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1. Self-rated health, epigenetic ageing, and long-term mortality in older Australians

Author: Li, Danmeng Lily, Hodge, Allison M., Southey, Melissa C., Giles, Graham G., Milne, Roger L., and Dugué, Pierre-Antoine
Abstract: Self-rated health (SRH) is a subjective indicator of overall health based on a single questionnaire item. Previous evidence found that it is a strong predictor of mortality, although the underlying mechanism is poorly understood. Epigenetic age is an objective, emerging biomarker of health, estimated using DNA methylation data at hundreds of sites across the genome. This study aimed to assess the overlap and interaction between SRH and epigenetic ageing in predicting mortality risk. We used DNA methylation data from 1059 participants in the Melbourne Collaborative Cohort Study (mean age: 69 years) to calculate three age-adjusted measures of epigenetic ageing: GrimAge, PhenoAge, and DunedinPACE. SRH was assessed using a five-category questionnaire item (“excellent, very good, good, fair, poor”). Cox models were used to assess the associations of SRH, epigenetic ageing, and their interaction, with all-cause mortality over up to 17 years of follow-up (Ndeaths= 345). The association of SRH with mortality per category increase was HR = 1.29; 95%CI: 1.14–1.46. The association was slightly attenuated after adjusting for all three epigenetic ageing measures (HR = 1.25, 95%CI: 1.10–1.41). A strong gradient was observed in the association of GrimAge(Pinteraction= 0.006) and DunedinPACE(Pinteraction= 0.002) with mortality across worsening SRH strata. For example, the association between DunedinPACEand mortality in participants with “excellent” SRH was HR = 1.02, 95%CI: 0.73–1.43 and for “fair/poor” HR = 1.72, 95%CI: 1.35–2.20. SRH and epigenetic ageing were synergistic risk factors of mortality in our study. These findings suggest that consideration of subjective and objective factors may improve general health assessment, which has implications for the ongoing development of molecular markers of ageing.
Published: 2024
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2. Dietary factors and DNA methylation-based markers of ageing in 5310 middle-aged and older Australian adults

Author: Cribb, Lachlan, Hodge, Allison M., Southey, Melissa C., Giles, Graham G., Milne, Roger L., and Dugué, Pierre-Antoine
Abstract: The role of nutrition in healthy ageing is acknowledged but details of optimal dietary composition are still uncertain. We aimed to investigate the cross-sectional associations between dietary exposures, including macronutrient composition, food groups, specific foods, and overall diet quality, with methylation-based markers of ageing. Blood DNA methylation data from 5310 participants (mean age 59 years) in the Melbourne Collaborative Cohort Study were used to calculate five methylation-based measures of ageing: PCGrimAge, PCPhenoAge, DunedinPACE, ZhangAge, TelomereAge. For a range of dietary exposures, we estimated (i) the ‘equal-mass substitution effect’, which quantifies the effect of adding the component of interest to the diet while keeping overall food mass constant, and (ii) the ‘total effect’, which quantifies the effect of adding the component of interest to the current diet. For ‘equal-mass substitution effects’, the strongest association for macronutrients was for fibre intake (e.g. DunedinPACE, per 12 g/day − 0.10 [standard deviations]; 95%CI − 0.15, − 0.05, p< 0.001). Associations were positive for protein (e.g. PCGrimAge, per 33 g/day 0.04; 95%CI 0.01–0.08, p= 0.005). For food groups, the evidence tended to be weak, though sugar-sweetened drinks showed positive associations, as did artificially-sweetened drinks (e.g. DunedinPACE, per 91 g/day 0.06, 95%CI 0.03–0.08, p< 0.001). ‘Total effect’ estimates were generally very similar. Scores reflecting overall diet quality suggested that healthier diets were associated with lower levels of ageing markers. High intakes of fibre and low intakes of protein and sweetened drinks, as well as overall healthy diets, showed the most consistent associations with lower methylation-based ageing in our study.
Published: 2024
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3. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Author: Wang, Anqi, Shen, Jiayi, Rodriguez, Alex A., Saunders, Edward J., Chen, Fei, Janivara, Rohini, Darst, Burcu F., Sheng, Xin, Xu, Yili, Chou, Alisha J., Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Plym, Anna, Sahimi, Ali, Hoffman, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Laisk, Triin, Figuerêdo, Jéssica, Muir, Kenneth, Ito, Shuji, Liu, Xiaoxi, Uchio, Yuji, Kubo, Michiaki, Kamatani, Yoichiro, Lophatananon, Artitaya, Wan, Peggy, Andrews, Caroline, Lori, Adriana, Choudhury, Parichoy P., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Rentsch, Christopher T., Cho, Kelly, Mcmahon, Benjamin H., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Borge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Andreas, Stroomberg, Hein V., Batra, Jyotsna, Chambers, Suzanne, Horvath, Lisa, Clements, Judith A., Tilly, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordstrom, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie, Cook, Michael B., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Koutros, Stella, Beane Freeman, Laura E., Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Geraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Butler, Ebonee N., Mohler, James L., Taylor, Jack A., Kogevinas, Manolis, Dierssen-Sotos, Trinidad, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Pilie, Patrick, Yu, Yao, Bohlender, Ryan J., Gu, Jian, Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Brenner, Hermann, Chen, Xuechen, Holleczek, Bernd, Schöttker, Ben, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine M., Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Abraham, Aswin, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer, Petrovics, Gyorgy, Casey, Graham, Wang, Ying, Tettey, Yao, Lachance, Joseph, Tang, Wei, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Yamoah, Kosj, Govindasami, Koveela, Chokkalingam, Anand P., Keaton, Jacob M., Hellwege, Jacklyn N., Clark, Peter E., Jalloh, Mohamed, Gueye, Serigne M., Niang, Lamine, Ogunbiyi, Olufemi, Shittu, Olayiwola, Amodu, Olukemi, Adebiyi, Akindele O., Aisuodionoe-Shadrach, Oseremen I., Ajibola, Hafees O., Jamda, Mustapha A., Oluwole, Olabode P., Nwegbu, Maxwell, Adusei, Ben, Mante, Sunny, Darkwa-Abrahams, Afua, Diop, Halimatou, Gundell, Susan M., Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Kachuri, Linda, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Preuss, Michael H., Loos, Ruth J. F., Zawistowski, Matthew, Zöllner, Sebastian, Lu, Zeyun, Van Den Eeden, Stephen K., Easton, Douglas F., Ambs, Stefan, Edwards, Todd L., Mägi, Reedik, Rebbeck, Timothy R., Fritsche, Lars, Chanock, Stephen J., Berndt, Sonja I., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Gaziano, J. Michael, Justice, Amy C., Mancuso, Nick, Terao, Chikashi, Eeles, Rosalind A., Kote-Jarai, Zsofia, Madduri, Ravi K., Conti, David V., and Haiman, Christopher A.
Abstract: The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P= 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
Published: 2023
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4. Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer

Author: Darst, Burcu F., Saunders, Ed, Dadaev, Tokhir, Sheng, Xin, Wan, Peggy, Pooler, Loreall, Xia, Lucy Y., Chanock, Stephen, Berndt, Sonja I., Wang, Ying, Patel, Alpa V., Albanes, Demetrius, Weinstein, Stephanie J., Gnanapragasam, Vincent, Huff, Chad, Couch, Fergus J., Wolk, Alicja, Giles, Graham G., Nguyen-Dumont, Tu, Milne, Roger L., Pomerantz, Mark M., Schmidt, Julie A., Travis, Ruth C., Key, Timothy J., Stopsack, Konrad H., Mucci, Lorelei A., Catalona, William J., Marosy, Beth, Hetrick, Kurt N., Doheny, Kimberly F., MacInnis, Robert J., Southey, Melissa C., Eeles, Rosalind A., Wiklund, Fredrik, Conti, David V., Kote-Jarai, Zsofia, and Haiman, Christopher A.
Abstract: IMPORTANCE: Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. OBJECTIVE: To identify genes associated with aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. EXPOSURE: Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. MAIN OUTCOMES AND MEASURES: The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. RESULTS: A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10−6), followed by NBN (P = 1.7 × 10−4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. CONCLUSIONS AND RELEVANCE: The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.
Published: 2023
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5. FANCMmissense variants and breast cancer risk: a case-control association study of 75,156 European women

Author: Figlioli, Gisella, Billaud, Amandine, Ahearn, Thomas U., Antonenkova, Natalia N., Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J., Bogdanova, Natalia V., Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Cessna, Melissa H., Chanock, Stephen J., Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine D., Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A., He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K., Ko, Yon-Dschun, Kristensen, Vessela N., Lindblom, Annika, Lissowska, Jolanta, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Newman, William G., Obi, Nadia, Panayiotidis, Mihalis I., Rashid, Muhammad U., Rhenius, Valerie, Rookus, Matti A., Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sironen, Reijo, Southey, Melissa C., Suvanto, Maija, Tollenaar, Rob A. E. M., Tomlinson, Ian, Truong, Thérèse, van der Kolk, Lizet E., van Veen, Elke M., Wappenschmidt, Barbara, Yang, Xiaohong R., Bolla, Manjeet K., Dennis, Joe, Dunning, Alison M., Easton, Douglas F., Lush, Michael, Michailidou, Kyriaki, Pharoah, Paul D. P., Wang, Qin, Adank, Muriel A., Schmidt, Marjanka K., Andrulis, Irene L., Chang-Claude, Jenny, Nevanlinna, Heli, Chenevix-Trench, Georgia, Evans, D. Gareth, Milne, Roger L., Radice, Paolo, and Peterlongo, Paolo
Abstract: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCMconfer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCMmissense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCMMVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04; P= 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCMMVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38; P= 0.002). Our results support the definition from previous analyses of FANCMas a moderate-risk breast cancer gene and provide evidence that FANCMMVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCMMVs.
Published: 2023
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6. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author: Levi, Hagai, Carmi, Shai, Rosset, Saharon, Yerushalmi, Rinat, Zick, Aviad, Yablonski-Peretz, Tamar, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Lush, Michael, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Augustinsson, Annelie, Auvinen, Pa¨ivi, Beane Freeman, Laura, Beckmann, Matthias, Behrens, Sabine, Bermisheva, Marina, Bodelon, Clara, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Byers, Helen, Camp, Nicola, Castelao, Jose, Chang-Claude, Jenny, Chirlaque, María-Dolores, Chung, Wendy, Clarke, Christine, Collee, Margriet J, Colonna, Sarah, Couch, Fergus, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary, Devilee, Peter, Dork, Thilo, Dossus, Laure, Eccles, Diana M, Eliassen, A. Heather, Eriksson, Mikael, Evans, Gareth, Fasching, Peter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Garcia-Saenz, Jose Angel, Genkinger, Jeanine, Giles, Graham G, Goldberg, Mark, Guénel, Pascal, Hall, Per, Hamann, Ute, He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John, Jakovchevska, Simona, Jakubowska, Anna, Jernstro¨m, Helena, John, Esther, Johnson, Nichola, Jones, Michael, Vijai, Joseph, Kaaks, Rudolf, Khusnutdinova, Elza, Kitahara, Cari, Koutros, Stella, Kristensen, Vessela, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Loibl, Sibylle, Lori, Adriana, Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Mavroudis, Dimitrios, Menon, Usha, Mulligan, AnnaMarie, Murphy, Rachel, Nevelsteen, Ines, Newman, William G, Obi, Nadia, O'Brien, Katie, Offit, Ken, Olshan, Andrew, Plaseska-Karanfilska, Dijana, Olson, Janet, Panico, Salvatore, Park-Simon, Tjoung-Won, Patel, Alpa, Peterlongo, Paolo, Rack, Brigitte, Radice, Paolo, Rennert, Gad, Rhenius, Valerie, Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale, Schmidt, Marjanka K, Schwentner, Lukas, Shah, Mitul, Sharma, Priyanka, Simard, Jacques, Southey, Melissa, Stone, Jennifer, Tapper, William J, Taylor, Jack, Teras, Lauren, Toland, Amanda E, Troester, Melissa, Truong, Thérèse, van der Kolk, Lizet E, Weinberg, Clarice, Wendt, Camilla, Yang, Xiaohong Rose, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M, Pharoah, Paul, Easton, Douglas F, Ben-Sachar, Shay, Elefant, Naama, Shamir, Ron, and Elkon, Ran
Abstract: BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Published: 2023
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7. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author: Fernandez-Rozadilla, Ceres, Timofeeva, Maria, Chen, Zhishan, Law, Philip, Thomas, Minta, Schmit, Stephanie, Díez-Obrero, Virginia, Hsu, Li, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah, Svinti, Victoria, Donnelly, Kevin, Farrington, Susan, Blackmur, James, Vaughan-Shaw, Peter, Shu, Xiao-ou, Long, Jirong, Cai, Qiuyin, Guo, Xingyi, Lu, Yingchang, Broderick, Peter, Studd, James, Huyghe, Jeroen, Harrison, Tabitha, Conti, David, Dampier, Christopher, Devall, Mathew, Schumacher, Fredrick, Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Moratalla-Navarro, Ferran, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John, Jenkins, Mark, Win, Aung Ko, Pai, Rish, Figueiredo, Jane, Haile, Robert, Gallinger, Steven, Woods, Michael, Newcomb, Polly, Duggan, David, Cheadle, Jeremy, Kaplan, Richard, Maughan, Timothy, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Lukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri, Rissanen, Harri, Pukkala, Eero, Eriksson, Johan, Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Zanke, Brent, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie, Ruiz-Narvaez, Edward, Palmer, Julie, Buchanan, Daniel, Platz, Elizabeth, Visvanathan, Kala, Ulrich, Cornelia, Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha, Potter, John, Tsilidis, Konstantinos, Schulze, Matthias, Gunter, Marc, Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Stern, Mariana, Pardamean, Bens, Bishop, Timothy, Giles, Graham, Southey, Melissa, Idos, Gregory, McDonnell, Kevin, Abu-Ful, Zomoroda, Greenson, Joel, Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope, van Guelpen, Bethany, Hudson, Thomas, Hampel, Heather, Pearlman, Rachel, Berndt, Sonja, Hayes, Richard, Martinez, Marie Elena, Thomas, Sushma, Corley, Douglas, Pharoah, Paul, Larsson, Susanna, Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly, Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew, Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David, Joshi, Amit, Schafmayer, Clemens, Scacheri, Peter, Kundaje, Anshul, Nickerson, Deborah, Schoen, Robert, Hampe, Jochen, Stadler, Zsofia, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Papadopoulos, Nickolas, Edlund, Chistopher, Gauderman, William, Thomas, Duncan, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen, van Duijnhoven, Franzel, Feskens, Edith, Sakoda, Lori, Gago-Dominguez, Manuela, Wolk, Alicja, Naccarati, Alessio, Pardini, Barbara, FitzGerald, Liesel, Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie, Kooperberg, Charles, Li, Christopher, Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Tangen, Catherine, Mardis, Elaine, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Haiman, Christopher, Le Marchand, Loic, Wu, Anna, Qu, Chenxu, McNeil, Caroline, Coetzee, Gerhard, Hayward, Caroline, Deary, Ian, Harris, Sarah, Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Moreno, Victor, Casey, Graham, Gruber, Stephen, Tomlinson, Ian, Zheng, Wei, Dunlop, Malcolm, Houlston, Richard, and Peters, Ulrike
Abstract: Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
Published: 2023
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8. Does genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?

Author: Yu, Chenglong, Hodge, Allison M, Wong, Ee Ming, Joo, Jihoon E, Makalic, Enes, Schmidt, Daniel F, Buchanan, Daniel D, Severi, Gianluca, Hopper, John L, English, Dallas R, Giles, Graham G, Milne, Roger L, Southey, Melissa C, and Dugué, Pierre-Antoine
Abstract: ABSTRACTLifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N= 7,431) and validation (N= 4,307) samples. Using paired genetic-methylation data (N= 4,307), gene–environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAgeand GrimAge. In the validation sample, PGS explained ~1.4% (P= 1 × 10−14), ~0.6% (P= 2 × 10−7), and ~8.7% (P= 7 × 10−87) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P< 0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption, and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with PhenoAgeand GrimAge, except for alcohol consumption with PhenoAge. There was weak evidence that the association of smoking with GrimAgewas attenuated in participants genetically predisposed to smoking (interaction term: −0.022, standard error [SE] = 0.012, P= 0.058) and that the association of alcohol consumption with PhenoAgewas attenuated in those genetically predisposed to drink alcohol (interaction term: −0.030, SE = 0.015, P= 0.041). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify the association between observed lifestyle behaviour and blood DNA methylation. Potential associations were observed for epigenetic ageing measures, which should be replicated in additional studies.
Published: 2022
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9. Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Author: Berndt, Sonja I., Vijai, Joseph, Benavente, Yolanda, Camp, Nicola J., Nieters, Alexandra, Wang, Zhaoming, Smedby, Karin E., Kleinstern, Geffen, Hjalgrim, Henrik, Besson, Caroline, Skibola, Christine F., Morton, Lindsay M., Brooks-Wilson, Angela R., Teras, Lauren R., Breeze, Charles, Arias, Joshua, Adami, Hans-Olov, Albanes, Demetrius, Anderson, Kenneth C., Ansell, Stephen M., Bassig, Bryan, Becker, Nikolaus, Bhatti, Parveen, Birmann, Brenda M., Boffetta, Paolo, Bracci, Paige M., Brennan, Paul, Brown, Elizabeth E., Burdett, Laurie, Cannon-Albright, Lisa A., Chang, Ellen T., Chiu, Brian C. H., Chung, Charles C., Clavel, Jacqueline, Cocco, Pierluigi, Colditz, Graham, Conde, Lucia, Conti, David V., Cox, David G., Curtin, Karen, Casabonne, Delphine, De Vivo, Immaculata, Diver, W. Ryan, Dogan, Ahmet, Edlund, Christopher K., Foretova, Lenka, Fraumeni, Joseph F., Gabbas, Attilio, Ghesquières, Hervé, Giles, Graham G., Glaser, Sally, Glenn, Martha, Glimelius, Bengt, Gu, Jian, Habermann, Thomas M., Haiman, Christopher A., Haioun, Corinne, Hofmann, Jonathan N., Holford, Theodore R., Holly, Elizabeth A., Hutchinson, Amy, Izhar, Aalin, Jackson, Rebecca D., Jarrett, Ruth F., Kaaks, Rudolph, Kane, Eleanor, Kolonel, Laurence N., Kong, Yinfei, Kraft, Peter, Kricker, Anne, Lake, Annette, Lan, Qing, Lawrence, Charles, Li, Dalin, Liebow, Mark, Link, Brian K., Magnani, Corrado, Maynadie, Marc, McKay, James, Melbye, Mads, Miligi, Lucia, Milne, Roger L., Molina, Thierry J., Monnereau, Alain, Montalvan, Rebecca, North, Kari E., Novak, Anne J., Onel, Kenan, Purdue, Mark P., Rand, Kristin A., Riboli, Elio, Riby, Jacques, Roman, Eve, Salles, Gilles, Sborov, Douglas W., Severson, Richard K., Shanafelt, Tait D., Smith, Martyn T., Smith, Alexandra, Song, Kevin W., Song, Lei, Southey, Melissa C., Spinelli, John J., Staines, Anthony, Stephens, Deborah, Sutherland, Heather J., Tkachuk, Kaitlyn, Thompson, Carrie A., Tilly, Hervé, Tinker, Lesley F., Travis, Ruth C., Turner, Jenny, Vachon, Celine M., Vajdic, Claire M., Van Den Berg, Anke, Van Den Berg, David J., Vermeulen, Roel C. H., Vineis, Paolo, Wang, Sophia S., Weiderpass, Elisabete, Weiner, George J., Weinstein, Stephanie, Doo, Nicole Wong, Ye, Yuanqing, Yeager, Meredith, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zhang, Yawei, Zheng, Tongzhang, Ziv, Elad, Sampson, Joshua, Chatterjee, Nilanjan, Offit, Kenneth, Cozen, Wendy, Wu, Xifeng, Cerhan, James R., Chanock, Stephen J., Slager, Susan L., and Rothman, Nathaniel
Abstract: Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P< 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P= 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P< 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
Published: 2022
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10. A validation of models for prediction of pathogenic variants in mismatch repair genes

Author: Shyr, Cathy, Blackford, Amanda L., Huang, Theodore, Ke, Jianfeng, Ouardaoui, Nofal, Trippa, Lorenzo, Syngal, Sapna, Ukaegbu, Chinedu, Uno, Hajime, Nafa, Khedoudja, Stadler, Zsofia K., Offit, Kenneth, Amos, Christopher I., Lynch, Patrick M., Chen, Sining, Giardiello, Francis M., Buchanan, Daniel D., Hopper, John L., Jenkins, Mark A., Southey, Melissa C., Win, Aung Ko, Figueiredo, Jane C., Braun, Danielle, and Parmigiani, Giovanni
Abstract: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer.
Published: 2022
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11. Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival

Author: Azzato, Elizabeth M., Tyrer, Jonathan, Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Schulz-Wendtland, Rudiger, Bojesen, Stig E., Nordestgaard, Berge G., Flyger, Henrik, Milne, Roger L., Arias, Jose Ignacio, Menendez, Primitiva, Benitez, Javier, Chang-Claude, Jenny, Hein, Rebecca, Wang-Gohrke, Shah, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomaki, Kristiina, Blomqvist, Carl, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Kataja, Vesa, Beesley, Jonathan, Chen, Xiaoqing, Chenevix-Trench, Georgia, Couch, Fergus J., Olson, Janet E., Fredericksen, Zachary S., Wang, Xianshu, Giles, Graham G., Severi, Gianluca, Baglietto, Laura, Southey, Melissa C., Devilee, Peter, Tollenaar, Rob A.E.M., Seynaeve, Caroline, Garcia-Closas, Montserrat, Lissowska, Jolanta, Sherman, Mark E., Bolton, Kelly L., Hall, Per, Czene, Kamila, Cox, Angela, Brock, Ian W., Elliott, Graeme C., Reed, Malcolm W.R., Greenberg, David, Anton-Culver, Hoda, Ziogas, Argyrios, Humphreys, Manjeet, Easton, Douglas F., Caporaso, Neil E., and Pharoah, Paul D.P.
Subjects: Breast cancer -- Genetic aspects, Breast cancer -- Care and treatment, Breast cancer -- Patient outcomes, Cancer survivors -- Genetic aspects, Cancer survivors -- Research, Genetic polymorphisms -- Health aspects, Genetic polymorphisms -- Research, Estrogen -- Receptors, Estrogen -- Physiological aspects, Estrogen -- Genetic aspects, Health
Abstract: BackgroundTraditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted twostage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. Methods We evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 gerreline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with highdensity oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. Results In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gone at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x [10.sup.-5]). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P= 5 x [10.sup.4]). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer. DOI: 10.1093/jnci/djq057
Published: 2010

12. ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer

Author: Severi, Gianluca, Giles, Graham G., Southey, Melissa C., Tesoriero, Andrea, Tilley, Wayne, Neufing, Petra, Morris, Howard, English, Dallas R., McCredie, Margaret R.E., Boyle, Peter, and Hopper, John L.
Subjects: Disease susceptibility -- Genetic aspects, Prostate cancer -- Genetic aspects, Prostate cancer -- Risk factors, Cancer -- Genetic aspects, Health
Abstract: Background: The ELAC2 gene has been proposed to be a prostate cancer susceptibility gene and is being referred to as HPC2, in part because three case-control studies suggested that two common polymorphisms (Ser217Leu and Ala541Thr) are associated with risk. However, four subsequent larger studies have not confirmed this association. In five of the seven total studies, subject selection was influenced by prostate-specific antigen (PSA) levels. We examined the association and possible effect of subject selection in a larger study and a meta-analysis. Methods: In a population-based study in Australia, 825 case patients and 732 control subjects were genotyped for the Ser217Leu and Ala541Thr polymorphisms of ELAC2. Odds ratios (ORs) for prostate cancer were estimated by unconditional logistic and polytomous regression. A meta-analysis was conducted combining our data with those from seven published studies. The association of genotype with the logarithm of plasma PSA levels in control subjects was analyzed by linear regression. Results: The ORs for prostate cancer were 0.74 (95% confidence interval [CI] = 0.50 to 1.09) for Leu217 homozygotes and 1.01 (95% CI = 0.68 to 1.50) for Thr541 heterozygotes and homozygotes compared with Ser217 and Ala541 homozygotes, respectively. ORs were not changed by excluding control subjects with elevated PSA levels. Among control subjects, there were no statistically significant associations between genotype frequencies and PSA level for either polymorphism (both P>.4). The meta-analysis gave pooled OR estimates of 1.04 (95% CI = 0.85 to 1.26) for Leu217 homozygotes and 1.18 (OR = 0.98 to 1.42) for Thr541 homozygotes and heterozygotes. Conclusion: There is no evidence that either ELAC2 polymorphism is associated with prostate cancer or PSA level.
Published: 2003

13. Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations

Author: Dite, Gillian S., Jenkins, Mark A., Southey, Melissa C., Hocking, Jane S., Giles, Graham G., McCredie, Margaret R.E., Venter, Deon J., and Hopper, John L.
Subjects: Breast cancer -- Genetic aspects, Disease susceptibility -- Genetic aspects, Health
Abstract: Background: Having a family history of breast cancer, particularly if it involves early-onset disease, is a risk factor for breast cancer, but little is known about specific causes of this association. Consequently, we studied mothers, sisters, and aunts of an age-stratified sample of 1567 unselected case patients diagnosed with breast cancer before age 60 years, recruited to a population-based, case-control-family study, in which case patients, control subjects, and their relatives were administered the same questionnaire. Methods: Extensive BRCA1 and BRCA2 mutation testing was carried out for 788 case patients diagnosed before age 40 years, including manual sequencing of DNA from 72 patients with two or more affected relatives. Standardized morbidity ratios, age-specific cumulative risks, and hazard ratios were calculated for groupings of relatives. Results: Cumulative risks of breast cancer to age 50 years in the sisters, mothers, and aunts of the case patients, respectively, were 6, 3, and 2 times the population risk if the case patient was younger than age 40 years at diagnosis but were considerably lower if the case patient was older at diagnosis. When relatives of the case patients with a BRCA1 or BRCA2 mutation were excluded, these risks fell by, at most, 20%. Sisters and aunts, but not mothers, who had an additional first-degree relative with breast cancer were at increased risk, and the risk was greater when that relative was younger at diagnosis. Hazard ratios were 10.7 (95% confidence interval [CI] = 4.2 to 26.8) for sisters and 4.2 (95% CI = 2.2 to 8.1) for aunts, if the relative was aged 40 years at diagnosis. Fewer than one-third of the excess of breast cancers in relatives of case patients diagnosed before age 40 years that are attributed to familial factors are BRCA1- or BRCA2-related. Conclusion: Mutations in genes other than BRCA1 and BRCA2 may be associated with a high risk of breast cancer, especially in young women. [J Natl Cancer Inst 2003; 95:448-57]
Published: 2003

14. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author: Howe, Laurence J., Nivard, Michel G., Morris, Tim T., Hansen, Ailin F., Rasheed, Humaira, Cho, Yoonsu, Chittoor, Geetha, Ahlskog, Rafael, Lind, Penelope A., Palviainen, Teemu, van der Zee, Matthijs D., Cheesman, Rosa, Mangino, Massimo, Wang, Yunzhang, Li, Shuai, Klaric, Lucija, Ratliff, Scott M., Bielak, Lawrence F., Nygaard, Marianne, Giannelis, Alexandros, Willoughby, Emily A., Reynolds, Chandra A., Balbona, Jared V., Andreassen, Ole A., Ask, Helga, Baras, Aris, Bauer, Christopher R., Boomsma, Dorret I., Campbell, Archie, Campbell, Harry, Chen, Zhengming, Christofidou, Paraskevi, Corfield, Elizabeth, Dahm, Christina C., Dokuru, Deepika R., Evans, Luke M., de Geus, Eco J. C., Giddaluru, Sudheer, Gordon, Scott D., Harden, K. Paige, Hill, W. David, Hughes, Amanda, Kerr, Shona M., Kim, Yongkang, Kweon, Hyeokmoon, Latvala, Antti, Lawlor, Deborah A., Li, Liming, Lin, Kuang, Magnus, Per, Magnusson, Patrik K. E., Mallard, Travis T., Martikainen, Pekka, Mills, Melinda C., Njølstad, Pål Rasmus, Overton, John D., Pedersen, Nancy L., Porteous, David J., Reid, Jeffrey, Silventoinen, Karri, Southey, Melissa C., Stoltenberg, Camilla, Tucker-Drob, Elliot M., Wright, Margaret J., Hewitt, John K., Keller, Matthew C., Stallings, Michael C., Lee, James J., Christensen, Kaare, Kardia, Sharon L. R., Peyser, Patricia A., Smith, Jennifer A., Wilson, James F., Hopper, John L., Hägg, Sara, Spector, Tim D., Pingault, Jean-Baptiste, Plomin, Robert, Havdahl, Alexandra, Bartels, Meike, Martin, Nicholas G., Oskarsson, Sven, Justice, Anne E., Millwood, Iona Y., Hveem, Kristian, Naess, Øyvind, Willer, Cristen J., Åsvold, Bjørn Olav, Koellinger, Philipp D., Kaprio, Jaakko, Medland, Sarah E., Walters, Robin G., Benjamin, Daniel J., Turley, Patrick, Evans, David M., Davey Smith, George, Hayward, Caroline, Brumpton, Ben, Hemani, Gibran, and Davies, Neil M.
Abstract: Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
Published: 2022
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15. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1and 12,337 BRCA2pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022
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16. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Lewis, Sarah J, Martin, Richard M, English, Dallas R, Boyle, Terry, Giles, Graham G, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Investigators, ABCTB, Ahearn, Thomas U, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Auvinen, Pa¨ivi, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Bru¨ning, Thomas, Buys, Saundra S, Camp, Nicola J, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Cessna, Melissa H, Chang-Claude, Jenny, Chanock, Stephen J, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Do¨rk, Thilo, Dwek, Miriam, Eccles, Diana M, Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Goldberg, Mark S, Guénel, Pascal, Gu¨ndert, Melanie, Hahnen, Eric, Haiman, Christopher A, Ha¨berle, Lothar, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hart, Steven N, Harvie, Michelle, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J, Hoppe, Reiner, Hopper, John, Howell, Anthony, Hunter, David J, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Loibl, Sibylle, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Menon, Usha, Mulligan, Anna Marie, Murphy, Rachel A, Collaborators, NBCS, Nevanlinna, Heli, Nevelsteen, Ines, Newman, William G, Offit, Kenneth, Olshan, Andrew F, Olsson, Håkan, Orr, Nick, Patel, Alpa, Peto, Julian, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rees-Punia, Erika, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale P, Schmidt, Marjanka K, Schmutzler, Rita K, Schwentner, Lukas, Scott, Christopher, Shah, Mitul, Shu, Xiao-Ou, Simard, Jacques, Southey, Melissa C, Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Terry, Mary Beth, Tollenaar, Rob A E M, Troester, Melissa A, Truong, Thérèse, Untch, Michael, Vachon, Celine M, Joseph, Vijai, Wappenschmidt, Barbara, Weinberg, Clarice R, Wolk, Alicja, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M, Pharoah, Paul D P, Easton, Douglas F, Milne, Roger L, and Lynch, Brigid M
Abstract: ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
Published: 2022
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17. Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1and BRCA2compared with those harboring protein truncating variants

Author: Li, Hongyan, Engel, Christoph, de la Hoya, Miguel, Peterlongo, Paolo, Yannoukakos, Drakoulis, Livraghi, Luca, Radice, Paolo, Thomassen, Mads, Hansen, Thomas V.O., Gerdes, Anne-Marie, Nielsen, Henriette R., Caputo, Sandrine M., Zambelli, Alberto, Borg, Ake, Solano, Angela, Thomas, Abigail, Parsons, Michael T., Antoniou, Antonis C., Leslie, Goska, Yang, Xin, Chenevix-Trench, Georgia, Caldes, Trinidad, Kwong, Ava, Pedersen, Inge Søkilde, Lautrup, Charlotte K., John, Esther M., Terry, Mary Beth, Hopper, John L., Southey, Melissa C., Andrulis, Irene L., Tischkowitz, Marc, Janavicius, Ramunas, Boonen, Susanne E., Kroeldrup, Lone, Varesco, Liliana, Hamann, Ute, Vega, Ana, Palmero, Edenir I., Garber, Judy, Montagna, Marco, Van Asperen, Christi J., Foretova, Lenka, Greene, Mark H., Selkirk, Tina, Moller, Pal, Toland, Amanda E., Domchek, Susan M., James, Paul A., Thorne, Heather, Eccles, Diana M., Nielsen, Sarah M., Manoukian, Siranoush, Pasini, Barbara, Caligo, Maria A., Lazaro, Conxi, Kirk, Judy, Wappenschmidt, Barbara, Spurdle, Amanda B., Couch, Fergus J., Schmutzler, Rita, and Goldgar, David E.
Abstract: Germline genetic testing for BRCA1and BRCA2variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.
Published: 2022
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18. The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study

Author: Armes, Jane E., Egan, A.J. Matthew, Southey, Melissa C., Dite, Gillian S., McCredie, Margaret R.E., Giles, Graham G., Hopper, John L., and Venter, Deon J.
Subjects: Breast cancer -- Genetic aspects, Young women -- Health aspects, Health
Published: 1998

19. Estrogen receptor polymorphism at codon 325 and risk of breast cancer in women before age forty

Author: Southey, Melissa C., Batten, Leigh E., McCredie, Margaret R.E., Giles, Graham G., Dite, Gillian, Hopper, John L., and Venter, Deon J.
Subjects: Hormone receptors -- Genetic aspects, Genetic polymorphisms -- Health aspects, Breast cancer -- Genetic aspects, Health
Abstract: Background: The estrogen receptor (ER) protein is believed to play a role in the development and progression of breast cancer. In a previously published U.S. clinic-based study, a polymorphism in the ER gene (codon 325, CCC [right arrow] CCG) was found to be more common in 34 case subjects with a family history of breast cancer than in 154 case subjects without such a history (mean allele frequencies [+ or -] standard error = 0.28 [+ or -] 0.05 versus 0.11 [+ or -] 0.02; P [is less than] .001). To determine whether this polymorphism is a risk factor for early onset breast cancer, we conducted a population-based, case-control-family study in Australia. Methods: Case subjects under the age of 40 years with a first primary breast cancer and control subjects, frequency-matched to the case subjects on the basis of age, and their relatives were interviewed to assess the family history of breast cancer. Polymorphism status of the ER gene was determined for 388 case subjects and 294 control subjects. All statistical tests were two-tailed. Results: There was no association between ER gene polymorphism status and breast cancer, before or after adjustment for risk factors. There was no difference in allele frequencies between case subjects and control subjects (0.232 [+ or -] 0.015 versus 0.209 [+ or -] 0.017; P = .4) or between women with and without a family history of breast cancer (P = .3), irrespective of case-control status. The findings were not altered when different definitions of family history of breast cancer were used and when allele frequencies were adjusted for residence and country of birth. Conclusion: We found no evidence that the ER codon 325 polymorphism is associated with breast cancer before the age of 40 years or with a family history of breast cancer, despite ample power to detect effects half the magnitude of those previously reported. [J Natl Cancer Inst 1998;90: 532-6]
Published: 1998

20. Lymphoproliferative disease of donor origin arising in patients after orthotopic liver transplantation

Author: Armes, Jane E., Angus, Peter, Southey, Melissa C., Battaglia, Samuel E., Ross, Bruce C., Jones, Robert M., and Venter, Deon J.
Subjects: Liver -- Transplantation, Transplantation of organs, tissues, etc. -- Complications, Lymphoproliferative disorders -- Development and progression, Health
Published: 1994

21. A BRCA1 promoter variant (rs11655505) and breast cancer risk

Author: Verderio, Paolo, Pizzamiglio, Sara, Southey, Melissa C., Spurdle, Amanda B., Hopper, John L., Chen, Xiaoqing, Beesley, Jonathan, Schmutzler, Rita K., Engel, Christoph, Burwinkel, Barbara, Bugert, Peter, Ficarazzi, Filomena, Manoukian, Siranoush, Barile, Monica, Wappenschmidt, Barbara, Chenevix-Trench, Georgia, Radice, Paolo, and Peterlongo, Paolo
Subjects: Breast cancer -- Risk factors, Breast cancer -- Genetic aspects, Breast cancer -- Demographic aspects, Breast cancer -- Research, Promoters (Genetics) -- Research, Health
Published: 2010

22. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, Katherine S., Day, Felix R., Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E., Azad, Ajuna, Thompson, Deborah J., Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L., Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B., Sulem, Patrick, Walters, Robin G., Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N. Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N., Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W., Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R. H. J., Ahearn, Thomas U., Alizadeh, Behrooz Z., Naderi, Elnaz, Andrulis, Irene L., Arnold, Alice M., Aronson, Kristan J., Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M., Beaumont, Robin N., Becher, Heiko, Beckmann, Matthias W., Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Boomsma, Dorret I., Bowker, Nicholas, Brody, Jennifer A., Broer, Linda, Buring, Julie E., Campbell, Archie, Campbell, Harry, Castelao, Jose E., Catamo, Eulalia, Chanock, Stephen J., Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J., Cox, Angela, Crisponi, Laura, Cross, Simon S., Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J. C. N., de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Dunning, Alison M., Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A., Faul, Jessica D., Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M., Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K., Hopper, John L., Hottenga, Jouke J., Hu, Frank, Hunter, David, Ikram, Mohammad A., Jackson, Rebecca D., Joaquim, Micaella D. R., John, Esther M., Joshi, Peter K., Karasik, David, Kardia, Sharon L. R., Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M., Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W., Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lawlor, Deborah A., Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G., Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mook-Kanamori, Dennis O., Mulas, Antonella, Mulligan, Anna M., Murray, Alison, Nalls, Mike A., Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R., Olshan, Andrew F., Olsson, Håkan, Painter, Jodie N., Patel, Alpa V., Pedersen, Nancy L., Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D. P., Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M., Rahman, Iffat, Rennert, Gad, Rennert, Hedy S., Ridker, Paul M., Ring, Susan M., Robino, Antonietta, Rose, Lynda M., Rosendaal, Frits R., Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Saloustros, Emmanouil, Sandler, Dale P., Sanna, Serena, Sawyer, Elinor J., Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K., Schoemaker, Minouk J., Schraut, Katharina E., Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V., Smith, Blair H., Smith, Jennifer A., Sorice, Rossella, Southey, Melissa C., Spector, Tim D., Spinelli, John J., Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B. J., Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J., Tanaka, Toshiko, Teras, Lauren R., Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J., Toniolo, Daniela, Traglia, Michela, Troester, Melissa A., Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G., Ulivi, Sheila, Vachon, Celine M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J., Weinberg, Clarice R., Weir, David R., Wilcox, Amber N., van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F., Wolffenbuttel, Bruce H. R., Wolk, Alicja, Wood, Andrew R., Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H., Grøndahl, Marie Louise, Andersen, Claus Yding, Pujol, Anna, Lopez-Contreras, Andres J., Daniel, Jeremy A., Stefansson, Kari, Chang-Claude, Jenny, van der Schouw, Yvonne T., Lunetta, Kathryn L., Chasman, Daniel I., Easton, Douglas F., Visser, Jenny A., Ozanne, Susan E., Namekawa, Satoshi H., Solc, Petr, Murabito, Joanne M., Ong, Ken K., Hoffmann, Eva R., Murray, Anna, Roig, Ignasi, and Perry, John R. B.
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021
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23. Rare Germline Variants in ATMPredispose to Prostate Cancer: A PRACTICAL Consortium Study

Author: Karlsson, Questa, Brook, Mark N., Dadaev, Tokhir, Wakerell, Sarah, Saunders, Edward J., Muir, Kenneth, Neal, David E., Giles, Graham G., MacInnis, Robert J., Thibodeau, Stephen N., McDonnell, Shannon K., Cannon-Albright, Lisa, Teixeira, Manuel R., Paulo, Paula, Cardoso, Marta, Huff, Chad, Li, Donghui, Yao, Yu, Scheet, Paul, Permuth, Jennifer B., Stanford, Janet L., Dai, James Y., Ostrander, Elaine A., Cussenot, Olivier, Cancel-Tassin, Géraldine, Hoegel, Josef, Herkommer, Kathleen, Schleutker, Johanna, Tammela, Teuvo L.J., Rathinakannan, Venkat, Sipeky, Csilla, Wiklund, Fredrik, Grönberg, Henrik, Aly, Markus, Isaacs, William B., Dickinson, Jo L., FitzGerald, Liesel M., Chua, Melvin L.K., Nguyen-Dumont, Tu, Schaid, Daniel J., Southey, Melissa C., Eeles, Rosalind A., and Kote-Jarai, Zsofia
Abstract: Germline ATMmutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.
Published: 2021
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24. Population DNA screening for medically actionable disease risk in adults

Author: Lacaze, Paul A, Tiller, Jane, Winship, Ingrid, Lacaze, Paul, Tiller, Jane, Winship, Ingrid, Brotchie, Adam, McNeil, John, Zalcberg, John, Thomas, David, Milne, Roger, James, Paul, Delatycki, Martin, Young, Mary‐Anne, Nowak, Kristen, Nguyen‐Dumont, Tu, Southey, Melissa, Ademi, Zanfina, Bruinsma, Fiona, Riaz, Moeen, Terrill, Bronwyn, Kirk, Judy, Tucker, Kathy, Andrews, Lesley, Pachter, Nicholas, Susman, Rachel, Poplawski, Nicola, Wallis, Matthew, Watts, Gerald, Nicholls, Steve, Macrae, Finlay, Sturm, Amy, Green, Robert, Ahern, Susannah, Revote, Jerico, Von Saldern, Simon, Powell, Sarah, and Rice, Toni
Published: 2022
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25. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author: Conti, David V., Darst, Burcu F., Moss, Lilit C., Saunders, Edward J., Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Sahimi, Ali, Hoffmann, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R., Stevens, Victoria L., Gapstur, Susan M., Carter, Brian D., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Børge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A., Tilley, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Geybels, Milan S., Koutros, Stella, Freeman, Laura E. Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Fontham, Elizabeth T. H., Mohler, James, Taylor, Jack A., Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine, Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer C., Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I., Van Den Eeden, Stephen K., Easton, Douglas F., Chanock, Stephen J., Cook, Michael B., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Eeles, Rosalind A., Kote-Jarai, Zsofia, and Haiman, Christopher A.
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Published: 2021
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26. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1and BRCA2pathogenic variants

Author: Barnes, Daniel R., Rookus, Matti A., McGuffog, Lesley, Leslie, Goska, Mooij, Thea M., Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L., Arnold, Norbert, Arun, Banu K., Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M., Blok, Marinus J., Bonanni, Bernardo, Boonen, Susanne E., Borg, Åke, Bozsik, Aniko, Bradbury, Angela R., Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K., Claes, Kathleen B.M., Colas, Chrystelle, Berthet, Pascaline, Colas, Chrystelle, Collonge-Rame, Marie-Agnès, Delnatte, Capucine, Faivre, Laurence, Giraud, Sophie, Lasset, Christine, Mari, Véronique, Mebirouk, Noura, Mouret-Fourme, Emmanuelle, Schuster, Hélène, Stoppa-Lyonnet, Dominique, Adlard, Julian, Ahmed, Munaza, Antoniou, Antonis, Barrowdale, Daniel, Brennan, Paul, Brewer, Carole, Cook, Jackie, Davidson, Rosemarie, Easton, Douglas, Eeles, Ros, Evans, D. Gareth, Frost, Debra, Hanson, Helen, Izatt, Louise, Ong, Kai-ren, Side, Lucy, O’Shaughnessy-Kirwan, Aoife, Tischkowitz, Marc, Walker, Lisa, Collonge-Rame, Marie-Agnès, Cook, Jackie, Daly, Mary B., Davidson, Rosemarie, de la Hoya, Miguel, de Putter, Robin, Delnatte, Capucine, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dorfling, Cecilia M., Dumont, Martine, Eeles, Ros, Ejlertsen, Bent, Engel, Christoph, Evans, D. Gareth, Faivre, Laurence, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Frost, Debra, Ganz, Patricia A., Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hentschel, Julia, Hogervorst, Frans B.L., Hooning, Maartje J., Horvath, Judit, Hu, Chunling, Hulick, Peter J., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, Phillips, Kelly-Anne, Spurdle, Amanda, Blok, Marinus, Devilee, Peter, Hogervorst, Frans, Hooning, Maartje, Koudijs, Marco, Mensenkamp, Arjen, Meijers-Heijboer, Hanne, Rookus, Matti, Engelen, Klaartje van, Andrieu, Nadine, Noguès, Catherine, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, John, Esther M., Joseph, Vijai, Karlan, Beth Y., Kast, Karin, Koudijs, Marco, Kruse, Torben A., Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loud, Jennifer T., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Mari, Véronique, Mebirouk, Noura, Meijers-Heijboer, Hanne E.J., Meindl, Alfons, Mensenkamp, Arjen R., Miller, Austin, Montagna, Marco, Mouret-Fourme, Emmanuelle, Mukherjee, Semanti, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Noguès, Catherine, Olah, Edith, Olopade, Olufunmilayo I., Ong, Kai-ren, O’Shaughnessy-Kirwan, Aoife, Osorio, Ana, Ott, Claus-Eric, Papi, Laura, Park, Sue K., Parsons, Michael T., Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Peterlongo, Paolo, Pfeiler, Georg, Phillips, Kelly-Anne, Prajzendanc, Karolina, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Ramus, Susan J., Rantala, Johanna, Rennert, Gad, Risch, Harvey A., Robson, Mark, Rønlund, Karina, Salani, Ritu, Schuster, Hélène, Senter, Leigha, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Singer, Christian F., Slavin, Thomas P., Soucy, Penny, Southey, Melissa C., Spurdle, Amanda B., Steinemann, Doris, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Thull, Darcy L., Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Trainer, Alison H., Tung, Nadine, van Engelen, Klaartje, van Rensburg, Elizabeth J., Vega, Ana, Vierstraete, Jeroen, Wagner, Gabriel, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Yadav, Siddhartha, Yang, Xin, Yannoukakos, Drakoulis, Zimbalatti, Dario, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J., Schmutzler, Rita K., Simard, Jacques, Easton, Douglas F., Chenevix-Trench, Georgia, and Antoniou, Antonis C.
Abstract: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1and BRCA2pathogenic variant carriers.
Published: 2020
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27. Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Author: Silvestri, Valentina, Leslie, Goska, Barnes, Daniel R., Agnarsson, Bjarni A., Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L., Barkardottir, Rosa B., Barroso, Alicia, Barrowdale, Daniel, Benitez, Javier, Bonanni, Bernardo, Borg, Ake, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Capalbo, Carlo, Campbell, Ian, Chung, Wendy K., Claes, Kathleen B.M., Colonna, Sarah V., Cortesi, Laura, Couch, Fergus J., de la Hoya, Miguel, Diez, Orland, Ding, Yuan Chun, Domchek, Susan, Easton, Douglas F., Ejlertsen, Bent, Engel, Christoph, Evans, D. Gareth, Feliubadalò, Lidia, Foretova, Lenka, Fostira, Florentia, Géczi, Lajos, Gerdes, Anne-Marie, Glendon, Gord, Godwin, Andrew K., Goldgar, David E., Hahnen, Eric, Hogervorst, Frans B.L., Hopper, John L., Hulick, Peter J., Isaacs, Claudine, Izquierdo, Angel, James, Paul A., Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M., Joseph, Vijai, Konstantopoulou, Irene, Kurian, Allison W., Kwong, Ava, Landucci, Elisabetta, Lesueur, Fabienne, Loud, Jennifer T., Machackova, Eva, Mai, Phuong L., Majidzadeh-A, Keivan, Manoukian, Siranoush, Montagna, Marco, Moserle, Lidia, Mulligan, Anna Marie, Nathanson, Katherine L., Nevanlinna, Heli, Ngeow, Joanne, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Osorio, Ana, Papi, Laura, Park, Sue K., Pedersen, Inge Sokilde, Perez-Segura, Pedro, Petersen, Annabeth H., Pinto, Pedro, Porfirio, Berardino, Pujana, Miquel Angel, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rosenzweig, Barak, Rossing, Maria, Santamariña, Marta, Schmutzler, Rita K., Senter, Leigha, Simard, Jacques, Singer, Christian F., Solano, Angela R., Southey, Melissa C., Steele, Linda, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo H., Terry, Mary Beth, Thomassen, Mads, Toland, Amanda E., Torres-Esquius, Sara, Tung, Nadine, van Asperen, Christi J., Vega, Ana, Viel, Alessandra, Vierstraete, Jeroen, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Wieme, Greet, Yoon, Sook-Yee, Zorn, Kristin K., McGuffog, Lesley, Parsons, Michael T., Hamann, Ute, Greene, Mark H., Kirk, Judy A., Neuhausen, Susan L., Rebbeck, Timothy R., Tischkowitz, Marc, Chenevix-Trench, Georgia, Antoniou, Antonis C., Friedman, Eitan, and Ottini, Laura
Abstract: IMPORTANCE: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. OBJECTIVE: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. MAIN OUTCOMES AND MEASURES: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. RESULTS: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. CONCLUSIONS AND RELEVANCE: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
Published: 2020
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28. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhang, Haoyu, Ahearn, Thomas U., Lecarpentier, Julie, Barnes, Daniel, Beesley, Jonathan, Qi, Guanghao, Jiang, Xia, O’Mara, Tracy A., Zhao, Ni, Bolla, Manjeet K., Dunning, Alison M., Dennis, Joe, Wang, Qin, Ful, Zumuruda Abu, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J., Arun, Banu K., Auer, Paul L., Azzollini, Jacopo, Barrowdale, Daniel, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bialkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Stig E., Bonanni, Bernardo, Bondavalli, Davide, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brucker, Sara Y., Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S., Byers, Helen, Caldés, Trinidad, Caligo, Maria A., Calvello, Mariarosaria, Campa, Daniele, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Christiaens, Melissa, Christiansen, Hans, Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Cornelissen, Sten, Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, Diez, Orland, Domchek, Susan M., Dörk, Thilo, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Foretova, Lenka, Fostira, Florentia, Friedman, Eitan, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M., Garber, Judy, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Gronwald, Jacek, Guénel, Pascal, Häberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Hake, Christopher R., Hall, Per, Hamann, Ute, Harkness, Elaine F., Heemskerk-Gerritsen, Bernadette A. M., Hillemanns, Peter, Hogervorst, Frans B. L., Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Robert N., Hopper, John L., Howell, Anthony, Huebner, Hanna, Hulick, Peter J., Imyanitov, Evgeny N., Isaacs, Claudine, Izatt, Louise, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M., Jones, Michael E., Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Khan, Sofia, Khusnutdinova, Elza, Kitahara, Cari M., Ko, Yon-Dschun, Konstantopoulou, Irene, Koppert, Linetta B., Koutros, Stella, Kristensen, Vessela N., Laenkholm, Anne-Vibeke, Lambrechts, Diether, Larsson, Susanna C., Laurent-Puig, Pierre, Lazaro, Conxi, Lazarova, Emilija, Lejbkowicz, Flavio, Leslie, Goska, Lesueur, Fabienne, Lindblom, Annika, Lissowska, Jolanta, Lo, Wing-Yee, Loud, Jennifer T., Lubinski, Jan, Lukomska, Alicja, MacInnis, Robert J., Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matricardi, Laura, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Mingazheva, Elvira, Montagna, Marco, Mulligan, Anna Marie, Mulot, Claire, Muranen, Taru A., Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Nielsen, Finn C., Nikitina-Zake, Liene, Nodora, Jesse, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olsson, Håkan, Orr, Nick, Papi, Laura, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T., Peissel, Bernard, Peixoto, Ana, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Phillips, Kelly-Anne, Piedmonte, Marion, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Prokofyeva, Darya, Rack, Brigitte, Radice, Paolo, Ramus, Susan J., Rantala, Johanna, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Risch, Harvey A., Romero, Atocha, Rookus, Matti A., Rübner, Matthias, Rüdiger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P., Sawyer, Elinor J., Scheuner, Maren T., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schöttker, Ben, Schürmann, Peter, Senter, Leigha, Sharma, Priyanka, Sherman, Mark E., Shu, Xiao-Ou, Singer, Christian F., Smichkoska, Snezhana, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony J., Szabo, Csilla I., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Teixeira, Manuel R., Terry, MaryBeth, Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Tollenaar, Rob A. E. M., Tomlinson, Ian, Torres, Diana, Troester, Melissa A., Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M., van den Ouweland, Ans M. W., van der Kolk, Lizet E., van Veen, Elke M., vanRensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zheng, Wei, Zorn, Kristin K., Milne, Roger L., Kraft, Peter, Simard, Jacques, Pharoah, Paul D. P., Michailidou, Kyriaki, Antoniou, Antonis C., Schmidt, Marjanka K., Chenevix-Trench, Georgia, Easton, Douglas F., Chatterjee, Nilanjan, and García-Closas, Montserrat
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P< 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P< 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020
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29. Smoking and blood DNA methylation: an epigenome-wide association study and assessment of reversibility

Author: Dugué, Pierre-Antoine, Jung, Chol-Hee, Joo, Jihoon E, Wang, Xiaochuan, Wong, Ee Ming, Makalic, Enes, Schmidt, Daniel F, Baglietto, Laura, Severi, Gianluca, Southey, Melissa C, English, Dallas R, Giles, Graham G, and Milne, Roger L
Abstract: ABSTRACTWe conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N = 3,327) and former (N = 172) smoking. A comprehensive smoking index accounting for the biological half-life of smoking compounds and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. This measure of lifetime exposure to smoking allowed us to detect more associations than comparing current with never smokers. We identified 4,496 cross-sectional associations at P < 10−7, including 3,296 annotated to 1,326 genes that were not previously implicated in smoking-associated DNA methylation changes at this significance threshold. We replicated the majority of previously reported associations (P < 10−7) for current and former smokers. In our data, we observed for former smokers a substantial degree of return to the methylation levels of never smokers, compared with current smokers (median: 74%, IQR = 63-86%), corresponding to small values (median: 2.75, IQR = 1.5–5.25) for the half-life parameter of the comprehensive smoking index. Longitudinal analyses identified 368 sites at which methylation changed upon smoking cessation. Our study demonstrates the usefulness of the comprehensive smoking index to detect associations between smoking and DNA methylation at CpGs across the genome, replicates the vast majority of previously reported associations, and quantifies the reversibility of smoking-induced methylation changes.
Published: 2020
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30. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author: Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R., Allen, Jamie, Kar, Siddhartha, Pooley, Karen A., Dennis, Joe, Michailidou, Kyriaki, Turman, Constance, Soucy, Penny, Lemaçon, Audrey, Lush, Michael, Tyrer, Jonathan P., Ghoussaini, Maya, Moradi Marjaneh, Mahdi, Jiang, Xia, Agata, Simona, Aittomäki, Kristiina, Alonso, M. Rosario, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J., Arun, Banu K., Auber, Bernd, Auer, Paul L., Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Amie M., Blomqvist, Carl, Blot, William, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Borg, Ake, Bosse, Kristin, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brock, Ian W., Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S., Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A., Camp, Nicola J., Campbell, Ian, Canzian, Federico, Carroll, Jason S., Carter, Brian D., Castelao, Jose E., Chiquette, Jocelyne, Christiansen, Hans, Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Collée, J. Margriet, Cornelissen, Sten, Couch, Fergus J., Cox, Angela, Cross, Simon S., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., de la Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S., Domchek, Susan M., Dörk, Thilo, dos-Santos-Silva, Isabel, Droit, Arnaud, Dubois, Stéphane, Dumont, Martine, Duran, Mercedes, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M., Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Fletcher, Olivia, Floris, Giuseppe, Flyger, Henrik, Foretova, Lenka, Foulkes, William D., Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Gambino, Gaetana, Ganz, Patricia A., Gapstur, Susan M., Garber, Judy, García-Sáenz, José A., Gaudet, Mia M., Georgoulias, Vassilios, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Tibiletti, Maria Grazia, Greene, Mark H., Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hartikainen, Jaana M., Hartman, Mikael, He, Wei, Healey, Catherine S., Heemskerk-Gerritsen, Bernadette A. M., Heyworth, Jane, Hillemanns, Peter, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hooning, Maartje J., Hopper, John L., Howell, Anthony, Huang, Guanmengqian, Hulick, Peter J., Imyanitov, Evgeny N., Isaacs, Claudine, Iwasaki, Motoki, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jankowitz, Rachel C., John, Esther M., Johnson, Nichola, Jones, Michael E., Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Kerin, Michael J., Khusnutdinova, Elza, Kiiski, Johanna I., Kirk, Judy, Kitahara, Cari M., Ko, Yon-Dschun, Konstantopoulou, Irene, Kosma, Veli-Matti, Koutros, Stella, Kubelka-Sabit, Katerina, Kwong, Ava, Kyriacou, Kyriacos, Laitman, Yael, Lambrechts, Diether, Lee, Eunjung, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindblom, Annika, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T., Lubiński, Jan, MacInnis, Robert J., Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matsuo, Keitaro, Maurer, Tabea, Mavroudis, Dimitrios, Mayes, Rebecca, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Miller, Nicola, Montagna, Marco, Moreno, Fernando, Muir, Kenneth, Mulligan, Anna Marie, Muñoz-Garzon, Victor M., Muranen, Taru A., Narod, Steven A., Nassir, Rami, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C., Nikitina-Zake, Liene, Norman, Aaron, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olsson, Håkan, Orr, Nick, Osorio, Ana, Pankratz, V. Shane, Papp, Janos, Park, Sue K., Park-Simon, Tjoung-Won, Parsons, Michael T., Paul, James, Pedersen, Inge Sokilde, Peissel, Bernard, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Presneau, Nadege, Prokofyeva, Darya, Pujana, Miquel Angel, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J., Rantala, Johanna, Rau-Murthy, Rohini, Rennert, Gad, Risch, Harvey A., Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sánchez-Herrero, Estela, Sandler, Dale P., Santamariña, Marta, Saunders, Christobel, Sawyer, Elinor J., Scheuner, Maren T., Schmidt, Daniel F., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schöttker, Ben, Schürmann, Peter, Scott, Christopher, Scott, Rodney J., Senter, Leigha, Seynaeve, Caroline M., Shah, Mitul, Sharma, Priyanka, Shen, Chen-Yang, Shu, Xiao-Ou, Singer, Christian F., Slavin, Thomas P., Smichkoska, Snezhana, Southey, Melissa C., Spinelli, John J., Spurdle, Amanda B., Stone, Jennifer, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony J., Tamimi, Rulla M., Tan, Yen Yen, Tapper, William J., Taylor, Jack A., Teixeira, Manuel R., Tengström, Maria, Teo, Soo Hwang, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Tollenaar, Rob A. E. M., Tomlinson, Ian, Torres, Diana, Torres-Mejía, Gabriela, Troester, Melissa A., Truong, Thérèse, Tung, Nadine, Tzardi, Maria, Ulmer, Hans-Ulrich, Vachon, Celine M., van Asperen, Christi J., van der Kolk, Lizet E., van Rensburg, Elizabeth J., Vega, Ana, Viel, Alessandra, Vijai, Joseph, Vogel, Maartje J., Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Wu, Anna H., Yannoukakos, Drakoulis, Zhang, Yan, Zheng, Wei, Hunter, David, Pharoah, Paul D. P., Chang-Claude, Jenny, García-Closas, Montserrat, Schmidt, Marjanka K., Milne, Roger L., Kristensen, Vessela N., French, Juliet D., Edwards, Stacey L., Antoniou, Antonis C., Chenevix-Trench, Georgia, Simard, Jacques, Easton, Douglas F., Kraft, Peter, and Dunning, Alison M.
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Published: 2020
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31. A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer

Author: Sun, Li, Brentnall, Adam, Patel, Shreeya, Buist, Diana S. M., Bowles, Erin J. A., Evans, D. Gareth R., Eccles, Diana, Hopper, John, Li, Shuai, Southey, Melissa, Duffy, Stephen, Cuzick, Jack, dos Santos Silva, Isabel, Miners, Alec, Sadique, Zia, Yang, Li, Legood, Rosa, and Manchanda, Ranjit
Abstract: IMPORTANCE: Moving to multigene testing for all women with breast cancer (BC) could identify many more mutation carriers who can benefit from precision prevention. However, the cost-effectiveness of this approach remains unaddressed. OBJECTIVE: To estimate incremental lifetime effects, costs, and cost-effectiveness of multigene testing of all patients with BC compared with the current practice of genetic testing (BRCA) based on family history (FH) or clinical criteria. DESIGN, SETTING, AND PARTICIPANTS: This cost-effectiveness microsimulation modeling study compared lifetime costs and effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing of all unselected patients with BC (strategy A) with BRCA1/BRCA2 testing based on FH or clinical criteria (strategy B) in United Kingdom (UK) and US populations. Data were obtained from 11 836 patients in population-based BC cohorts (regardless of FH) recruited to 4 large research studies. Data were collected and analyzed from January 1, 2018, through June 8, 2019. The time horizon is lifetime. Payer and societal perspectives are presented. Probabilistic and 1-way sensitivity analyses evaluate model uncertainty. INTERVENTIONS: In strategy A, all women with BC underwent BRCA1/BRCA2/PALB2 testing. In strategy B, only women with BC fulfilling FH or clinical criteria underwent BRCA testing. Affected BRCA/PALB2 carriers could undertake contralateral preventive mastectomy; BRCA carriers could choose risk-reducing salpingo-oophorectomy (RRSO). Relatives of mutation carriers underwent cascade testing. Unaffected relative carriers could undergo magnetic resonance imaging or mammography screening, chemoprevention, or risk-reducing mastectomy for BC risk and RRSO for ovarian cancer (OC) risk. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained and compared with standard £30 000/QALY and $100 000/QALY UK and US thresholds, respectively. Incidence of OC, BC, excess deaths due to heart disease, and the overall population effects were estimated. RESULTS: BRCA1/BRCA2/PALB2 multigene testing for all patients detected with BC annually would cost £10 464/QALY (payer perspective) or £7216/QALY (societal perspective) in the United Kingdom or $65 661/QALY (payer perspective) or $61 618/QALY (societal perspective) in the United States compared with current BRCA testing based on clinical criteria or FH. This is well below UK and US cost-effectiveness thresholds. In probabilistic sensitivity analysis, unselected multigene testing remained cost-effective for 98% to 99% of UK and 64% to 68% of US health system simulations. One year’s unselected multigene testing could prevent 2101 cases of BC and OC and 633 deaths in the United Kingdom and 9733 cases of BC and OC and 2406 deaths in the United States. Correspondingly, 8 excess deaths due to heart disease occurred in the United Kingdom and 35 in the United States annually. CONCLUSIONS AND RELEVANCE: This study found unselected, high-risk multigene testing for all patients with BC to be extremely cost-effective compared with testing based on FH or clinical criteria for UK and US health systems. These findings support changing current policy to expand genetic testing to all women with BC.
Published: 2019
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32. Analytical validation of an error-corrected ultra-sensitive ctDNA next-generation sequencing assay

Author: Fettke, Heidi, Steen, Jason A, Kwan, Edmond M, Bukczynska, Patricia, Keerthikumar, Shivakumar, Goode, David, Docanto, Maria, Ng, Nicole, Martelotto, Luciano, Hauser, Christine, Southey, Melissa C, Azad, Arun A, and Nguyen-Dumont, Tu
Abstract: Plasma circulating tumor DNA (ctDNA) analysis has emerged as a minimally invasive means to perform molecular tumor typing. Here we developed a custom ultra-sensitive ctDNA next-generation sequencing assay using molecular barcoding technology and off-the-shelf reagents combined with bioinformatics tools for enhanced ctDNA analysis. Assay performance was assessed via a spike-in experiment and the technique was applied to analyze 41 plasma samples from men with advanced prostate cancer. Orthogonal validation was performed using a commercial assay. Sensitivity and specificity of 93 and 99.5% were recorded for ultra-rare somatic variants (<1%), with high concordance observed between the in-house and commercial assays. The optimized protocol dramatically improved the efficiency of the assay and enabled the detection of low-frequency somatic variants from plasma cell-free DNA (cfDNA).
Published: 2024
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33. Is uptake of genetic testing for colorectal cancer influenced by knowledge of insurance implications?

Author: Keogh, Louise A., van Vliet, Christine M., Studdert, David M., Maskiell, Judith A., Macrae, Finlay A., John, D. James, Gaff, Clara L., Young, Mary Anne, Southey, Melissa C., Giles, Graham G., Rosenthal, Doreen A., Hopper, John L., and Jenkins, Mark A.
Subjects: Colorectal cancer -- Care and treatment, DNA mismatch repair -- Research, Gene mutations -- Usage, Genetic screening -- Usage, Health
Abstract: The impact of the knowledge of insurance implications on the use of genetic testing of colorectal cancer by the participants is determined. A need for various changes to be made in the existing insurance practices is also demonstrated.
Published: 2009

34. Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author: Fernandez-Rozadilla, Ceres, Timofeeva, Maria, Chen, Zhishan, Law, Philip, Thomas, Minta, Schmit, Stephanie, Díez-Obrero, Virginia, Hsu, Li, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah, Svinti, Victoria, Donnelly, Kevin, Farrington, Susan, Blackmur, James, Vaughan-Shaw, Peter, Shu, Xiao-ou, Long, Jirong, Cai, Qiuyin, Guo, Xingyi, Lu, Yingchang, Broderick, Peter, Studd, James, Huyghe, Jeroen, Harrison, Tabitha, Conti, David, Dampier, Christopher, Devall, Mathew, Schumacher, Fredrick, Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Moratalla-Navarro, Ferran, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John, Jenkins, Mark, Win, Aung Ko, Pai, Rish, Figueiredo, Jane, Haile, Robert, Gallinger, Steven, Woods, Michael, Newcomb, Polly, Duggan, David, Cheadle, Jeremy, Kaplan, Richard, Maughan, Timothy, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Lukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri, Rissanen, Harri, Pukkala, Eero, Eriksson, Johan, Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Zanke, Brent, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie, Ruiz-Narvaez, Edward, Palmer, Julie, Buchanan, Daniel, Platz, Elizabeth, Visvanathan, Kala, Ulrich, Cornelia, Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha, Potter, John, Tsilidis, Konstantinos, Schulze, Matthias, Gunter, Marc, Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Stern, Mariana, Pardamean, Bens, Bishop, Timothy, Giles, Graham, Southey, Melissa, Idos, Gregory, McDonnell, Kevin, Abu-Ful, Zomoroda, Greenson, Joel, Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope, van Guelpen, Bethany, Hudson, Thomas, Hampel, Heather, Pearlman, Rachel, Berndt, Sonja, Hayes, Richard, Martinez, Marie Elena, Thomas, Sushma, Corley, Douglas, Pharoah, Paul, Larsson, Susanna, Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly, Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew, Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David, Joshi, Amit, Schafmayer, Clemens, Scacheri, Peter, Kundaje, Anshul, Nickerson, Deborah, Schoen, Robert, Hampe, Jochen, Stadler, Zsofia, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Papadopoulos, Nickolas, Edlund, Chistopher, Gauderman, William, Thomas, Duncan, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen, van Duijnhoven, Franzel, Feskens, Edith, Sakoda, Lori, Gago-Dominguez, Manuela, Wolk, Alicja, Naccarati, Alessio, Pardini, Barbara, FitzGerald, Liesel, Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie, Kooperberg, Charles, Li, Christopher, Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Tangen, Catherine, Mardis, Elaine, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Haiman, Christopher, Le Marchand, Loic, Wu, Anna, Qu, Chenxu, McNeil, Caroline, Coetzee, Gerhard, Hayward, Caroline, Deary, Ian, Harris, Sarah, Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Moreno, Victor, Casey, Graham, Gruber, Stephen, Tomlinson, Ian, Zheng, Wei, Dunlop, Malcolm, Houlston, Richard, and Peters, Ulrike
Published: 2023
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35. Hi-Plex2: a simple and robust approach to targeted sequencing-based genetic screening

Author: Hammet, Fleur, Mahmood, Khalid, Green, Thomas R, Nguyen-Dumont, Tu, Southey, Melissa C, Buchanan, Daniel D, Lonie, Andrew, Nathanson, Katherine L, Couch, Fergus J, Pope, Bernard J, and Park, Daniel J
Abstract: We have previously reported Hi-Plex, a multiplex PCR methodology for building targeted DNA sequencing libraries that offers a low-cost protocol compatible with high-throughput processing. Here, we detail an improved protocol, Hi-Plex2, that more effectively enables the robust construction of small-to-medium panel-size libraries while maintaining low cost, simplicity and accuracy benefits of the Hi-Plex platform. Hi-Plex2 was applied to three panels, comprising 291, 740 and 1193 amplicons, targeting genes associated with risk for breast and/or colon cancer. We show substantial reduction of off-target amplification to enable library construction for small-to-medium-sized design panels not possible using the previous Hi-Plex chemistry.
Published: 2019
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36. Incident Chronic Kidney Disease After Radical Nephrectomy for Renal Cell Carcinoma

Author: Ellis, Robert J., White, Victoria M., Bolton, Damien M., Coory, Michael D., Davis, Ian D., Francis, Ross S., Giles, Graham G., Gobe, Glenda C., Marco, David J.T., Neale, Rachel E., Wood, Simon T., Jordan, Susan J., Giles, Graham, White, Victoria, Coory, Michael, Millar, Jeremy, Bolton, Damien, Davis, Ian, Winship, Ingrid, Roos, Ian, Southey, Melissa, Severi, Gianlucca, Prince, Miles, Harrison, Simon, Seymour, John, Jefford, Michael, Hill, David, and Kay, Anne
Abstract: Chronic kidney disease (CKD) after surgery for kidney cancer is common, and is associated with increased morbidity and mortality. This study aimed to identify factors associated with incident CKD in patients managed with radical nephrectomy.
Published: 2019
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37. Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report

Author: Lopez-Perolio, Irene, Leman, Raphae¨l, Behar, Raquel, Lattimore, Vanessa, Pearson, John F, Castéra, Laurent, Martins, Alexandra, Vaur, Dominique, Goardon, Nicolas, Davy, Grégoire, Garre, Pilar, García-Barberán, Vanesa, Llovet, Patricia, Pérez-Segura, Pedro, Díaz-Rubio, Eduardo, Caldés, Trinidad, Hruska, Kathleen S, Hsuan, Vickie, Wu, Sitao, Pesaran, Tina, Karam, Rachid, Vallon-Christersson, Johan, Borg, Ake, Investigators, kConFab, Valenzuela-Palomo, Alberto, Velasco, Eladio A, Southey, Melissa, Vreeswijk, Maaike P G, Devilee, Peter, Kvist, Anders, Spurdle, Amanda B, Walker, Logan C, Krieger, Sophie, and de la Hoya, Miguel
Abstract: BackgroundPALB2monoallelic loss-of-functiongerm-line variants confer a breast cancer risk comparable to the average BRCA2pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-functionvariants in PALB2—without incurring overprediction—is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.MethodsAlternative splicing was characterised in RNAs extracted from blood, breast and fimbriae/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in PALB2c.212–1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant.ResultsWe identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies.ConclusionsPVS1 is not necessarily warranted for splice site variants targeting four PALB2acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenicwithout further evidences. Our study puts a warning in up to five PALB2genetic variants that are currently reported as pathogenic/likely pathogenicin ClinVar.
Published: 2019
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38. Discovery of common and rare genetic risk variants for colorectal cancer

Author: Huyghe, Jeroen R., Bien, Stephanie A., Harrison, Tabitha A., Kang, Hyun Min, Chen, Sai, Schmit, Stephanie L., Conti, David V., Qu, Conghui, Jeon, Jihyoun, Edlund, Christopher K., Greenside, Peyton, Wainberg, Michael, Schumacher, Fredrick R., Smith, Joshua D., Levine, David M., Nelson, Sarah C., Sinnott-Armstrong, Nasa A., Albanes, Demetrius, Alonso, M. Henar, Anderson, Kristin, Arnau-Collell, Coral, Arndt, Volker, Bamia, Christina, Banbury, Barbara L., Baron, John A., Berndt, Sonja I., Bézieau, Stéphane, Bishop, D. Timothy, Boehm, Juergen, Boeing, Heiner, Brenner, Hermann, Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D., Burnett-Hartman, Andrea, Butterbach, Katja, Caan, Bette J., Campbell, Peter T., Carlson, Christopher S., Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Chanock, Stephen J., Chirlaque, Maria-Dolores, Cho, Sang Hee, Connolly, Charles M., Cross, Amanda J., Cuk, Katarina, Curtis, Keith R., de la Chapelle, Albert, Doheny, Kimberly F., Duggan, David, Easton, Douglas F., Elias, Sjoerd G., Elliott, Faye, English, Dallas R., Feskens, Edith J. M., Figueiredo, Jane C., Fischer, Rocky, FitzGerald, Liesel M., Forman, David, Gala, Manish, Gallinger, Steven, Gauderman, W. James, Giles, Graham G., Gillanders, Elizabeth, Gong, Jian, Goodman, Phyllis J., Grady, William M., Grove, John S., Gsur, Andrea, Gunter, Marc J., Haile, Robert W., Hampe, Jochen, Hampel, Heather, Harlid, Sophia, Hayes, Richard B., Hofer, Philipp, Hoffmeister, Michael, Hopper, John L., Hsu, Wan-Ling, Huang, Wen-Yi, Hudson, Thomas J., Hunter, David J., Ibañez-Sanz, Gemma, Idos, Gregory E., Ingersoll, Roxann, Jackson, Rebecca D., Jacobs, Eric J., Jenkins, Mark A., Joshi, Amit D., Joshu, Corinne E., Keku, Temitope O., Key, Timothy J., Kim, Hyeong Rok, Kobayashi, Emiko, Kolonel, Laurence N., Kooperberg, Charles, Kühn, Tilman, Küry, Sébastien, Kweon, Sun-Seog, Larsson, Susanna C., Laurie, Cecelia A., Le Marchand, Loic, Leal, Suzanne M., Lee, Soo Chin, Lejbkowicz, Flavio, Lemire, Mathieu, Li, Christopher I., Li, Li, Lieb, Wolfgang, Lin, Yi, Lindblom, Annika, Lindor, Noralane M., Ling, Hua, Louie, Tin L., Männistö, Satu, Markowitz, Sanford D., Martín, Vicente, Masala, Giovanna, McNeil, Caroline E., Melas, Marilena, Milne, Roger L., Moreno, Lorena, Murphy, Neil, Myte, Robin, Naccarati, Alessio, Newcomb, Polly A., Offit, Kenneth, Ogino, Shuji, Onland-Moret, N. Charlotte, Pardini, Barbara, Parfrey, Patrick S., Pearlman, Rachel, Perduca, Vittorio, Pharoah, Paul D. P., Pinchev, Mila, Platz, Elizabeth A., Prentice, Ross L., Pugh, Elizabeth, Raskin, Leon, Rennert, Gad, Rennert, Hedy S., Riboli, Elio, Rodríguez-Barranco, Miguel, Romm, Jane, Sakoda, Lori C., Schafmayer, Clemens, Schoen, Robert E., Seminara, Daniela, Shah, Mitul, Shelford, Tameka, Shin, Min-Ho, Shulman, Katerina, Sieri, Sabina, Slattery, Martha L., Southey, Melissa C., Stadler, Zsofia K., Stegmaier, Christa, Su, Yu-Ru, Tangen, Catherine M., Thibodeau, Stephen N., Thomas, Duncan C., Thomas, Sushma S., Toland, Amanda E., Trichopoulou, Antonia, Ulrich, Cornelia M., Van Den Berg, David J., van Duijnhoven, Franzel J. B., Van Guelpen, Bethany, van Kranen, Henk, Vijai, Joseph, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Weigl, Korbinian, Weinstein, Stephanie J., White, Emily, Win, Aung Ko, Wolf, C. Roland, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zaidi, Syed H., Zanke, Brent W., Zhang, Qing, Zheng, Wei, Scacheri, Peter C., Potter, John D., Bassik, Michael C., Kundaje, Anshul, Casey, Graham, Moreno, Victor, Abecasis, Goncalo R., Nickerson, Deborah A., Gruber, Stephen B., Hsu, Li, and Peters, Ulrike
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P<5 × 10−8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
Published: 2019
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39. Epigenetic supersimilarity of monozygotic twin pairs

Author: Van Baak, Timothy, Coarfa, Cristian, Dugué, Pierre-Antoine, Fiorito, Giovanni, Laritsky, Eleonora, Baker, Maria, Kessler, Noah, Dong, Jianrong, Duryea, Jack, Silver, Matt, Saffari, Ayden, Prentice, Andrew, Moore, Sophie, Ghantous, Akram, Routledge, Michael, Gong, Yun, Herceg, Zdenko, Vineis, Paolo, Severi, Gianluca, Hopper, John, Southey, Melissa, Giles, Graham, Milne, Roger, and Waterland, Robert
Abstract: Monozygotic twins have long been studied to estimate heritability and explore epigenetic influences on phenotypic variation. The phenotypic and epigenetic similarities of monozygotic twins have been assumed to be largely due to their genetic identity. Here, by analyzing data from a genome-scale study of DNA methylation in monozygotic and dizygotic twins, we identified genomic regions at which the epigenetic similarity of monozygotic twins is substantially greater than can be explained by their genetic identity. This “epigenetic supersimilarity” apparently results from locus-specific establishment of epigenotype prior to embryo cleavage during twinning. Epigenetically supersimilar loci exhibit systemic interindividual epigenetic variation and plasticity to periconceptional environment and are enriched in sub-telomeric regions. In case-control studies nested in a prospective cohort, blood DNA methylation at these loci years before diagnosis is associated with risk of developing several types of cancer. These results establish a link between early embryonic epigenetic development and adult disease. More broadly, epigenetic supersimilarity is a previously unrecognized phenomenon that may contribute to the phenotypic similarity of monozygotic twins.
Published: 2018
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40. Correction: Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Author: Berndt, Sonja I., Vijai, Joseph, Benavente, Yolanda, Camp, Nicola J., Nieters, Alexandra, Wang, Zhaoming, Smedby, Karin E., Kleinstern, Geffen, Hjalgrim, Henrik, Besson, Caroline, Skibola, Christine F., Morton, Lindsay M., Brooks-Wilson, Angela R., Teras, Lauren R., Breeze, Charles, Arias, Joshua, Adami, Hans-Olov, Albanes, Demetrius, Anderson, Kenneth C., Ansell, Stephen M., Bassig, Bryan, Becker, Nikolaus, Bhatti, Parveen, Birmann, Brenda M., Boffetta, Paolo, Bracci, Paige M., Brennan, Paul, Brown, Elizabeth E., Burdett, Laurie, Cannon-Albright, Lisa A., Chang, Ellen T., Chiu, Brian C. H., Chung, Charles C., Clavel, Jacqueline, Cocco, Pierluigi, Colditz, Graham, Conde, Lucia, Conti, David V., Cox, David G., Curtin, Karen, Casabonne, Delphine, De Vivo, Immaculata, Diepstra, Arjan, Diver, W. Ryan, Dogan, Ahmet, Edlund, Christopher K., Foretova, Lenka, Fraumeni, Joseph F., Gabbas, Attilio, Ghesquières, Hervé, Giles, Graham G., Glaser, Sally, Glenn, Martha, Glimelius, Bengt, Gu, Jian, Habermann, Thomas M., Haiman, Christopher A., Haioun, Corinne, Hofmann, Jonathan N., Holford, Theodore R., Holly, Elizabeth A., Hutchinson, Amy, Izhar, Aalin, Jackson, Rebecca D., Jarrett, Ruth F., Kaaks, Rudolph, Kane, Eleanor, Kolonel, Laurence N., Kong, Yinfei, Kraft, Peter, Kricker, Anne, Lake, Annette, Lan, Qing, Lawrence, Charles, Li, Dalin, Liebow, Mark, Link, Brian K., Magnani, Corrado, Maynadie, Marc, McKay, James, Melbye, Mads, Miligi, Lucia, Milne, Roger L., Molina, Thierry J., Monnereau, Alain, Montalvan, Rebecca, North, Kari E., Novak, Anne J., Onel, Kenan, Purdue, Mark P., Rand, Kristin A., Riboli, Elio, Riby, Jacques, Roman, Eve, Salles, Gilles, Sborov, Douglas W., Severson, Richard K., Shanafelt, Tait D., Smith, Martyn T., Smith, Alexandra, Song, Kevin W., Song, Lei, Southey, Melissa C., Spinelli, John J., Staines, Anthony, Stephens, Deborah, Sutherland, Heather J., Tkachuk, Kaitlyn, Thompson, Carrie A., Tilly, Hervé, Tinker, Lesley F., Travis, Ruth C., Turner, Jenny, Vachon, Celine M., Vajdic, Claire M., Van Den Berg, Anke, Van Den Berg, David J., Vermeulen, Roel C. H., Vineis, Paolo, Wang, Sophia S., Weiderpass, Elisabete, Weiner, George J., Weinstein, Stephanie, Doo, Nicole Wong, Ye, Yuanqing, Yeager, Meredith, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zhang, Yawei, Zheng, Tongzhang, Ziv, Elad, Sampson, Joshua, Chatterjee, Nilanjan, Offit, Kenneth, Cozen, Wendy, Wu, Xifeng, Cerhan, James R., Chanock, Stephen J., Slager, Susan L., and Rothman, Nathaniel
Published: 2023
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41. CYP17 Promoter Polymorphism and Breast Cancer in Australian Women Under Age Forty Years

Author: Spurdle, Amanda B., Hopper, John L., Dite, Gillian S., Chen, Xiaoqing, Cui, Jisheng, McCredie, Margaret R. E., Giles, Graham G., Southey, Melissa C., Venter, Deon J., Easton, Douglas F., and Chenevix-Trench, Georgia
Subjects: Breast cancer -- Genetic aspects, Genetic polymorphisms -- Demographic aspects, Health
Abstract: Background: The cytochrome P450c17[Alpha] enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer. Methods: Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed. Results: Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P = .7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1.81 (95% confidence interval [CI] = 1.15-2.86; P = .01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P = .05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P = .006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI - 1.13-10.74; P = .04), which is equivalent to a cumulative risk of 16% to age 70 years. Conclusions: The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer. [J Natl Cancer Inst 2000;92:1674-81]
Published: 2000

42. HRAS1 Rare Minisatellite Alleles and Breast Cancer in Australian Women Under Age Forty Years

Author: Firgaira, Frank A., Seshadri, Ram, McEvoy, Christopher R. E., Dite, Gillian S., Giles, Graham G., McCredie, Margaret R. E., Southey, Melissa C., Venter, Deon J., and Hopper, John L.
Subjects: Breast cancer -- Genetic aspects, Health
Abstract: Background: A recent meta-analysis of 23 studies supported the empirically derived hypothesis that women who lack one of the four common minisatellite alleles at the HRAS1 locus are at increased risk of breast cancer. These studies relied on visual sizing of alleles on electrophoretic gels and may have underreported rare alleles. We determined whether this hypothesis applied to early-onset breast cancer by using a new method to size minisatellite alleles. Methods: We conducted a population-based, case-control-family study of 249 Australian women under 40 years old at diagnosis of a first primary breast cancer and 234 randomly selected women, frequency matched for age. We sized HRAS1 minisatellite alleles with an Applied Biosystems model 373 automated DNA sequencer and GENESCAN[TM] software. All P values are two-sided. Results: We found no association of rare alleles with breast cancer, before or after adjustment for risk factors and irrespective of how their effects were modeled (crude odds ratio = 1.04; 95% confidence interval [CI] = 0.071-1.53; P = .8). The rare allele frequency was 0.173 (95% CI = 0.149-0.197), three times the pooled estimate of 0.058 (95% CI = 0.050-0.066) from previous studies (P [is less than] .001), and was similar for case subjects, 0.177 (95% CI = 0.143-0.221), and control subjects, 0.169 (95% CI = 0.135-0.203) (P = .7). Conclusion: There was no support for an association between rare HRAS1 alleles and the risk of early-onset breast cancer, despite 80% power to detect effects of the magnitude of those associations (1.7-fold) previously suggested. Implications: The question of whether cancer risk is associated with rare minisatellite HRAS1 alleles needs to be revisited with the use of new methods that have a greater ability to distinguish rare alleles from similarly sized common alleles. [J Natl Cancer Inst 1999;91:2107-11]
Published: 1999

43. Androgen Receptor Exon 1 CAG Repeat Length and Breast Cancer in Women Before Age Forty Years

Author: Spurdle, Amanda B., Dite, Gillian S., Chen, Xiaoqing, Mayne, Carol J., Southey, Melissa C., Batten, Leigh E., Chy, Hun, Trute, Lynne, McCredie, Margaret R. E., Giles, Graham G., Armes, Jane, Venter, Deon J., Hopper, John L., and Chenevix-Trench, Georgia
Subjects: Breast cancer -- Genetic aspects, Hormone receptors -- Health aspects, Health
Abstract: Background: We conducted a population-based, case-control-family study to determine whether androgen receptor (AR) exon 1 polymorphic CAG repeat length ([CAG.sub.n]) was a risk factor for early-onset breast cancer in the Australian population. Methods: Case subjects under 40 years of age at diagnosis of a first primary breast cancer and age-matched control subjects were interviewed to assess family history and other risk factors. AR [CAG.sub.n] length was determined for 368 case subjects and 284 control subjects. Distributions in the two groups were compared by linear and logistic regression, allowing adjustment for measured risk factors. All statistical tests were two-tailed. Results: When analyzed as either a continuous or a dichotomous variable, there was no association between CAG. length and breast cancer risk, before or after adjustment for risk factors. Mean (95% confidence interval [CI]) [CAG.sub.n] lengths were 22.0 (21.8-22.2) for case subjects and 22.0 (21.7-22.3) for control subjects (P = .9). The frequency (95% CI) of alleles with 22 or more [CAG.sub.n] repeats was 0.531 (0.494-0.568) for case subjects and 0.507 (0.465-0.549) for control subjects (P = .4). After adjustment, the average effect on log OR (odds ratio) per allele was 0.16 (95% CI = -0.03 to 0.40; P = .2), and the effect of any allele was equivalent to an OR of 1.40 (95% CI = 0.94-2.09; P = .1). Stratification by family history also failed to reveal any association. Similar results were obtained when alleles were defined by other cutoff points. Conclusion: We found no evidence for an association between AR exon 1 [CAG.sub.n] length and breast cancer risk in women under the age of 40, despite having 80% power to detect modest effects. [J Natl Cancer Inst 1999;91:961-6]
Published: 1999

44. PALB2 Genetic Variants: Can Functional Assays Assist Translation?

Author: Southey, Melissa C., Rewse, Amanda, and Nguyen-Dumont, Tu
Abstract: PALB2loss-of-function variants are associated with increased risk of breast and other cancers, but the clinical relevance of missense variants (MVs) remains uncertain. Recent findings reported by Wiltshire et al., Rodrigue et al., and Boonen et al.demonstrate that some MVs disrupt PALB2 function. This new information will support the clinical management of families who carry these MVs and inform their treatment.
Published: 2020
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45. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Author: Schumacher, Fredrick, Al Olama, Ali, Berndt, Sonja, Benlloch, Sara, Ahmed, Mahbubl, Saunders, Edward, Dadaev, Tokhir, Leongamornlert, Daniel, Anokian, Ezequiel, Cieza-Borrella, Clara, Goh, Chee, Brook, Mark, Sheng, Xin, Fachal, Laura, Dennis, Joe, Tyrer, Jonathan, Muir, Kenneth, Lophatananon, Artitaya, Stevens, Victoria, Gapstur, Susan, Carter, Brian, Tangen, Catherine, Goodman, Phyllis, Thompson, Ian, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Håkansson, Niclas, West, Catharine, Dunning, Alison, Burnet, Neil, Mucci, Lorelei, Giovannucci, Edward, Andriole, Gerald, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Beane Freeman, Laura, Sorensen, Karina, Orntoft, Torben, Borre, Michael, Maehle, Lovise, Grindedal, Eli, Neal, David, Donovan, Jenny, Hamdy, Freddie, Martin, Richard, Travis, Ruth, Key, Tim, Hamilton, Robert, Fleshner, Neil, Finelli, Antonio, Ingles, Sue, Stern, Mariana, Rosenstein, Barry, Kerns, Sarah, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham, Southey, Melissa, MacInnis, Robert, FitzGerald, Liesel, Kibel, Adam, Drake, Bettina, Vega, Ana, Gómez-Caamaño, Antonio, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn, Stampfer, Meir, Park, Jong, Sellers, Thomas, Lin, Hui-Yi, Stanford, Janet, Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Ostrander, Elaine, Geybels, Milan, Nordestgaard, Børge, Nielsen, Sune, Weischer, Maren, Bisbjerg, Rasmus, Røder, Martin, Iversen, Peter, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Maier, Christiane, Luedeke, Manuel, Schnoeller, Thomas, Kim, Jeri, Logothetis, Christopher, John, Esther, Teixeira, Manuel, Paulo, Paula, Cardoso, Marta, Neuhausen, Susan, Steele, Linda, Ding, Yuan, Ruyck, Kim, Meerleer, Gert, Ost, Piet, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Lin, Daniel, Newcomb, Lisa, Lessel, Davor, Gamulin, Marija, Kulis, Tomislav, Kaneva, Radka, Usmani, Nawaid, Singhal, Sandeep, Slavov, Chavdar, Mitev, Vanio, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Broeck, Thomas, Larkin, Samantha, Townsend, Paul, Aukim-Hastie, Claire, Gago-Dominguez, Manuela, Castelao, Jose, Martinez, Maria, Roobol, Monique, Jenster, Guido, Schaik, Ron, Menegaux, Florence, Truong, Thérèse, Koudou, Yves, Xu, Jianfeng, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Michael, Agnieszka, Thibodeau, Stephen, McDonnell, Shannon, Schaid, Daniel, Lindstrom, Sara, Turman, Constance, Ma, Jing, Hunter, David, Riboli, Elio, Siddiq, Afshan, Canzian, Federico, Kolonel, Laurence, Marchand, Loic, Hoover, Robert, Machiela, Mitchell, Cui, Zuxi, Kraft, Peter, Amos, Christopher, Conti, David, Easton, Douglas, Wiklund, Fredrik, Chanock, Stephen, Henderson, Brian, Kote-Jarai, Zsofia, Haiman, Christopher, and Eeles, Rosalind
Abstract: Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P< 5.0 × 10−8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P= 8.2 × 10−9; G>C, p.Pro1054Arg) in ATMand rs2066827 (OR = 1.06; P= 2.3 × 10−9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1. A large meta-analysis combining genome-wide and custom high-density genotyping array data identifies 63 new susceptibility loci for prostate cancer, enhancing fine-mapping efforts and providing insights into the underlying biology.
Published: 2018
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46. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author: Wu, Lang, Shi, Wei, Long, Jirong, Guo, Xingyi, Michailidou, Kyriaki, Beesley, Jonathan, Bolla, Manjeet, Shu, Xiao-Ou, Lu, Yingchang, Cai, Qiuyin, Al-Ejeh, Fares, Rozali, Esdy, Wang, Qin, Dennis, Joe, Li, Bingshan, Zeng, Chenjie, Feng, Helian, Gusev, Alexander, Barfield, Richard, Andrulis, Irene, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan, Auer, Paul, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia, Bojesen, Stig, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara, Burwinkel, Barbara, Caldés, Trinidad, Canzian, Federico, Carter, Brian, Castelao, J., Chang-Claude, Jenny, Chen, Xiaoqing, Cheng, Ting-Yuan, Christiansen, Hans, Clarke, Christine, Collée, Margriet, Cornelissen, Sten, Couch, Fergus, Cox, David, Cox, Angela, Cross, Simon, Cunningham, Julie, Czene, Kamila, Daly, Mary, Devilee, Peter, Doheny, Kimberly, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Eccles, Diana, Eilber, Ursula, Eliassen, A., Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Fasching, Peter, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan, García-Closas, Montserrat, Gaudet, Mia, Ghoussaini, Maya, Giles, Graham, Goldberg, Mark, Goldgar, David, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hollestelle, Antoinette, Hoover, Robert, Hopper, John, Huang, Guanmengqian, Humphreys, Keith, Hunter, David, Jakubowska, Anna, Janni, Wolfgang, John, Esther, Johnson, Nichola, Jones, Kristine, Jones, Michael, Jung, Audrey, Kaaks, Rudolf, Kerin, Michael, Khusnutdinova, Elza, Kosma, Veli-Matti, Kristensen, Vessela, Lambrechts, Diether, Marchand, Loic, Li, Jingmei, Lindström, Sara, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubinski, Jan, Luccarini, Craig, Lux, Michael, MacInnis, Robert, Maishman, Tom, Kostovska, Ivana, Mannermaa, Arto, Manson, JoAnn, Margolin, Sara, Mavroudis, Dimitrios, Meijers-Heijboer, Hanne, Meindl, Alfons, Menon, Usha, Meyer, Jeffery, Mulligan, Anna, Neuhausen, Susan, Nevanlinna, Heli, Neven, Patrick, Nielsen, Sune, Nordestgaard, Børge, Olopade, Olufunmilayo, Olson, Janet, Olsson, Håkan, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Prentice, Ross, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rahman, Nazneen, Rennert, Gad, Rennert, Hedy, Rhenius, Valerie, Romero, Atocha, Romm, Jane, Rudolph, Anja, Saloustros, Emmanouil, Sandler, Dale, Sawyer, Elinor, Schmidt, Marjanka, Schmutzler, Rita, Schneeweiss, Andreas, Scott, Rodney, Scott, Christopher, Seal, Sheila, Shah, Mitul, Shrubsole, Martha, Smeets, Ann, Southey, Melissa, Spinelli, John, Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony, Tamimi, Rulla, Tapper, William, Taylor, Jack, Terry, Mary, Tessier, Daniel, Thomas, Abigail, Thöne, Kathrin, Tollenaar, Rob, Torres, Diana, Truong, Thérèse, Untch, Michael, Vachon, Celine, Berg, David, Vincent, Daniel, Waisfisz, Quinten, Weinberg, Clarice, Wendt, Camilla, Whittemore, Alice, Wildiers, Hans, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Xia, Lucy, Yang, Xiaohong, Ziogas, Argyrios, Ziv, Elad, Dunning, Alison, Pharoah, Paul, Simard, Jacques, Milne, Roger, Edwards, Stacey, Kraft, Peter, Easton, Douglas, Chenevix-Trench, Georgia, and Zheng, Wei
Abstract: The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P< 5.82 × 10−6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology. A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.
Published: 2018
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47. Obtaining high quality transcriptome data from formalin-fixed, paraffin-embedded diagnostic prostate tumor specimens

Author: FitzGerald, Liesel M., Jung, Chol-hee, Wong, Ee Ming, Joo, JiHoon E., Gould, Jodee A., Vasic, Vivien, Bassett, Julie K., O’Callaghan, Neil, Nottle, Tim, Pedersen, John, Giles, Graham G., and Southey, Melissa C.
Abstract: Prognostic genomic biomarkers that can be measured at diagnosis to aid choice of treatment options are unavailable for most common cancers. This is due in part to the poor quality and quantity of available diagnostic specimens for discovery research and to limitations in genomic technologies. Recent technical advances now enable high-density molecular analyses using suboptimal biological specimens. Here we describe the optimization of a transcriptome-specific protocol for use with formalin-fixed, paraffin-embedded (FFPE) diagnostic prostate cancer (PrCa) specimens. We applied the Ion AmpliSeq Transcriptome Human Gene Expression Kit (AmpliSeq Kit) to RNA samples extracted from 36 tumor-enriched and 16 adjacent normal tissues (ADJNT) from 37 FFPE PrCa specimens over a series of eight pilot studies, incorporating protocol modifications from Pilots 2 to 5. Data quality were measured by (1) the total number of mapped reads; (2) the percentage of reads that mapped to AmpliSeq target regions (OnTarget%); (3) the percentage of genes on the AmpliSeq panel with a read count =10 (TargetsDetected%); and (4) comparing the gene read-count distribution of the prostate tissue samples with the median gene read-count distribution of cell line-derived RNA samples. Modifications incorporated into Pilot study 5 provided gene expression data equivalent to cell line-derived RNA samples. These modifications included the use of freshly cut slides for macrodissection; increased tissue section thickness (8?µm); RNA extraction using the RecoverAll Total Nucleic Acid Isolation Kit for FFPE (ThermoFisher); 18 target amplification cycles; and processing six samples per Ion PI chip. This protocol will facilitate the discovery of prognostic biomarkers for cancer by allowing researchers to exploit previously underutilized diagnostic FFPE specimens.
Published: 2018
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48. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author: Milne, Roger L, Kuchenbaecker, Karoline B, Michailidou, Kyriaki, Beesley, Jonathan, Kar, Siddhartha, Lindström, Sara, Hui, Shirley, Lemaçon, Audrey, Soucy, Penny, Dennis, Joe, Jiang, Xia, Rostamianfar, Asha, Finucane, Hilary, Bolla, Manjeet K, McGuffog, Lesley, Wang, Qin, Aalfs, Cora M, Adams, Marcia, Adlard, Julian, Agata, Simona, Ahmed, Shahana, Ahsan, Habibul, Aittomäki, Kristiina, Al-Ejeh, Fares, Allen, Jamie, Ambrosone, Christine B, Amos, Christopher I, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Auber, Bernd, Auer, Paul L, Ausems, Margreet G E M, Azzollini, Jacopo, Bacot, François, Balmaña, Judith, Barile, Monica, Barjhoux, Laure, Barkardottir, Rosa B, Barrdahl, Myrto, Barnes, Daniel, Barrowdale, Daniel, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Bignon, Yves-Jean, Blazer, Kathleen R, Blok, Marinus J, Blomqvist, Carl, Blot, William, Bobolis, Kristie, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Bozsik, Aniko, Bradbury, Angela R, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Bressac-de Paillerets, Brigitte, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Brunet, Joan, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byun, Jinyoung, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canzian, Federico, Caron, Olivier, Carracedo, Angel, Carter, Brian D, Castelao, J Esteban, Castera, Laurent, Caux-Moncoutier, Virginie, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Xiaoqing, Cheng, Ting-Yuan David, Chiquette, Jocelyne, Christiansen, Hans, Claes, Kathleen B M, Clarke, Christine L, Conner, Thomas, Conroy, Don M, Cook, Jackie, Cordina-Duverger, Emilie, Cornelissen, Sten, Coupier, Isabelle, Cox, Angela, Cox, David G, Cross, Simon S, Cuk, Katarina, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Damiola, Francesca, Darabi, Hatef, Davidson, Rosemarie, De Leeneer, Kim, Devilee, Peter, Dicks, Ed, Diez, Orland, Ding, Yuan Chun, Ditsch, Nina, Doheny, Kimberly F, Domchek, Susan M, Dorfling, Cecilia M, Dörk, Thilo, dos-Santos-Silva, Isabel, Dubois, Stéphane, Dugué, Pierre-Antoine, Dumont, Martine, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Dworniczak, Bernd, Eccles, Diana, Eeles, Ros, Ehrencrona, Hans, Eilber, Ursula, Ejlertsen, Bent, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Faivre, Laurence, Fasching, Peter A, Faust, Ulrike, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foulkes, William D, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Gaddam, Pragna, Gammon, Marilie D, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Sáenz, José A, Gaudet, Mia M, Gauthier-Villars, Marion, Gehrig, Andrea, Georgoulias, Vassilios, Gerdes, Anne-Marie, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Goodfellow, Paul, Greene, Mark H, Alnæs, Grethe I Grenaker, Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Gschwantler-Kaulich, Daphne, Guénel, Pascal, Guo, Qi, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hallberg, Emily, Hamann, Ute, Hamel, Nathalie, Hankinson, Susan, Hansen, Thomas V O, Harrington, Patricia, Hart, Steven N, Hartikainen, Jaana M, Healey, Catherine S, Hein, Alexander, Helbig, Sonja, Henderson, Alex, Heyworth, Jane, Hicks, Belynda, Hillemanns, Peter, Hodgson, Shirley, Hogervorst, Frans B, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Bob, Hopper, John L, Hu, Chunling, Huang, Guanmengqian, Hulick, Peter J, Humphreys, Keith, Hunter, David J, Imyanitov, Evgeny N, Isaacs, Claudine, Iwasaki, Motoki, Izatt, Louise, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, Jensen, Uffe Birk, John, Esther M, Johnson, Nichola, Jones, Kristine, Jones, Michael, Jukkola-Vuorinen, Arja, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kang, Daehee, Kast, Karin, Keeman, Renske, Kerin, Michael J, Kets, Carolien M, Keupers, Machteld, Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I, Kim, Sung-Won, Knight, Julia A, Konstantopoulou, Irene, Kosma, Veli-Matti, Kristensen, Vessela N, Kruse, Torben A, Kwong, Ava, Lænkholm, Anne-Vibeke, Laitman, Yael, Lalloo, Fiona, Lambrechts, Diether, Landsman, Keren, Lasset, Christine, Lazaro, Conxi, Le Marchand, Loic, Lecarpentier, Julie, Lee, Andrew, Lee, Eunjung, Lee, Jong Won, Lee, Min Hyuk, Lejbkowicz, Flavio, Lesueur, Fabienne, Li, Jingmei, Lilyquist, Jenna, Lincoln, Anne, Lindblom, Annika, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Long, Jirong, Loud, Jennifer T, Lubinski, Jan, Luccarini, Craig, Lush, Michael, MacInnis, Robert J, Maishman, Tom, Makalic, Enes, Kostovska, Ivana Maleva, Malone, Kathleen E, Manoukian, Siranoush, Manson, JoAnn E, Margolin, Sara, Martens, John W M, Martinez, Maria Elena, Matsuo, Keitaro, Mavroudis, Dimitrios, Mazoyer, Sylvie, McLean, Catriona, Meijers-Heijboer, Hanne, Menéndez, Primitiva, Meyer, Jeffery, Miao, Hui, Miller, Austin, Miller, Nicola, Mitchell, Gillian, Montagna, Marco, Muir, Kenneth, Mulligan, Anna Marie, Mulot, Claire, Nadesan, Sue, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nevelsteen, Ines, Niederacher, Dieter, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, Nussbaum, Robert L, Olah, Edith, Olopade, Olufunmilayo I, Olson, Janet E, Olswold, Curtis, Ong, Kai-ren, Oosterwijk, Jan C, Orr, Nick, Osorio, Ana, Pankratz, V Shane, Papi, Laura, Park-Simon, Tjoung-Won, Paulsson-Karlsson, Ylva, Lloyd, Rachel, Pedersen, Inge Søkilde, Peissel, Bernard, Peixoto, Ana, Perez, Jose I A, Peterlongo, Paolo, Peto, Julian, Pfeiler, Georg, Phelan, Catherine M, Pinchev, Mila, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Porteous, Mary E, Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pugh, Elizabeth, Pujana, Miquel Angel, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rahman, Nazneen, Rantala, Johanna, Rappaport-Fuerhauser, Christine, Rennert, Gad, Rennert, Hedy S, Rhenius, Valerie, Rhiem, Kerstin, Richardson, Andrea, Rodriguez, Gustavo C, Romero, Atocha, Romm, Jane, Rookus, Matti A, Rudolph, Anja, Ruediger, Thomas, Saloustros, Emmanouil, Sanders, Joyce, Sandler, Dale P, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Daniel F, Schoemaker, Minouk J, Schumacher, Fredrick, Schürmann, Peter, Schwentner, Lukas, Scott, Christopher, Scott, Rodney J, Seal, Sheila, Senter, Leigha, Seynaeve, Caroline, Shah, Mitul, Sharma, Priyanka, Shen, Chen-Yang, Sheng, Xin, Shimelis, Hermela, Shrubsole, Martha J, Shu, Xiao-Ou, Side, Lucy E, Singer, Christian F, Sohn, Christof, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stegmaier, Christa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Surowy, Harald, Sutter, Christian, Swerdlow, Anthony, Szabo, Csilla I, Tamimi, Rulla M, Tan, Yen Y, Taylor, Jack A, Tejada, Maria-Isabel, Tengström, Maria, Teo, Soo H, Terry, Mary B, Tessier, Daniel C, Teulé, Alex, Thöne, Kathrin, Thull, Darcy L, Tibiletti, Maria Grazia, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob A E M, Tomlinson, Ian, Tong, Ling, Torres, Diana, Tranchant, Martine, Truong, Thérèse, Tucker, Kathy, Tung, Nadine, Tyrer, Jonathan, Ulmer, Hans-Ulrich, Vachon, Celine, van Asperen, Christi J, Van Den Berg, David, van den Ouweland, Ans M W, van Rensburg, Elizabeth J, Varesco, Liliana, Varon-Mateeva, Raymonda, Vega, Ana, Viel, Alessandra, Vijai, Joseph, Vincent, Daniel, Vollenweider, Jason, Walker, Lisa, Wang, Zhaoming, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Wesseling, Jelle, Whittemore, Alice S, Wijnen, Juul T, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Wu, Anna H, Xia, Lucy, Yang, Xiaohong R, Yannoukakos, Drakoulis, Zaffaroni, Daniela, Zheng, Wei, Zhu, Bin, Ziogas, Argyrios, Ziv, Elad, Zorn, Kristin K, Gago-Dominguez, Manuela, Mannermaa, Arto, Olsson, Håkan, Teixeira, Manuel R, Stone, Jennifer, Offit, Kenneth, Ottini, Laura, Park, Sue K, Thomassen, Mads, Hall, Per, Meindl, Alfons, Schmutzler, Rita K, Droit, Arnaud, Bader, Gary D, Pharoah, Paul D P, Couch, Fergus J, Easton, Douglas F, Kraft, Peter, Chenevix-Trench, Georgia, García-Closas, Montserrat, Schmidt, Marjanka K, Antoniou, Antonis C, and Simard, Jacques
Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Published: 2017
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49. Towards more effective and equitable genetic testing for BRCA1 and BRCA2 mutation carriers

Author: Hopper, John L., Dowty, James G., Apicella, Carmel, Southey, Melissa C., Giles, Graham G., and Winship, Ingrid
Subjects: BRCA mutations -- Identification and classification, BRCA mutations -- Reports, Genetic screening -- Reports, Health
Published: 2008

50. Improving breast cancer risk prediction with epigenetic risk factors

Author: Southey, Melissa C. and Dugué, Pierre-Antoine
Abstract: Over the past decade, iterative improvements to models predicting breast cancer risk have primarily come from new information about genetic risk factors and improvements to mammogram-based risk scores. Epigenetic risk factors offer some potential to further improve risk stratification. However, the recently developed DNA methylation score (the WID-BC index) is not yet convincing for predicting breast cancer risk.
Published: 2022
Full Text: View/download PDF

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