906 for endometrial to 133 384 for breast cancer). Results: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95%CI: 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85); and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer etiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Published
2021

22. Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men

Author

Minh-Phuong Huynh-Le, Roshan Karunamuni, Chun Chieh Fan, Wesley K Thompson, Kenneth Muir, Artitaya Lophatananon, Karen Tye, Alicja Wolk, Hakansson Niclas, Ian G. Mills, Ole A Andreassen, Anders M Dale, Tyler M Seibert, and The PRACTICAL Consortium

Subjects
Male, Urologic Diseases, Cancer Research, medicine.medical_specialty, Aging, Clinical variables, Oncology and Carcinogenesis, Prostate cancer, Clinical Research, Internal medicine, 80 and over, Medicine, PRACTICAL Consortium, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Longitudinal Studies, Family history, Aetiology, Aged, Cancer, Prostate cancer risk, Sweden, Tumor, business.industry, Prostate Cancer, Prevention, Prostatic Neoplasms, Urology & Nephrology, medicine.disease, Prognosis, Survival Rate, Good Health and Well Being, Oncology, Case-Control Studies, Cohort, business, Clinical risk factor, Biomarkers, Follow-Up Studies
Abstract

65 Background: Clinical variables (age, family history, and genetics) are commonly used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores, including PHS, are associated with all prostate cancer and are not specific for fatal cancers, PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to available clinical variables improves associations with prostate cancer death. Methods: Genotype and phenotype data were obtained from a nested case-control subset (n=3,279; 2,163 were diagnosed with prostate cancer, 278 died of prostate cancer) of the longitudinal, population-based Cohort of Swedish Men. PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes history, and body mass index) were independently tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models were constructed with clinical variables and PHS. Log-likelihood tests compared models. Results: Median age at last follow-up and at prostate cancer death were 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol intake (HR 1.74 [1.40-2.15]), and diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. A multivariable clinical model including PHS46 improved associations for fatal disease ( p−15). On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol intake (HR 1.45 [1.19-1.76]), and diabetes (HR 0.62 [0.42-0.90]) all remained associated with prostate cancer death. Similar results were found using the newer PHS166. Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common clinical risk factors, including family history. Adding PHS to clinical variables may improve individualized prostate cancer risk stratification strategies.

Published
2021

23. An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Author

Wu, Lang, Yang, Yaohua, Guo, Xingyi, Shu, Xiao Ou, Cai, Qiuyin, Shu, Xiang, Li, Bingshan, Tao, Ran, Wu, Chong, Nikas, Jason B., Sun, Yanfa, Zhu, Jingjing, Roobol, Monique J., Giles, Graham G., Brenner, Hermann, John, Esther M., Clements, Judith, Grindedal, Eli Marie, Park, Jong Y., Stanford, Janet L., Kote-Jarai, Zsofia, Haiman, Christopher A., Eeles, Rosalind A., Zheng, Wei, Long, Jirong, Henderson, Brian E., Schumacher, Fredrick R., Easton, Douglas, Benlloch, Sara, Olama, Ali Amin Al, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Gapstur, Susan M., Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Nordestgaard, Børge G., Li, Bingshan [0000-0003-2129-168X], Wu, Chong [0000-0002-8400-1785], Nikas, Jason B [0000-0001-9703-0422], Roobol, Monique J [0000-0001-6967-1708], Giles, Graham G [0000-0003-4946-9099], Park, Jong Y [0000-0002-6384-6447], Eeles, Rosalind A [0000-0002-3698-6241], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Hunter, DJ, consortium, PRACTICAL, Consortium, CRUK, Consortium, BPC3, Consortium, CAPS, Consortium, PEGASUS, and Urology

Subjects
0301 basic medicine, Male, General Physics and Astronomy, 02 engineering and technology, VARIANTS, urologic and male genital diseases, DISEASE, CRUK Consortium, Prostate cancer, BPC3 Consortium, Risk Factors, Epidemiology of cancer, GWAS, lcsh:Science, Cancer genetics, GENE-EXPRESSION, Genetics, Multidisciplinary, Methylation, 021001 nanoscience & nanotechnology, STATISTICS, Multidisciplinary Sciences, CpG site, DNA methylation, Science & Technology - Other Topics, 0210 nano-technology, SUSCEPTIBILITY LOCI, Science, Biology, Article, General Biochemistry, Genetics and Molecular Biology, PRACTICAL consortium, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, REVEALS, Genetic model, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Gene, Genetic Association Studies, Genetic association, Science & Technology, Models, Genetic, MORTALITY, Prostatic Neoplasms, General Chemistry, DNA Methylation, medicine.disease, CAPS Consortium, 030104 developmental biology, TISSUE, ANTIGEN LEVEL, Case-Control Studies, lcsh:Q, CpG Islands, PEGASUS Consortium
Abstract

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes., Genome wide association studies have identified multiple loci associated with risk of developing prostate cancer but the functional significance of many of these are unknown. Here, after generating models to predict methylation, the authors identify CpG methylation sites associated with prostate cancer.

Published
2021
Full Text
View/download PDF

24. Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Author

Sara Benlloch, Roger L. Milne, Azad Hassan Abdul Razack, José Manuel Ruiz-Dominguez, Steven Joniau, Maria P. Silva, Martin Andreas Røder, Constance Turman, Anne-Maree Haynes, Jin Ling, Robert N. Hoover, Jong Y. Park, Johanna Schleutker, Brian E. Henderson, Amy Hutchinson, Stephanie J. Weinstein, Manolis Kogevinas, Melissa Papargiris, Monique J. Roobol, Gill Barnett, Wayne D. Tilley, Elio Riboli, Samantha E.T. Larkin, Melissa C. Southey, Michelle Guy, Jeanette T. Bensen, Henrik Grönberg, Fredrick R. Schumacher, Karina Dalsgaard Sørensen, Davor Lessel, Carin Cavalli-Bjoerkman, Tomislav Kuliš, Barry S. Rosenstein, Paula Kujala, Michael Davis, Andrzej M. Kierzek, Antonio Finelli, Gerald L. Andriole, Leire Moya, Antonio Gómez-Caamaño, Demetrius Albanes, Jianming Guo, Lisa F. Newcomb, Koveela Govindasami, Ji Lin, Gert De Meerleer, Manuel Luedeke, Richard M. Martin, Zeljko Kastelan, Kay-Tee Khaw, Ruth C. Travis, Rebecca Elliott, Alexandre R. Zlotta, Xin Guo, Kirsi Talala, Yangling Zhang, Lorelei A. Mucci, Marie Sanchez, Paul D.P. Pharoah, Mariona Bustamante, Peter Klarskov, Aleksandrina Vlahova, Srilakshmi Srinivasan, Aik T. Ong, David E. Neal, Sylvie Cénée, Esther M. John, Sonja I. Berndt, Kan Wang, Peter Iversen, Harry Ostrer, Michael Borre, Freddie C. Hamdy, Christopher A. Haiman, Ji Wu, Florence Menegaux, Jacek Marzec, Sara S. Strom, David P. Dearnaley, Jyotsna Batra, Piet Ost, Mariana C. Stern, Kim De Ruyck, Hyun Soo Park, Trina Yeadon, Elenko Popov, Yudong Wu, Svetlana Christova, Thomas Van den Broeck, Loic Le Marchand, Daniel J. Schaid, Babu Zachariah, Sune F. Nielsen, Mary-Anne Kedda, Judith A. Clements, Olivier Cussenot, Robert Szulkin, Shiro Saito, Andrew Evans, Douglas F. Easton, Gemma Castaño-Vinyals, Steve Hazel, Thérèse Truong, Guomin Wang, Katarina Cuk, Ants Toi, Rosalind A. Eeles, Darina Kachakova, Lourdes Mengual, Lisa G. Horvath, Yuan Chun Ding, Catharine M L West, Ana Carballo, Suzanne K. Chambers, Aurelie Vogt, Angela Cox, Daniel W. Lin, Dominika Wokołorczyk, Manuela Gago-Dominguez, Stephen J. Chanock, Federico Canzian, Aleksandra Klim, Tokhir Dadaev, Kathleen Herkommer, Tihomir Dikov, Lovise Maehle, Jasmine Lim, Janet L. Stanford, Martin Eklund, Guido Jenster, Soo-Hwang Teo, Teemu J. Murtola, Torben F. Ørntoft, Stella Koutros, Christa Stegmaier, Sofia Maia, Mitchell J. Machiela, Lisa A. Cannon-Albright, Clare Berry, Pamela Saunders, Lluís Cecchini, Jeri Kim, Radka Kaneva, Brigitte Trétarre, Anne George, Meir J. Stampfer, Marija Gamulin, Meng H. Tan, Angela Morgan, Jenny L Donovan, Graham G. Giles, Geraldine Cancel-Tassin, Neil Fleshner, Shannon K. McDonnell, Hardeep Ranu, Naomi Livni, Kimmo Taari, Sarah L. Kerns, Csilla Sipeky, Alicja Wolk, Edward Giovannucci, Ninghan Feng, Marta Cardoso, Jan-Erik Johansson, Catherine M. Tangen, Guangwen Cao, Adam S. Kibel, Robert J. MacInnis, Bernd Holleczek, Sarah J Lewis, Bo Zhou, Michael Broms, Maria Elena Martinez, Renea A. Taylor, Børge G. Nordestgaard, Fritz H. Schröder, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jie Li, Lori S. Tillmans, Ana Vega, Patricia Calvo, Christopher J. Logothetis, David V. Conti, Miguel Aguado, Inés Gómez-Acebo, Tobias Nordström, Meiling Li, Elaine A. Ostrander, C.H. Bangma, Cyril Fisher, Joanne F. Aitken, Matthew Parliament, Gail P. Risbridger, John L. Hopper, Takashi Imai, Belynda Hicks, Victoria L. Stevens, Cezary Cybulski, G Marsden, Brian D. Carter, Vanessa M. Hayes, Nawaid Usmani, Vanio Mitev, Shan-Chao Zhao, Margaret Cook, Milan S. Geybels, Phyllis J. Goodman, Mark N. Brook, Nora Pashayan, Timothy J. Key, Yongwei Yu, Xavier Rebillard, David J. Hunter, Laura Fachal, Javier Llorca, Afshan Siddiq, Claire Aukim-Hastie, Trinidad Dierssen-Sotos, Walther Vogel, Angel Carracedo, Laura E. Beane Freeman, Julio M. Pow-Sang, Hardev Pandha, Robert A. Gardiner, Shaun M. Riska, Yong-Jie Lu, Zan Sun, Ramón Lobato-Busto, Ami Karlsson, Hongwei Zhang, Guoping Ren, Jing Ma, Huihai Wu, Søren M. Bentzen, John Pedersen, Claire Mulot, Girish S. Kulkarni, Jan Lubinski, Antonio Alcaraz, Jose E. Castelao, Athene Lane, Rasmus Bisbjerg, Thomas A. Sellers, Robert J. Hamilton, Jianfeng Xu, Sofie De Langhe, Artitaya Lophatananon, Maren Weisher, Agnieszka Michael, Yves Akoli Koudou, Niclas Håkansson, Alison M. Dunning, Hubert Thierens, Matthew L. Freedman, Kenneth Muir, Ian M. Thompson, Ian Whitmore, Susan L. Neuhausen, Chavdar Slavov, Wojciech Kluzniak, Laurence N. Kolonel, Lisa M. Butler, Teuvo L.J. Tammela, Alison Thwaites, Theodorus van der Kwast, Liesel M. FitzGerald, Thomas J. Schnoeller, Hermann Brenner, Christiane Maier, Amanda B. Spurdle, Jan Adolfsson, Atanaska Mitkova, Peter Kraft, Paula Peleteiro, Pär Stattin, Xin Sheng, Paul D. Brown, Ron H.N. van Schaik, Zsofia Kote-Jarai, Susan M. Gapstur, Paul A. Townsend, Edward J. Saunders, Bettina F. Drake, Stephen N. Thibodeau, Fredrik Wiklund, Paula Paulo, Esther Gracia-Lavedan, Xueying Mao, Marco Matejcic, Neil G. Burnet, A. L. Eckert, Manuel R. Teixeira, Sara Lindström, Weiyang He, Hui-Yi Lin, Suzanne Kolb, Linda Steele, Philipp Bohnert, Anssi Auvinen, Eli Marie Grindedal, Frank Claessens, and Kathryn L. Penney

Subjects
Urologic Diseases, 0301 basic medicine, Oncology, medicine.medical_specialty, Science, MEDLINE, General Physics and Astronomy, 02 engineering and technology, General Biochemistry, Genetics and Molecular Biology, Germline, 03 medical and health sciences, Internal medicine, medicine, PRACTICAL Consortium, lcsh:Science, Cancer, Prostate cancer risk, Multidisciplinary, business.industry, Prostate Cancer, Published Erratum, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, Spelling, 3. Good health, 030104 developmental biology, Variation (linguistics), lcsh:Q, 0210 nano-technology, business
Abstract

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

25. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author

Florence Menegaux, William J. Blot, Henrik Grönberg, Luc Multigner, Sune F. Nielsen, Stella Koutros, Frank Claessens, Manuela Gago-Dominguez, Kathryn L. Penney, Tyler M. Seibert, Cezary Cybulski, Jennifer J. Hu, Hermann Brenner, Radka Kaneva, Sue A. Ingles, Catherine M. Tangen, Ian G. Mills, Janet L. Stanford, Karina Dalsgaard Sørensen, Ruth C. Travis, Marie-Élise Parent, Monique J. Roobol, Nora Pashayan, Jyotsna Batra, Maria Elena Martinez, Anders M. Dale, Wei Zheng, Kay-Tee Khaw, Chad D. Huff, Chun Chieh Fan, Paul A. Townsend, Kim De Ruyck, Yong-Jie Lu, Eli Marie Grindedal, Hardev Pandha, Sonja I. Berndt, Susan L. Neuhausen, Alicja Wolk, Apcb, Wesley K. Thompson, Maureen Sanderson, Demetrius Albanes, Stephen N. Thibodeau, Christiane Maier, Kenneth Muir, Robin J. Leach, Børge G. Nordestgaard, Ole A. Andreassen, Fredrik Wiklund, Graham G. Giles, Zsofia Kote-Jarai, Catharine M L West, Minh-Phuong Huynh-Le, Manolis Kogevinas, Manuel R. Teixeira, Jong Y. Park, Johanna Schleutker, Marija Gamulin, Freddie C. Hamdy, William S. Bush, Barry S. Rosenstein, Stephen Watya, Roshan Karunamuni, Richard M. Martin, Nc-La PCaP Investigators, Ana Vega, Adam S. Kibel, Lisa A. Cannon-Albright, Azad Hassan Abdul Razack, Esther M. John, Christopher J. Logothetis, Jay H. Fowke, Nawaid Usmani, David E. Neal, Canary Pass Investigators, Rosalind A. Eeles, Robert J. Hamilton, Lisa F. Newcomb, Jenny L Donovan, Olivier Cussenot, Lorelei A. Mucci, University of California [San Diego] (UC San Diego), University of California, The institute of cancer research [London], University of Manchester [Manchester], University of Turku, Centre for Cancer Genetic Epidemiology [Cambridge], Department of Oncology-University of Cambridge [UK] (CAM), University College of London [London] (UCL), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), This study was funded in part by a grant from the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), United States Department of Defense (#W81XWH-13-1-0391), University of California CRCC C21CR2060, the Research Council of Norway (#223273), K.G. Jebsen Stiftelsen, and South East Norway Health Authority. RM Martin is supported in part by the National Institute for Health Research Bristol Biomedical Research Centre. The CAP trial is funded by Cancer Research UK and the UK Department of Health (C11043/A4286, C18281/A8145, C18281/A11326, C18281/A15064, and C18281/A24432). R.M. Martin was supported by a Cancer Research UK (C18281/A19169) program grant (the Integrative Cancer Epidemiology Programme). Funding for the PRACTICAL consortium member studies is detailed in the Supplementary Information., University of California (UC), University of Cambridge [UK] (CAM)-Department of Oncology, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Huynh-Le, Minh-Phuong [0000-0002-5025-4709], Fan, Chun Chieh [0000-0001-9437-2128], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Schleutker, Johanna [0000-0002-1863-0305], Pashayan, Nora [0000-0003-0843-2468], Batra, Jyotsna [0000-0003-4646-6247], Grönberg, Henrik [0000-0002-1073-2753], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Wiklund, Fredrik [0000-0002-4623-0544], Giles, Graham G [0000-0003-4946-9099], Wolk, Alicja [0000-0001-7387-6845], Travis, Ruth C [0000-0002-9571-0763], Zheng, Wei [0000-0003-1226-070X], West, Catharine ML [0000-0002-0839-3449], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Park, Jong Y [0000-0002-6384-6447], Vega, Ana [0000-0002-7416-5137], Teixeira, Manuel R [0000-0002-4896-5982], Multigner, Luc [0000-0003-3205-8568], Cannon-Albright, Lisa [0000-0003-2602-3668], Gamulin, Marija [0000-0003-2431-7910], Bush, William S [0000-0002-9729-6519], Roobol, Monique J [0000-0001-6967-1708], Andreassen, Ole A [0000-0002-4461-3568], Seibert, Tyler M [0000-0002-4089-7399], Apollo - University of Cambridge Repository, and Clinical Chemistry

Subjects
0301 basic medicine, Oncology, Male, Multifactorial Inheritance, Aging, Multivariate analysis, Ethnic Groups/genetics, General Physics and Astronomy, UKGPCS collaborators, Prostate cancer, 0302 clinical medicine, Urologi och njurmedicin, Ethnicity, risk factors, PRACTICAL Consortium, genetics, Stage (cooking), AgedEthnic Groups / genetics, Cancer, Multidisciplinary, Manchester Cancer Research Centre, Prostatic Neoplasms/genetics, Prostate Cancer, Hazard ratio, APCB, Middle Aged, Hazard, Health equity, 3. Good health, Multidisciplinary Sciences, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, polygenic hazard score (PHS1), prostate cancer, ICEP, Medical Genetics, Urologic Diseases, medicine.medical_specialty, hazard, precision medicine, Science, Prostatic Neoplasms / genetics, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ethnic Groups, survival, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Medical research, SDG 3 - Good Health and Well-being, Internal medicine, NC-LA PCaP Investigators, Genetic model, medicine, Urology and Nephrology, Humans, Neoplasm Invasiveness, Multifactorial Inheritance/genetics, Medicinsk genetik, Aged, Canary PASS Investigators, Science & Technology, IMPACT Study Steering Committee and Collaborators, business.industry, Profile Study Steering Committee, ResearchInstitutes_Networks_Beacons/mcrc, Prostatic Neoplasms, General Chemistry, medicine.disease, Multifactorial Inheritance / genetics, 030104 developmental biology, Multivariate Analysis, Self Report, business, Biomarkers
Abstract

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p, A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Published
2021

26. The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition

Author

Smith Byrne, K, Appleby, PN, Key, TJ, Holmes, MV, Fensom, GK, Agudo, A, Ardanaz, E, Boeing, H, Bueno-de-Mesquita, HB, Chirlaque, MD, Kaaks, R, Larrañaga, N, Palli, D, Perez-Cornago, A, Quirós, JR, Ricceri, F, Sánchez, MJ, Tagliabue, G, Tsilidis, KK, Tumino, R, Fortner, RT, Ferrari, P, Consortium, PRACTICAL, Riboli, E, Lilja, H, and Travis, RC

Subjects
Male, EPIC cohort, Mendelian randomization, microseminoprotein-beta, prospective study, prostate cancer, prostate-specific antigen, Biomarkers, Tumor, Case-Control Studies, Follow-Up Studies, Humans, Mendelian Randomization Analysis, Middle Aged, Nutritional Status, Prognosis, Prospective Studies, Prostatic Neoplasms, Prostatic Secretory Proteins, Risk Factors, Epidemiology, parasitic diseases, PRACTICAL Consortium, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Nutrició, Nutrition, Tumor, Càncer de pròstata, Original Articles, Editor's Choice, Biomarkers
Abstract

BACKGROUND: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods.PATIENTS AND METHODS: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method.RESULTS: Plasma MSP concentrations were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stage or histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP.CONCLUSIONS: In this large prospective European study and using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate cancer.

Published
2020

27. Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018)

Author

Matejcic, M, Saunders, EJ, Dadaev, T, Brook, MN, Wang, K, Sheng, X, Al Olama, AA, Schumacher, FR, Ingles, SA, Govindasami, K, Benlloch, S, Berndt, SI, Albanes, D, Koutros, S, Muir, K, Stevens, VL, Gapstur, SM, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Pashayan, N, Schleutker, J, Wolk, A, West, C, Mucci, L, Kraft, P, Cancel-Tassin, G, Sorensen, KD, Maehle, L, Grindedal, EM, Strom, SS, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Bensen, JT, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, LA, Pandha, H, Thibodeau, SN, Schaid, DJ, Wiklund, F, Chanock, SJ, Easton, DF, Eeles, RA, Kote-Jarai, Z, Conti, DV, Haiman, CA, Henderson, BE, Stern, MC, Thwaites, A, Guy, M, Whitmore, I, Morgan, A, Fisher, C, Hazel, S, Livni, N, Cook, M, Fachal, L, Weinstein, S, Freeman, LEB, Hoover, RN, Machiela, MJ, Lophatananon, A, Carter, BD, Goodman, P, Moya, L, Srinivasan, S, Kedda, M-A, Yeadon, T, Eckert, A, Eklund, M, Cavalli-Bjoerkman, C, Dunning, AM, Sipeky, C, Hakansson, N, Elliott, R, Ranu, H, Giovannucci, E, Turman, C, Hunter, DJ, Cussenot, O, Orntoft, TF, Lane, A, Lewis, SJ, Davis, M, Key, TJ, Brown, P, Kulkarni, GS, Zlotta, AR, Fleshner, NE, Finelli, A, Mao, X, Marzec, J, MacInnis, RJ, Milne, R, Hopper, JL, Aguado, M, Bustamante, M, Castano-Vinyals, G, Gracia-Lavedan, E, Cecchini, L, Stampfer, M, Ma, J, Sellers, TA, Geybels, MS, Park, H, Zachariah, B, Kolb, S, Wokolorczyk, D, Lubinski, J, Kluzniak, W, Nielsen, SF, Weisher, M, Cuk, K, Vogel, W, Luedeke, M, Logothetis, CJ, Paulo, P, Cardoso, M, Maia, S, Silva, MP, Steele, L, Ding, YC, De Meerleer, G, De Langhe, S, Thierens, H, Lim, J, Tan, MH, Ong, AT, Lin, DW, Kachakova, D, Mitkova, A, Mitev, V, Parliament, M, Jenster, G, Bangma, C, Schroder, FH, Truong, T, Koudou, YA, Michael, A, Kierzek, A, Karlsson, A, Broms, M, Wu, H, Aukim-Hastie, C, Tillmans, L, Riska, S, McDonnell, SK, Dearnaley, D, Spurdle, A, Gardiner, R, Hayes, V, Butler, L, Taylor, R, Papargiris, M, Saunders, P, Kujala, P, Talala, K, Taari, K, Bentzen, S, Hicks, B, Vogt, A, Hutchinson, A, Cox, A, George, A, Toi, A, Evans, A, Van der Kwast, TH, Imai, T, Saito, S, Zhao, S-C, Ren, G, Zhang, Y, Yu, Y, Wu, Y, Wu, J, Zhou, B, Pedersen, J, Lobato-Busto, R, Manuel Ruiz-Dominguez, J, Mengual, L, Alcaraz, A, Pow-Sang, J, Herkommer, K, Vlahova, A, Dikov, T, Christova, S, Carracedo, A, Tretarre, B, Rebillard, X, Mulot, C, Adolfsson, J, Stattin, P, Johansson, J-E, Martin, RM, Thompson, IM, Chambers, S, Aitken, J, Horvath, L, Haynes, A-M, Tilley, W, Risbridger, G, Aly, M, Nordstrom, T, Pharoah, P, Tammela, TLJ, Murtola, T, Auvinen, A, Burnet, N, Barnett, G, Andriole, G, Klim, A, Drake, BF, Borre, M, Kerns, S, Ostrer, H, Zhang, H-W, Cao, G, Lin, J, Ling, J, Li, M, Feng, N, Li, J, He, W, Guo, X, Sun, Z, Wang, G, Guo, J, Southey, MC, FitzGerald, LM, Marsden, G, Gomez-Caamano, A, Carballo, A, Peleteiro, P, Calvo, P, Szulkin, R, Llorca, J, Dierssen-Sotos, T, Gomez-Acebo, I, Lin, H-Y, Ostrander, EA, Bisbjerg, R, Klarskov, P, Roder, MA, Iversen, P, Holleczek, B, Stegmaier, C, Schnoeller, T, Bohnert, P, John, EM, Ost, P, Teo, S-H, Gamulin, M, Kulis, T, Kastelan, Z, Slavov, C, Popov, E, Van den Broeck, T, Joniau, S, Larkin, S, Esteban Castelao, J, Martinez, ME, Van Schaik, RHN, Xu, J, Lindstrom, S, Riboli, E, Berry, C, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Freedman, M, Cenee, S, Sanchez, M, and Commission of the European Communities

Subjects
Multidisciplinary Sciences, Science & Technology, MD Multidisciplinary, Science & Technology - Other Topics, PRACTICAL Consortium
Abstract

Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-06863-1, published online 5 November 2018.

Published
2019

28. Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium

Author

Lophatananon, Artitaya, Stewart-Brown, Sarah, Kote-Jarai, Zsofia, Olama, Ali Amin Al, Garcia, Sara Benlloch, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Giles, Graham G, Fitzgerald, Liesel M, Southey, Melissa C, Pharoah, Paul, Pashayan, Nora, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Stanford, Janet L, Brenner, Hermann, Dieffenbach, Aida K, Arndt, Volker, Park, Jong Y, Lin, Hui-Yi, Sellers, Thomas, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Spurdle, Amanda, Clements, Judith A, APCB BioResource, PRACTICAL Consortium, Easton, Douglas, Eeles, Rosalind A, Muir, Kenneth, Amin Al Olama, Ali [0000-0002-7178-3431], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Male, Case-Control Studies, Humans, Prostatic Neoplasms, Gene-Environment Interaction, Middle Aged, Neoplasm Grading, Polymorphism, Single Nucleotide, Risk Assessment, APCB BioResource, Body Height, PRACTICAL consortium, Aged
Abstract

BACKGROUND: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer. METHODS: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions. RESULTS: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height

Published
2018
Full Text
View/download PDF

29. Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

Author

Seibert, Tyler M, Seibert, Tyler M, Fan, Chun Chieh, Wang, Yunpeng, Zuber, Verena, Karunamuni, Roshan, Parsons, J Kellogg, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, ZSofia, Al Olama, Ali Amin, Garcia, Sara Benlloch, Muir, Kenneth, Grönberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo Lj, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bisbjerg, Rasmus, Røder, M Andreas, Iversen, Peter, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Cuk, Katarina, Saum, Kai-Uwe, Park, Jong Y, Sellers, Thomas A, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej, Karow, David S, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, PRACTICAL Consortium*, Seibert, Tyler M, Seibert, Tyler M, Fan, Chun Chieh, Wang, Yunpeng, Zuber, Verena, Karunamuni, Roshan, Parsons, J Kellogg, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, ZSofia, Al Olama, Ali Amin, Garcia, Sara Benlloch, Muir, Kenneth, Grönberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo Lj, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bisbjerg, Rasmus, Røder, M Andreas, Iversen, Peter, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Cuk, Katarina, Saum, Kai-Uwe, Park, Jong Y, Sellers, Thomas A, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej, Karow, David S, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and PRACTICAL Consortium*

Abstract

ObjectivesTo develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.DesignAnalysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa.SettingMultiple institutions that were members of international PRACTICAL consortium.ParticipantsAll consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men.Main outcome measuresPrediction with hazard score of age of onset of aggressive cancer in validation set.ResultsIn the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positi

Published
2018

30. Polygenic hazard score to guide screening for aggressive - prostate cancer: development and validation in large scale - cohorts

Author

Ruth C. Travis, Markus Aly, Chun Chieh Fan, Dominika Wokołorczyk, Fredrik Wiklund, Ole A. Andreassen, Børge G. Nordestgaard, Adam S. Kibel, Amanda B. Spurdle, Verena Zuber, Douglas F. Easton, J. Kellogg Parsons, Agnieszka Michael, Lisa A. Cannon-Albright, Judith A. Clements, Cezary Cybulski, Roshan Karunamuni, M. Andreas Røder, Kathleen Herkommer, Vanio Mitev, Zsofia Kote-Jarai, Walther Vogel, Jong Y. Park, Johanna Schleutker, Tyler M. Seibert, Paul D.P. Pharoah, Hermann Brenner, Ian G. Mills, Kai Uwe Saum, Manuel R. Teixeira, Nora Pashayan, Timothy J. Key, Henrik Grönberg, Maren Weischer, Hardev Pandha, Andrzej M. Kierzek, Manuel Luedeke, Rasmus Bisbjerg, Christiane Maier, Freddie C. Hamdy, Katarina Cuk, Sofia Maia, Paula Paulo, Kay-Tee Khaw, Anders M. Dale, Thomas A. Sellers, Csilla Sipeky, Rosalind A. Eeles, Jenny L Donovan, Wojciech Kluzniak, David E. Neal, Yunpeng Wang, David S. Karow, Teuvo L.J. Tammela, Peter Iversen, Chavdar Slavov, Jyotsna Batra, Sune F. Nielsen, Kenneth Muir, Sara Benlloch Garcia, Radka Kaneva, and Ali Amin Al Olama

Subjects
0301 basic medicine, Oncology, Male, Percentile, IMPACT, urologic and male genital diseases, Cohort Studies, Prostate cancer, PSA, 0302 clinical medicine, Outcome Assessment, Health Care, Overdiagnosis, Age of Onset, European Continental Ancestry Group/genetics, Early Detection of Cancer, risk, OUTCOMES, OVERDIAGNOSIS, Hazard ratio, Prostatic Neoplasms/blood, General Medicine, Middle Aged, Polymorphism, Single Nucleotide/genetics, STATISTICS, ddc, Prostate-specific antigen, Editorial, Centre for Surgical Research, 030220 oncology & carcinogenesis, TRIAL, Kallikreins, Risk assessment, Life Sciences & Biomedicine, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Genotype, European Continental Ancestry Group, Prostate-Specific Antigen/analysis, Polymorphism, Single Nucleotide, Risk Assessment, White People, Disease-Free Survival, 03 medical and health sciences, Outcome Assessment (Health Care), Medicine, General & Internal, AGE, Predictive Value of Tests, Internal medicine, General & Internal Medicine, medicine, Journal Article, BREAST-CANCER, Humans, Kallikreins/analysis, Survival analysis, Aged, Science & Technology, RISK PREDICTION, business.industry, screening, Prostatic Neoplasms, prediction, Prostate-Specific Antigen, medicine.disease, ta3122, PREVENTION, PRACTICAL Consortium, Survival Analysis, 030104 developmental biology, age, Age of onset, genetic, Early Detection of Cancer/methods, business
Abstract

Objectives To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Main Outcome Measure Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

Published
2018

31. Circulating vitamin D concentration and risk of seven cancers: a Mendelian randomization study

Author

Dimitrakopoulou, VI, Tsilidis, KK, Haycock, PC, Dimou, NL, Al-Dabhani, K, Martin, RM, Lewis, SJ, Gunter, MJ, Mondul, A, Shui, IM, Theodoratou, E, Nimptsch, K, Lindström, S, Albanes, D, Kühn, T, Key, TJ, Travis, RC, Vimaleswaran, KS, GECCO Consortium, PRACTICAL Consortium, GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO), Kraft, P, Pierce, BL, and Schildkraut, JM

Subjects
Male, 25-HYDROXYVITAMIN D, Lung Neoplasms, SUSCEPTIBILITY LOCI, Breast Neoplasms, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Risk Assessment, COLORECTAL-CANCER, 1117 Public Health and Health Services, Neuroblastoma, Medicine, General & Internal, General & Internal Medicine, Neoplasms, BREAST-CANCER, Humans, PRACTICAL Consortium, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Vitamin D, METAANALYSIS, GECCO Consortium, Ovarian Neoplasms, Science & Technology, Incidence, GENETIC-VARIATION, Genetic Variation, Prostatic Neoplasms, 1103 Clinical Sciences, Mendelian Randomization Analysis, Vitamin D Deficiency, PREVENTION, PROSTATE-CANCER, Pancreatic Neoplasms, Case-Control Studies, Female, GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO), Colorectal Neoplasms, Life Sciences & Biomedicine, Genome-Wide Association Study
Abstract

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer. Design Mendelian randomisation study. Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform). Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls. Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined. Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated. Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.

Published
2017

32. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author

Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., Fernández Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, André G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

Published
2017

33. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author

Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Zheng, W, Pettaway, CA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, John, EM, Murphy, AB, Signorello, LB, Carpten, J, Leske, MC, Wu, S-Y, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Southey, MC, Fitzgerald, LM, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schleutker, J, Wahlfors, T, Tammela, TLJ, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Stanford, JL, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Teerlink, C, Brenner, H, Dieffenbach, AK, Arndt, V, Park, JY, Sellers, TA, Lin, H-Y, Slavov, C, Kaneva, R, Mitev, V, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Pandha, HS, Michael, A, Paulo, P, Maia, S, Kierzek, A, Conti, DV, Albanes, D, Berg, C, Berndt, SI, Campa, D, Crawford, ED, Diver, WR, Gapstur, SM, Gaziano, JM, Giovannucci, E, Hoover, R, Hunter, DJ, Johansson, M, Kraft, P, Le Marchand, L, Lindstrom, S, Navarro, C, Overvad, K, Riboli, E, Siddiq, A, Stevens, VL, Trichopoulos, D, Vineis, P, Yeager, M, Trynka, G, Raychaudhuri, S, Schumacher, FR, Price, AL, Freedman, ML, Haiman, CA, Pasaniuc, B, Cook, M, Guy, M, Govindasami, K, Leongamornlert, D, Sawyer, EJ, Wilkinson, R, Saunders, EJ, Tymrakiewicz, M, Dadaev, T, Morgan, A, Fischer, C, Hazel, S, Livni, N, Lophatananon, A, Pedersen, J, Hopper, JL, Adolfson, J, Stattin, P, Johansson, J-E, Cavalli-Bjoerkman, C, Karlsson, A, Broms, M, Auvinen, A, Kujala, P, Maeaettaenen, L, Murtola, T, Taari, K, Weischer, M, Nielsen, SF, Klarskov, P, Roder, A, Iversen, P, Wallinder, H, Tillmans, L, Riska, S, Wang, L, Rinckleb, A, Lubiski, J, Stegmaier, C, Pow-Sang, J, Park, H, Radlein, S, Rincon, M, Haley, J, Zachariah, B, Kachakova, D, Popov, E, Mitkova, A, Vlahova, A, Dikov, T, Christova, S, Heathcote, P, Wood, G, Malone, G, Saunders, K, Eckert, A, Yeadon, T, Kerr, K, Collins, A, Turner, M, Srinivasan, S, Kedda, M-A, Alexander, K, Omara, T, Wu, H, Henrique, R, Pinto, P, Santos, J, Barros-Silva, J, Pharoah, Paul [0000-0001-8494-732X], Trynka, Gosia [0000-0002-6955-9529], Apollo - University of Cambridge Repository, Clinicum, Department of Surgery, Urologian yksikkö, and University of Helsinki

Subjects
0301 basic medicine, Male, Genetics and Molecular Biology (all), Linkage disequilibrium, Inheritance Patterns, COMMON DISEASES, General Physics and Astronomy, Genome-wide association study, urologic and male genital diseases, Biochemistry, Linkage Disequilibrium, Epigenesis, Genetic, Histones, Prostate cancer, Genotype, ELEMENTS, genetics, SNPS, ENCODE, RISK, PITFALLS, Genetics, African Americans, Multidisciplinary, Tumor, biological sciences, Chemistry (all), Acetylation, Single Nucleotide, 3. Good health, Centre for Surgical Research, SUSCEPTIBILITY LOCI, Science, 3122 Cancers, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, PRACTICAL consortium, General Biochemistry, Genetics and Molecular Biology, White People, Article, Cell Line, RC0254, 03 medical and health sciences, Physics and Astronomy (all), Atlases as Topic, Genetic, Cell Line, Tumor, MD Multidisciplinary, medicine, SNP, Humans, cancer, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Polymorphism, Genetic association, Cancer och onkologi, COMPLEX TRAITS, Prostatic Neoplasms, General Chemistry, Heritability, ta3122, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Black or African American, ENHANCERS, 030104 developmental biology, Genetic Loci, Genome-Wide Association Study, Biochemistry, Genetics and Molecular Biology (all), Cancer and Oncology, 3111 Biomedicine, Epigenesis
Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa., Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results