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1. Cluster effect for SNP–SNP interaction pairs for predicting complex traits

Author

Hui-Yi Lin, Harun Mazumder, Indrani Sarkar, Po-Yu Huang, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth R. Muir, UKGPCS collaborators, Johanna Schleutker, Nora Pashayan, Jyotsna Batra, APCB (Australian Prostate Cancer BioResource), David E. Neal, Sune F. Nielsen, Børge G. Nordestgaard, Henrik Grönberg, Fredrik Wiklund, Robert J. MacInnis, Christopher A. Haiman, Ruth C. Travis, Janet L. Stanford, Adam S. Kibel, Cezary Cybulski, Kay-Tee Khaw, Christiane Maier, Stephen N. Thibodeau, Manuel R. Teixeira, Lisa Cannon-Albright, Hermann Brenner, Radka Kaneva, Hardev Pandha, The PRACTICAL consortium, and Jong Y. Park

Subjects
SNP interaction, Cluster, False positivity, Simulation, Medicine, Science
Abstract

Abstract Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP–SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP–SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP–SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP–SNP interaction detection accuracy.

Published
2024
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2. Identification of rare genetic variants for rotator cuff tearing and repair in high-risk pedigrees

Author

Robert Z. Tashjian, MD, Michael J. Jurynec, PhD, Kyle Christy, BS, Jeff Stevens, BS, Craig C. Teerlink, PhD, Lisa Cannon-Albright, PhD, and Kristina Allen-Brady, PhD

Subjects
Rotator cuff tear, Genetic variants, Pedigrees, High risk, UPDB, APBB1, Orthopedic surgery, RD701-811, Diseases of the musculoskeletal system, RC925-935
Abstract

Background: Common genetic variants with small effect sizes have been associated with rotator cuff tearing although very few rare, highly penetrant variants have been identified. The purpose of this pilot study was to identify dominant coding variants that segregated with affected individuals in pedigrees at high risk for rotator cuff tears (RCTs). We hypothesize that rare variants contribute to symptomatic RCTs and that they can be identified in related cases with a full-thickness tear requiring surgical management. Methods: We used the Utah Population Database to identify pedigrees that exhibited a significant excess of individuals who had undergone surgical repair of a full-thickness RCT. We analyzed whole exome sequence analysis to identify rare coding variants in 9 independent affected cousin pairs (first or second cousins) who had undergone arthroscopic surgery for repair of a full-thickness RCT (mean age at diagnosis 68 years). Validation of association of the candidate variants with risk for rotator cuff tearing was accomplished utilizing data from the UK Biobank and a separate cohort of unrelated cases of full-thickness RCTs. Results: A total of 82 rare (minor allele frequency

Published
2024
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3. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysisResearch in context

Author

James Yarmolinsky, Jamie W. Robinson, Daniela Mariosa, Ville Karhunen, Jian Huang, Niki Dimou, Neil Murphy, Kimberley Burrows, Emmanouil Bouras, Karl Smith-Byrne, Sarah J. Lewis, Tessel E. Galesloot, Lambertus A. Kiemeney, Sita Vermeulen, Paul Martin, Demetrius Albanes, Lifang Hou, Polly A. Newcomb, Emily White, Alicja Wolk, Anna H. Wu, Loïc Le Marchand, Amanda I. Phipps, Daniel D. Buchanan, Sizheng Steven Zhao, Dipender Gill, Stephen J. Chanock, Mark P. Purdue, George Davey Smith, Paul Brennan, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Chris I. Amos, Rayjean J. Hung, Abbas Dehghan, Mattias Johansson, Marc J. Gunter, Kostas K. Tsilidis, Richard M. Martin, Maria Teresa Landi, Victoria Stevens, Ying Wang, Demetrios Albanes, Neil Caporaso, Christopher I. Amos, Sanjay Shete, Heike Bickeböller, Angela Risch, Richard Houlston, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, H-Erich Wichmann, David Christiani, Gadi Rennert, Susanne Arnold, John K. Field, Loic Le Marchand, Olle Melander, Hans Brunnström, Geoffrey Liu, Angeline Andrew, Hongbing Shen, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, M. Dawn Teare, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Sara Benlloch, Ali Amin Al Olama, Kenneth R. Muir, Sonja I. Berndt, David V. Conti, Fredrik Wiklund, Stephen Chanock, Catherine M. Tangen, Jyotsna Batra, Judith A. Clements, Henrik Grönberg, Nora Pashayan, Johanna Schleutker, Stephanie J. Weinstein, Catharine M.L. West, Lorelei A. Mucci, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sørensen, Eli Marie Grindedal, David E. Neal, Freddie C. Hamdy, Jenny L. Donovan, Ruth C. Travis, Robert J. Hamilton, Sue Ann Ingles, Barry S. Rosenstein, Yong-Jie Lu, Graham G. Giles, Robert J. MacInnis, Adam S. Kibel, Ana Vega, Manolis Kogevinas, Kathryn L. Penney, Jong Y. Park, Janet L. Stanfrod, Cezary Cybulski, Børge G. Nordestgaard, Sune F. Nielsen, Hermann Brenner, Christiane Maier, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Susan L. Neuhausen, Kim De Ruyck, Azad Razack, Lisa F. Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A. Townsend, Jose Esteban Castelao, Monique J. Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Stephen N. Thibodeau, David J. Hunter, Peter Kraft, William J. Blot, and Elio Riboli

Subjects
Inflammation, Cancer, Mendelian randomization, Genetic epidemiology, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Published
2024
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4. KLK3 SNP–SNP interactions for prediction of prostate cancer aggressiveness

Author

Hui-Yi Lin, Po-Yu Huang, Chia-Ho Cheng, Heng-Yuan Tung, Zhide Fang, Anders E. Berglund, Ann Chen, Jennifer French-Kwawu, Darian Harris, Julio Pow-Sang, Kosj Yamoah, John L. Cleveland, Shivanshu Awasthi, Robert J. Rounbehler, Travis Gerke, Jasreman Dhillon, Rosalind Eeles, Zsofia Kote-Jarai, Kenneth Muir, UKGPCS collaborators, Johanna Schleutker, Nora Pashayan, APCB (Australian Prostate Cancer BioResource), David E. Neal, Sune F. Nielsen, Børge G. Nordestgaard, Henrik Gronberg, Fredrik Wiklund, Graham G. Giles, Christopher A. Haiman, Ruth C. Travis, Janet L. Stanford, Adam S. Kibel, Cezary Cybulski, Kay-Tee Khaw, Christiane Maier, Stephen N. Thibodeau, Manuel R. Teixeira, Lisa Cannon-Albright, Hermann Brenner, Radka Kaneva, Hardev Pandha, The PRACTICAL consortium, Srilakshmi Srinivasan, Judith Clements, Jyotsna Batra, and Jong Y. Park

Subjects
Medicine, Science
Abstract

Abstract Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP–SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P

Published
2021
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5. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author

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

Subjects
Science
Abstract

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
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6. A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk

Author

Yao Yu, Kyle Chang, Jiun-Sheng Chen, Ryan J. Bohlender, Jerry Fowler, Di Zhang, Maosheng Huang, Ping Chang, Yanan Li, Justin Wong, Huamin Wang, Jian Gu, Xifeng Wu, Joellen Schildkraut, Lisa Cannon-Albright, Yuanqing Ye, Hua Zhao, Michelle A.T. Hildebrandt, Jennifer B. Permuth, Donghui Li, Paul Scheet, and Chad D. Huff

Subjects
Pancreatic Cancer, Case-Control Study, Association Analysis, ATM, SIK3, Genetics, QH426-470
Abstract

Summary: Pancreatic cancer is a deadly disease that accounts for approximately 5% of cancer deaths worldwide, with a dismal 5-year survival rate of 10%. Known genetic risk factors explain only a modest proportion of the heritable risk of pancreatic cancer. We conducted a whole-exome case-control sequencing study in 1,591 pancreatic cancer cases and 2,134 cancer-free controls of European ancestry. In our gene-based analysis, ATM ranked first, with a genome-wide significant p value of 1 × 10−8. The odds ratio for protein-truncating variants in ATM was 24, which is substantially higher than prior estimates, although ours includes a broad 95% confidence interval (4.0–1000). SIK3 was the second highest ranking gene (p = 3.84 × 10−6, false discovery rate or FDR = 0.032). We observed nominally significant association signals in several genes of a priori interest, including BRCA2 (p = 4.3 × 10−4), STK11 (p = 0.003), PALB2 (p = 0.019), and TP53 (p = 0.037), and reported risk estimates for known pathogenic variants and variants of uncertain significance (VUS) in these genes. The rare variants in established susceptibility genes explain approximately 24% of log familial relative risk, which is comparable to the contribution from established common susceptibility variants (17%). In conclusion, this study provides new insights into the genetic susceptibility of pancreatic cancer, refining rare variant risk estimates in known pancreatic cancer susceptibility genes and identifying SIK3 as a novel candidate susceptibility gene. This study highlights the prominent importance of ATM truncating variants and the underappreciated role of VUS in pancreatic cancer etiology.

Published
2022
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7. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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8. The contribution of the rs55705857 G allele to familial cancer risk as estimated in the Utah population database

Author

Sarah Hummel, Wendy Kohlmann, Thomas M. Kollmeyer, Robert Jenkins, Joshua Sonnen, Cheryl A. Palmer, Howard Colman, Diana Abbott, Lisa Cannon-Albright, and Adam L. Cohen

Subjects
Molecular epidemiology, IDH, rs55705857, Oligodendroglioma, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background IDH1/2 mutated glioma has been associated with a germline risk variant, the rs55705857 G allele. The Utah Population Database (UPDB), a computerized genealogy of people in Utah, is a unique resource to evaluate cancer risk in related individuals. Methods One hundred and two individuals with IDH1/2 mutant or 1p/19q co-deleted glioma were genotyped and linked to the UPDB. DNA came from blood (21), tumor tissue (43), or both (38). We determined congruence between somatic and germline samples and estimated the relative risk for developing cancer to first and second-degree relatives of G and A allele carriers at rs55705857. Results Somatic (glioma) DNA had 85.7% sensitivity (CI 57.2–98.2%) and 95.8% specificity (CI 78.9–99.89%) for germline rs55705857 G allele. Forty-one patients were linked to pedigrees in the UPDB with at least three generations of data. First-degree relatives of rs55705857 G allele carriers were at significantly increased risk for developing cancer (RR = 1.72, p = 0.045, CI 1.02–2.94), and specifically for oligodendroglioma (RR = 57.61, p = 0.017, CI 2.96–320.98) or prostate cancer (RR = 4.10, p = 0.008, CI 1.62–9.58); relatives of individuals without the G allele were not at increased risk. Second-degree relatives of G allele carriers also had significantly increased risk for developing cancer (RR = 1.50, p = 0.007, CI 1.15–2.01). Conclusions Tumor DNA may approximate genotype at the rs55705857 locus. We confirmed this locus confers an increased risk of all cancers and especially of oligodendroglioma. No increased cancer or brain tumor risk is seen in family members of individuals without the high-risk G allele.

Published
2019
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9. Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Published
2019
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10. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

Tokhir Dadaev, Edward J. Saunders, Paul J. Newcombe, Ezequiel Anokian, Daniel A. Leongamornlert, Mark N. Brook, Clara Cieza-Borrella, Martina Mijuskovic, Sarah Wakerell, Ali Amin Al Olama, Fredrick R. Schumacher, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Chee Goh, Xin Sheng, Zhuo Zhang, Kenneth Muir, Koveela Govindasami, Artitaya Lophatananon, Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L. J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Hakansson, Catharine West, Alison M. Dunning, Neil Burnet, Lorelei Mucci, Edward Giovannucci, Gerald Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E. Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry Rosenstein, Sarah Kerns, Harry Ostrer, Yong-Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. FitzGerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez-Caamaño, Laura Fachal, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Kathryn L. Penney, Meir Stampfer, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weisher, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Sandeep Singhal, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H. N. van Schaik, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Peter Kraft, The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Matthew Freedman, Fredrik Wiklund, Stephen Chanock, Brian E. Henderson, Douglas F. Easton, Christopher A. Haiman, Rosalind A. Eeles, David V. Conti, and Zsofia Kote-Jarai

Subjects
Science
Abstract

Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

Published
2018
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11. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author

Alexander Gusev, Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W. Long, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Wei Zheng, Curtis A. Pettaway, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P. Chokkalingam, Esther M. John, Adam B. Murphy, Lisa B. Signorello, John Carpten, M. Cristina Leske, Suh-Yuh Wu, Anslem J. M. Hennis, Christine Neslund-Dudas, Ann W. Hsing, Lisa Chu, Phyllis J. Goodman, Eric A. Klein, John S. Witte, Graham Casey, Sam Kaggwa, Michael B. Cook, Daniel O. Stram, William J. Blot, Rosalind A. Eeles, Douglas Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Melissa C. Southey, Liesel M. Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E. Henderson, Johanna Schleutker, Tiina Wahlfors, Teuvo L. J. Tammela, Børge G. Nordestgaard, Tim J. Key, Ruth C. Travis, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L. Stanford, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S. Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Craig Teerlink, Hermann Brenner, Aida K. Dieffenbach, Volker Arndt, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A. Clements, Manuel R. Teixeira, Hardev Pandha, Agnieszka Michael, Paula Paulo, Sofia Maia, Andrzej Kierzek, The PRACTICAL consortium, David V. Conti, Demetrius Albanes, Christine Berg, Sonja I. Berndt, Daniele Campa, E. David Crawford, W. Ryan Diver, Susan M. Gapstur, J. Michael Gaziano, Edward Giovannucci, Robert Hoover, David J. Hunter, Mattias Johansson, Peter Kraft, Loic Le Marchand, Sara Lindström, Carmen Navarro, Kim Overvad, Elio Riboli, Afshan Siddiq, Victoria L. Stevens, Dimitrios Trichopoulos, Paolo Vineis, Meredith Yeager, Gosia Trynka, Soumya Raychaudhuri, Frederick R. Schumacher, Alkes L. Price, Matthew L. Freedman, Christopher A. Haiman, and Bogdan Pasaniuc

Subjects
Science
Abstract

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
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12. Parapneumonic Empyema Deaths during Past Century, Utah

Author

Jeffrey M. Bender, Krow Ampofo, Xiaoming Sheng, Andrew T. Pavia, Lisa Cannon-Albright, and Carrie L. Byington

Subjects
complicated pneumonia, Spanish flu, Streptococcus pneumoniae, methicillin resistant Staphylococcus aureus, Utah Population Database, vaccine, Medicine, Infectious and parasitic diseases, RC109-216
Abstract

Bacterial pneumonia with empyema is a serious complication of influenza and commonly resulted in death during the 1918 influenza pandemic. We hypothesize that deaths caused by parapneumonic empyema are increasing in Utah once again despite advances in critical care and the availability of antimicrobial drugs and new vaccines. In this study, we analyzed the historical relationship between deaths caused by empyema and influenza pandemics by using 100 years of data from Utah. Deaths caused by empyema have indeed increased from 2000–2004 when compared with the historic low death rates of 1950–1975. Vaccine strategies and antimicrobial drug stockpiling to control empyema will be important as we prepare for the next influenza pandemic.

Published
2009
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13. Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

Author

Edward J Saunders, Tokhir Dadaev, Daniel A Leongamornlert, Sarah Jugurnauth-Little, Malgorzata Tymrakiewicz, Fredrik Wiklund, Ali Amin Al Olama, Sara Benlloch, David E Neal, Freddie C Hamdy, Jenny L Donovan, Graham G Giles, Gianluca Severi, Henrik Gronberg, Markus Aly, Christopher A Haiman, Fredrick Schumacher, Brian E Henderson, Sara Lindstrom, Peter Kraft, David J Hunter, Susan Gapstur, Stephen Chanock, Sonja I Berndt, Demetrius Albanes, Gerald Andriole, Johanna Schleutker, Maren Weischer, Børge G Nordestgaard, Federico Canzian, Daniele Campa, Elio Riboli, Tim J Key, Ruth C Travis, Sue A Ingles, Esther M John, Richard B Hayes, Paul Pharoah, Kay-Tee Khaw, Janet L Stanford, Elaine A Ostrander, Lisa B Signorello, Stephen N Thibodeau, Daniel Schaid, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Y Park, Radka Kaneva, Jyotsna Batra, Judith A Clements, Manuel R Teixeira, Jianfeng Xu, Christos Mikropoulos, Chee Goh, Koveela Govindasami, Michelle Guy, Rosemary A Wilkinson, Emma J Sawyer, Angela Morgan, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, PRACTICAL Consortium, Douglas F Easton, Ken Muir, Rosalind A Eeles, and Zsofia Kote-Jarai

Subjects
Genetics, QH426-470
Abstract

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Published
2014
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14. At-Risk Populations for Osteosarcoma: The Syndromes and Beyond

Author

George T. Calvert, R. Lor Randall, Kevin B. Jones, Lisa Cannon-Albright, Stephen Lessnick, and Joshua D. Schiffman

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Osteosarcoma is the most common primary malignancy of bone. Most cases are sporadic without a known genetic or environmental cause. Heritable genetic predisposition syndromes are associated with a small percentage of osteosarcomas. Study of these rare disorders has provided insight into the molecular pathogenesis of osteosarcoma. Screening of at-risk families and surveillance of affected individuals for these syndromes may permit earlier diagnosis and more effective treatment of osteosarcoma in these populations. This paper reviews the genetic and clinical features of the known osteosarcoma predisposition syndromes.

Published
2012
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15. Supplementary Grant Support from 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

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Grant Support

Published
2023

16. Supplementary Methods, Figures S1 - S3 from 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

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Figure S1. LocusZoom regional association plots for the seven new cross-cancer loci that were > 1 Mb from known index SNPs. Supplementary Figure S2A-B. Box plots showing eQTL associations between (A) rs9375701 and L3MBTL3 in normal breast and prostate tissues and (B) rs8037137 and RCCD1 in normal breast and ovarian tissues. Supplementary Figure S3. Interactions between BCL2L11 and the 32 Biocarta "Death Pathway" genes. Interactions were identified using the GeneMania server. Circles contain gene names, lines represent interactions, and the color of the line indicates a specific type of interaction as listed in the legend.

Published
2023

17. Supplementary Tables S1 - S10 from 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

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Table S1. Known risk loci for each cancer. Supplementary Table S2. Regions where known index SNPs for at least two of the three cancers lie within 1 Mb of each other. Supplementary Table S3. Full results from the meta-analysis of breast, ovarian, and prostate cancer showing the 18 independent loci associated at P < 10-8 with the same direction of effect across all three cancers. Supplementary Table S4. Conditional analysis of the rs1469713 (breast-ovarian-prostate cancer) signal, conditioning on the rs4808801 (breast cancer-specific) signal that was < 1 Mb away using GCTA software. Supplementary Table S5. Most significantly-associated genotyped SNP at new loci where index SNPs were imputed. Supplementary Table S6. Expression QTL analysis results from the GTEx Portal for the new cross-cancer risk loci listed in main Table 2. Supplementary Table S7. SNPs with P < 10-8 at the new cross-cancer risk loci listed in main Table 2 that overlap predicted enhancers in at least two cell types. Supplementary Table S8. HaploReg and non-coding RNA annotation of variants with P < 10-8 at the new cross-cancer risk loci listed in main Table 2. Supplementary Table S9. Eight of the 32 genes involved in induction of apoptosis through DR3 and DR4/5 Death Receptors (MSigDB: Biocarta "Death Pathway") a that were < 1 Mb away from an independent P < 10-5 index SNP in the 3-cancer meta-analysis. Supplementary Table S10. INRICH pathway analysis results for pathways with empirical P < 0.05. Apoptosis-related pathways containing BCL2L11 are shaded.

Published
2023

18. Supplementary Tables 2 - 5, Figures 2 - 3 from A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer

Author

Jyotsna Batra, Jong Y. Park, Judith A. Clements, Amanda B. Spurdle, Manuel R. Teixeira, Radka Kaneva, Hermann Brenner, Lisa Cannon-Albright, Cezary Cybulski, Adam S. Kibel, Christiane Maier, Stephen Thibodeau, William J. Blot, Janet L. Stanford, Kay-Tee Khaw, Paul Pharoah, David Neal, Ruth C. Travis, Børge G. Nordestgaard, Johanna Schleutker, Christopher A. Haiman, Henrik Gronberg, Fredrik Wiklund, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Doug Easton, Rosalind Eeles, Srilakshmi Srinivasan, Thomas A. Sellers, Jennifer Permuth-Wey, Hui-Yi Lin, Donghwa Kim, Tracy A. O'Mara, Kerenaftali Klein, Ernest Amankwah, and Shane Stegeman

Abstract

Supplementary Table 2. Indolent versus aggressive disease analysis. Supplementary Table 3. Geometric mean PSA levels by genotype in cases and controls. Supplementary Table 4. Association of miRSNPs with prostate cancer risk in different age categories. Supplementary Table 5. Association of miRSNPs with expression of genes located in cis using TCGA SNP array and RNASeq data. Supplementary Figure 2. miRNA target reporter vector assays. Supplementary Figure 3. miR-3162-5p is expressed in prostate and prostate cancer-derived cell lines as well as in prostate cancer patient tissue samples.

Published
2023

19. Supplementary Table 1 from A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer

Author

Jyotsna Batra, Jong Y. Park, Judith A. Clements, Amanda B. Spurdle, Manuel R. Teixeira, Radka Kaneva, Hermann Brenner, Lisa Cannon-Albright, Cezary Cybulski, Adam S. Kibel, Christiane Maier, Stephen Thibodeau, William J. Blot, Janet L. Stanford, Kay-Tee Khaw, Paul Pharoah, David Neal, Ruth C. Travis, Børge G. Nordestgaard, Johanna Schleutker, Christopher A. Haiman, Henrik Gronberg, Fredrik Wiklund, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Doug Easton, Rosalind Eeles, Srilakshmi Srinivasan, Thomas A. Sellers, Jennifer Permuth-Wey, Hui-Yi Lin, Donghwa Kim, Tracy A. O'Mara, Kerenaftali Klein, Ernest Amankwah, and Shane Stegeman

Abstract

Supplementary Table 1. Prostate cancer risk estimates for 2169 putative miRSNPs.

Published
2023

20. Supplementary Figure 1 from A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer

Author

Jyotsna Batra, Jong Y. Park, Judith A. Clements, Amanda B. Spurdle, Manuel R. Teixeira, Radka Kaneva, Hermann Brenner, Lisa Cannon-Albright, Cezary Cybulski, Adam S. Kibel, Christiane Maier, Stephen Thibodeau, William J. Blot, Janet L. Stanford, Kay-Tee Khaw, Paul Pharoah, David Neal, Ruth C. Travis, Børge G. Nordestgaard, Johanna Schleutker, Christopher A. Haiman, Henrik Gronberg, Fredrik Wiklund, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Doug Easton, Rosalind Eeles, Srilakshmi Srinivasan, Thomas A. Sellers, Jennifer Permuth-Wey, Hui-Yi Lin, Donghwa Kim, Tracy A. O'Mara, Kerenaftali Klein, Ernest Amankwah, and Shane Stegeman

Abstract

Supplementary Figure 1. Forest Plot (Fixed effects model) of the 22 prostate cancer risk associated miRSNPs.

Published
2023

21. Supplemental Figure Legend from Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus

Author

Angela Cox, Jason Gertz, Malcolm W.R. Reed, Theresa L. Werner, Ryan Abo, Stacey Knight, Lisa Cannon-Albright, Philip S. Bernard, Rachel E. Factor, Guoying Wang, Robert Sargent, Dan Connley, Brandt Jones, Ian W. Brock, Rachel Cosby, Venkatesh Rajamanickam, Kristofer Berrett, Pei-Yi Tai, Sushilaben H. Rigas, Rosalie G. Waller, Marina A. Parry, Timothy L. Mosbruger, George J. Burghel, Alex Bigelow, Wei-Yu Lin, and Nicola J. Camp

Abstract

Supplemental Figure Legend

Published
2023

22. Supplementary Figure 3 from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Author

Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama

Abstract

Supplementary Figure 3. Absolute Risk (A model with only family history of prostate cancer)

Published
2023

23. Supplementary notes from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author

Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin

Abstract

Supplementary acknowledgments.

Published
2023

24. Supplemental Figure from Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus

Author

Angela Cox, Jason Gertz, Malcolm W.R. Reed, Theresa L. Werner, Ryan Abo, Stacey Knight, Lisa Cannon-Albright, Philip S. Bernard, Rachel E. Factor, Guoying Wang, Robert Sargent, Dan Connley, Brandt Jones, Ian W. Brock, Rachel Cosby, Venkatesh Rajamanickam, Kristofer Berrett, Pei-Yi Tai, Sushilaben H. Rigas, Rosalie G. Waller, Marina A. Parry, Timothy L. Mosbruger, George J. Burghel, Alex Bigelow, Wei-Yu Lin, and Nicola J. Camp

Abstract

Supplemental Figure: Description of sample sets for the DNAseq and RNAseq experiments.

Published
2023

25. Supplementary Notes from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Author

Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama

Abstract

Supplementary Notes. This document includes description of studies that they have been used for the analysis.

Published
2023

26. Supplemental Methods and Supplemental Table from Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus

Author

Angela Cox, Jason Gertz, Malcolm W.R. Reed, Theresa L. Werner, Ryan Abo, Stacey Knight, Lisa Cannon-Albright, Philip S. Bernard, Rachel E. Factor, Guoying Wang, Robert Sargent, Dan Connley, Brandt Jones, Ian W. Brock, Rachel Cosby, Venkatesh Rajamanickam, Kristofer Berrett, Pei-Yi Tai, Sushilaben H. Rigas, Rosalie G. Waller, Marina A. Parry, Timothy L. Mosbruger, George J. Burghel, Alex Bigelow, Wei-Yu Lin, and Nicola J. Camp

Abstract

Equations to calculate sample size in a homozygous discordant design. Supplemental Table: Sample size requirements (n in each group)

Published
2023

27. Supplementary Figure 1 from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Author

Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama

Abstract

Supplementary Figure 1. Absolute Risk (With family history of prostate cancer)

Published
2023

28. Data from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Author

Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama

Abstract

Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09).Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.

Published
2023

29. Data from Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus

Author

Angela Cox, Jason Gertz, Malcolm W.R. Reed, Theresa L. Werner, Ryan Abo, Stacey Knight, Lisa Cannon-Albright, Philip S. Bernard, Rachel E. Factor, Guoying Wang, Robert Sargent, Dan Connley, Brandt Jones, Ian W. Brock, Rachel Cosby, Venkatesh Rajamanickam, Kristofer Berrett, Pei-Yi Tai, Sushilaben H. Rigas, Rosalie G. Waller, Marina A. Parry, Timothy L. Mosbruger, George J. Burghel, Alex Bigelow, Wei-Yu Lin, and Nicola J. Camp

Abstract

The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916–25. ©2016 AACR.

Published
2023

30. Supplementary Tables 1-8 from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Author

Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama

Abstract

Supplementary Tables 1-8. Supplementary table 1: Total number of cases and controls in PRACTICAL III and GWAS stage 3 by population and study. Supplementary Table 2: Data information for family history and age at diagnosis/observation. Supplementary Table 3: Grade-specific and family history-specific odds ratios. Supplementary Table 4: PSA levels by genotype in controls. Supplementary Table 5: Age-specific odds ratios. Supplementary Table 6: The results of 29 pair wise interaction of 25 SNPs significant at P

Published
2023

31. Data from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author

Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin

Abstract

Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).Results: We observed no significant association between genetic variants and prostate cancer survival.Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study.Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.

Published
2023

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

Author

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

Subjects
Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, Proportional hazards model, Genetic genealogy, Ethnic group, Distant metastasis, Ethnic populations, medicine.disease, Health equity, 3. Good health, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Genotype, Medicine, business, 030304 developmental biology
Abstract

ObjectivesA polygenic hazard score (PHS1)—weighted sum of 54 single-nucleotide polymorphism genotypes—was previously associated with age at prostate cancer (PCa) diagnosis and improved PCa screening accuracy in Europeans. Performance in more diverse populations is unknown. We evaluated PHS association with PCa in multi-ethnic populations.DesignPHS1 was adapted for compatibility with genotype data from the OncoArray project (PHS2) and tested for association with age at PCa diagnosis, at aggressive PCa diagnosis, and at PCa death.SettingMultiple international institutions.ParticipantsMen with available OncoArray data from the PRACTICAL consortium who were not included in PHS1 development/validation.Main Outcomes and MeasuresPHS2 was tested via Cox proportional hazards models for age at PCa diagnosis, age at aggressive PCa diagnosis (any of: Gleason score ≥7, stage T3-T4, PSA≥10 ng/mL, nodal/distant metastasis), and age at PCa-specific death.Results80,491 men of various self-reported race/ethnicities were included (30,575 controls, 49,916 PCa cases; genetic ancestry groups: 71,856 European, 6,253 African, 2,382 Asian). Median age at last follow-up was 70 years (IQR 63-76); 3,983 PCa deaths, 5,806 other deaths, 70,702 still alive. PHS2 had 46 polymorphisms: 24 directly genotyped and 22 acceptable proxies (r2 ≥0.94). PHS2 was associated with age at PCa diagnosis in the multi-ethnic dataset (z=54, p-16) and in each genetic ancestry group: European (z=56, p-16), Asian (z=47, p-16), African (z=29, p-16). PHS2 was also associated with age at aggressive PCa diagnosis in each genetic ancestry group (p-16) and with age of PCa death in the full dataset (p-16). Comparing the 80th and 20th percentiles of genetic risk, men with high PHS had hazard ratios of 5.3 [95% CI: 5.0-5.7], 5.9 [5.5-6.3], and 5.7 [4.6-7.0] for PCa, aggressive PCa, and PCa-specific death, respectively. Within European, Asian, and African ancestries, analogous hazard ratios for PCa were 5.5 [5.2-5.9], 4.5 [3.2-6.3], and 2.5 [2.1-3.1], respectively.ConclusionsPHS2 is strongly associated with age at PCa diagnosis in a multi-ethnic dataset. PHS2 stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal PCa.Summary boxesWhat is already known on this topicGenetic risk stratification can identify men with greater predisposition for developing prostate cancer, but these risk models may worsen health disparities, as most have only been validated for men of European ancestryA polygenic hazard score was previously associated with age at prostate cancer diagnosis and improved PCa screening accuracy in EuropeansPerformance of the polygenic hazard score in multi-ethnic populations is unknownWhat this study addsIn a dataset from 80,491 men of various self-reported race/ethnicities, the polygenic hazard score was associated with age at prostate cancer diagnosis, aggressive prostate cancer diagnosis, and prostate cancer death.PHS stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal prostate cancer.

Published
2019

34. Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

Author

Edward J, Saunders, Tokhir, Dadaev, Daniel A, Leongamornlert, Ali Amin, Al Olama, Sara, Benlloch, Graham G, Giles, Fredrik, Wiklund, Henrik, Gronberg, Christopher A, Haiman, Johanna, Schleutker, Borge G, Nordestgaard, Ruth C, Travis, David, Neal, Nora, Pasayan, Kay-Tee, Khaw, Janet L, Stanford, William J, Blot, Stephen N, Thibodeau, Christiane, Maier, Adam S, Kibel, Cezary, Cybulski, Lisa, Cannon-Albright, Hermann, Brenner, Jong Y, Park, Radka, Kaneva, Jyotsna, Batra, Manuel R, Teixeira, Hardev, Pandha, Koveela, Govindasami, Ken, Muir, Douglas F, Easton, Rosalind A, Eeles, and Sarah, Tidball

Subjects
Male, Risk, genome-wide association study, Genotype, BRCA1 Protein, Genes, BRCA2, Prostatic Neoplasms, DNA repair, Cell Cycle Proteins, Genetics and Genomics, DNA, urologic and male genital diseases, prostate cancer, Polymorphism, Single Nucleotide, iCOGS, DNA-Binding Proteins, DNA Repair Enzymes, Case-Control Studies, Humans, GWAS, Genetic Predisposition to Disease, Prospective Studies, Corrigendum, Germ-Line Mutation
Abstract

Background: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. Methods: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. Results: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. Conclusions: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Published
2016

35. Prediction of Individual Genetic Risk to Prostate Cancer Using a Polygenic Score

Author

Robert, Szulkin, Thomas, Whitington, Martin, Eklund, Markus, Aly, Rosalind A, Eeles, Douglas, Easton, Z Sofia, Kote-Jarai, Ali, Amin Al Olama, Sara, Benlloch, Kenneth, Muir, Graham G, Giles, Melissa C, Southey, Liesel M, Fitzgerald, Brian E, Henderson, Fredrick, Schumacher, Christopher A, Haiman, Johanna, Schleutker, Tiina, Wahlfors, Teuvo L J, Tammela, Børge G, Nordestgaard, Tim J, Key, Ruth C, Travis, David E, Neal, Jenny L, Donovan, Freddie C, Hamdy, Paul, Pharoah, Nora, Pashayan, Kay-Tee, Khaw, Janet L, Stanford, Stephen N, Thibodeau, Shannon K, McDonnell, Daniel J, Schaid, Christiane, Maier, Walther, Vogel, Manuel, Luedeke, Kathleen, Herkommer, Adam S, Kibel, Cezary, Cybulski, Jan, Lubiński, Wojciech, Kluźniak, Lisa, Cannon-Albright, Hermann, Brenner, Katja, Butterbach, Christa, Stegmaier, Jong Y, Park, Thomas, Sellers, Hui-Yi, Lin, Hui-Yi, Lim, Chavdar, Slavov, Radka, Kaneva, Vanio, Mitev, Jyotsna, Batra, Judith A, Clements, Amanda, Spurdle, Manuel R, Teixeira, Paula, Paulo, Sofia, Maia, Hardev, Pandha, Agnieszka, Michael, Andrzej, Kierzek, Henrik, Gronberg, and Danielle M, Karyadi

Subjects
Genetic Markers, Male, Risk Factors, Genetic Variation, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Linkage Disequilibrium, Article
Abstract

BACKGROUND. Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS. We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS. The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5 E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS. Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.

Published
2015

36. Haplotype and Phenotype Analysis of Nine Recurrent BRCA2 Mutations in 111 Families: Results of an International Study

Author

Susan L. Neuhausen, Andrew K. Godwin, Ruth Gershoni-Baruch, Elizabeth Schubert, Judy Garber, Dominique Stoppa-Lyonnet, Edith Olah, Bela Csokay, Olga Serova, Fiona Lalloo, Ana Osorio, Michael Stratton, Kenneth Offit, Jeff Boyd, M. Adelaide Caligo, Rodney J. Scott, Andy Schofield, Eric Teugels, Manfred Schwab, Lisa Cannon-Albright, Timothy Bishop, Douglas Easton, Javier Benitez, Mary-Claire King, Bruce A.J. Ponder, Barbara Weber, Peter Devilee, Åke Borg, Steven A. Narod, and David Goldgar

Subjects
Adult, Genetic Markers, Male, Cancer, breast, Genotype, endocrine system diseases, Breast Neoplasms, Biology, Gene mutation, Genetic determinism, Breast Neoplasms, Male, Evolution, Molecular, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Ovarian cancer, Haplotype, Genetics, medicine, Humans, Genetics(clinical), skin and connective tissue diseases, Genetics (clinical), Repetitive Sequences, Nucleic Acid, 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, 0303 health sciences, Polymorphism, Genetic, mutation origin, medicine.disease, BRCA2, Neoplasm Proteins, 3. Good health, Phenotype, Haplotypes, 030220 oncology & carcinogenesis, Mutation, Cancer, ovarian, Female, Age of onset, Transcription Factors, Research Article
Abstract

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P

Published
1998

37. A population-based analysis of clustering identifies a strong genetic contribution to lethal prostate cancer

Author

Quentin eNelson, Neeraj eAgarwal, Robert eStephenson, and Lisa Cannon Albright

Subjects
Oncology, medicine.medical_specialty, lcsh:QH426-470, lethal, Pedigree chart, Disease cluster, Body Mass Index, Familial prostate cancer, Prostate cancer, recurrent, Genetic linkage, Internal medicine, Genetics, medicine, Original Research Article, UPDB, Cluster analysis, Genetics (clinical), business.industry, Cancer, prostate cancer, medicine.disease, Familiality, lcsh:Genetics, Molecular Medicine, business, Body mass index
Abstract

Background: Prostate cancer is a common and often deadly cancer. Decades of study have yet to identify genes that explain much familial prostate cancer. Traditional linkage analysis of pedigrees has yielded results that are rarely validated. We hypothesize that there are rare segregating variants responsible for high-risk prostate cancer pedigrees, but recognize that within-pedigree heterogeneity is responsible for significant noise that overwhelms signal. Here we introduce a new method to identify homogeneous subsets of prostate cancer, based on cancer characteristics, that show the best evidence for an inherited contribution. Methods: We have modified an existing method, the Genealogical Index of Familiality used to show evidence for significant familial clustering. The modification allows a test for excess familial clustering of a subset of prostate cancer cases when compared to all prostate cancer cases.Results: Consideration of the familial clustering of 8 clinical subsets of prostate cancer cases compared to the expected familial clustering of all prostate cancer cases identified four subsets of prostate cancer cases with evidence for familial clustering significantly in excess of expected. These subsets include prostate cancer cases diagnosed before age 50 years, prostate cancer cases who survived at least 10 years after diagnosis, prostate cancer cases with BMI greater than or equal to 30, and prostate cancer cases for whom prostate cancer contributed to death.Conclusions: This analysis identified several subsets of prostate cancer cases that cluster significantly more than expected when compared to all prostate cancer familial clustering. A focus on high-risk prostate cancer pedigrees with these characteristics will reduce noise and could allow identification of the rare predisposition genes or variants responsible.

Published
2013

39. Enabling GeneHunter as a grid service: a case study for implementing analytical services for biomedical grids

Author

Sergey, Krikov, Ronald C, Price, Kristina, Allen-Brady, Lisa, Cannon-Albright, and Julio C, Facelli

Subjects
Internet, User-Computer Interface, Utah, Chromosome Mapping, Computational Biology, Software
Abstract

Advances in grid computing show promise for easier provisioning of analytical services to biomedical researchers. In this poster we present our experiences in creating a grid analytical service based on the popular genetic linkage analysis tool GeneHunter. We have implemented and deployed this grid service using tools available from the caGrid project. Our results show that caGrid tools are quite effective and compare favorably with other existing methodologies.

Published
2008

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