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1. Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses.

Author

Dimou, Niki, Omiyale, Wemimo, Biessy, Carine, Viallon, Vivian, Kaaks, Rudolf, O'Mara, Tracy A., Aglago, Elom K., Ardanaz, Eva, Bergmann, Manuela M., Bondonno, Nicola P., Braaten, Tonje, Colorado-Yohar, Sandra M., Crous-Bou, Marta, Dahm, Christina C., Fortner, Renée T., Gram, Inger T., Harlid, Sophia, Heath, Alicia K., Idahl, Annika, and Kvaskoff, Marina

Abstract

Background: Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses. Methods: The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined. Results: In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer. Conclusions: Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer. [ABSTRACT FROM AUTHOR]

Published
2022
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2. Development and evaluation of polygenic risk scores for prediction of endometrial cancer risk in European women

Author

Bafligil, Cemsel, Thompson, Deborah J., Lophatananon, Artitaya, Ryan, Neil A.J., Smith, Miriam J., Dennis, Joe, Mekli, Krisztina, O’Mara, Tracy A., Evans, D. Gareth, and Crosbie, Emma J.

Abstract

Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention.

Published
2022
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3. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.

Author

Quinn, Michael C. J., McCue, Karen, Wei Shi, Johnatty, Sharon E., Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A., Glubb, Dylan M., Tyrer, Jonathan P., Armasu, Sebastian M., Jue-Sheng Ong, Gharahkhani, Puya, Yi Lu, Bo Gao, Patch, Ann-Marie, Fasching, Peter A., Beckmann, Matthias W., Lambrechts, Diether, Vergote, Ignace, and Edwards, Digna R. Velez

Abstract

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. [ABSTRACT FROM AUTHOR]

Published
2021
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4. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.

Author

Quinn, Michael C. J., McCue, Karen, Wei Shi, Johnatty, Sharon E., Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A., Glubb, Dylan M., Tyrer, Jonathan P., Armasu, Sebastian M., Jue-Sheng Ong, Gharahkhani, Puya, Yi Lu, Bo Gao, Patch, Ann-Marie, Fasching, Peter A., Beckmann, Matthias W., Lambrechts, Diether, Vergote, Ignace, and Edwards, Digna R. Velez

Abstract

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. [ABSTRACT FROM AUTHOR]

Published
2021
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5. The splicing effect of variants at branchpoint elements in cancer genes

Author

Canson, Daffodil M., Dumenil, Troy, Parsons, Michael T., O’Mara, Tracy A., Davidson, Aimee L., Okano, Satomi, Signal, Bethany, Mercer, Tim R., Glubb, Dylan M., and Spurdle, Amanda B.

Abstract

Branchpoint elements are required for intron removal, and variants at these elements can result in aberrant splicing. We aimed to assess the value of branchpoint annotations generated from recent large-scale studies to select branchpoint-abrogating variants, using hereditary cancer genes as model.

Published
2022
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7. 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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8. Using human genetics to understand the disease impacts of testosterone in men and women

Author

Ruth, Katherine S, Day, Felix R, Tyrrell, Jessica, Thompson, Deborah J, Wood, Andrew R, Mahajan, Anubha, Beaumont, Robin N, Wittemans, Laura, Martin, Susan, Busch, Alexander S., Erzurumluoglu, A. Mesut, Hollis, Benjamin, O’Mara, Tracy A., McCarthy, Mark I, Langenberg, Claudia, Easton, Douglas F, Wareham, Nicholas J, Burgess, Stephen, Murray, Anna, Ong, Ken K, Frayling, Timothy M, and Perry, John R. B.

Abstract

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22–1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33–1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76–0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.

Published
2020
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9. Genome-Wide Association Studies of Endometrial Cancer: Latest Developments and Future Directions.

Author

O'Mara, Tracy A., Glubb, Dylan M., Kho, Pik Fang, Thompson, Deborah J., and Spurdle, Amanda B.

Abstract

Endometrial cancer, the most commonly diagnosed cancer of the female reproductive tract in developed countries, has a heritable component. To date, 16 genetic risk regions have been robustly discovered by genome-wide association studies (GWAS) of endometrial cancer. Post-GWAS analyses including expression quantitative trait loci analysis and laboratory-based functional studies have been successful in identifying genes and pathways involved in endometrial carcinogenesis. Mendelian randomization analysis studies have confirmed factors causal for endometrial cancer risk, including increased body mass index and early onset of menarche. In this review, we summarize findings from GWAS and post-GWAS analyses of endometrial cancer. We discuss clinical implications of these findings, current knowledge gaps, and future directions for the study of endometrial cancer genetics. [ABSTRACT FROM AUTHOR]

Published
2019
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10. Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer.

Author

Painter, Jodie N., O'Mara, Tracy A., Marquart, Louise, Webb, Penelope M., Attia, John, Medland, Sarah E., Cheng, Timothy, Dennis, Joe, Holliday, Elizabeth G., McEvoy, Mark, Scott, Rodney J., Ahmed, Shahana, Healey, Catherine S., Shah, Mitul, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley V., Beckmann, Matthias W., Ekici, Arif B., and Fasching, Peter A.

Abstract

Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m² of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m²). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. [ABSTRACT FROM AUTHOR]

Published
2016
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11. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author

Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brüning, Thomas, Buring, Julie E, Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J, Cousminer, Diana L, Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, de Geus, Eco J C N, de Mutsert, Renée, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, dos-Santos-Silva, Isabel, Dunning, Alison M, Eriksson, Johan G, Fasching, Peter A, Fernández-Rhodes, Lindsay, Ferrucci, Luigi, Flesch-Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Guénel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B, Hartman, Catharina A, Heiss, Gerardo, Hooning, Maartje J, Hopper, John L, Hu, Frank, Hunter, David J, Ikram, M Arfan, Im, Hae Kyung, Järvelin, Marjo-Riitta, Joshi, Peter K, Karasik, David, Kellis, Manolis, Kutalik, Zoltan, LaChance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J, Laven, Joop S E, Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A, Lindstrom, Sara, Liu, YongMei, Luan, Jian'an, Mägi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, McCarthy, Mark I, Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L, Montgomery, Grant W, Mulligan, Anna M, Nalls, Mike A, Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R, Oldehinkel, Albertine J, O'Mara, Tracy A, Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D P, Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M, Robino, Antonietta, Rosendaal, Frits R, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F, Schmidt, Marjanka K, Scott, Robert A, Shah, Mitul, Sorice, Rossella, Southey, Melissa C, Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J, Traglia, Michela, Truong, Thérèse, Tyrer, Jonathan P, Uitterlinden, André G, Edwards, Digna R Velez, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, van Dijk, Ko Willems, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H R, Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z, Boomsma, Dorret I, Ciullo, Marina, Cucca, Francesco, Esko, Tõnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A, Magnusson, Patrik K E, Martin, Nicholas G, Mook-Kanamori, Dennis O, Nohr, Ellen A, Polasek, Ozren, Porteous, David, Price, Alkes L, Ridker, Paul M, Snieder, Harold, Spector, Tim D, Stöckl, Doris, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A, Völzke, Henry, Wareham, Nicholas J, Wilson, James F, Spurdle, Amanda B, Thorsteindottir, Unnur, Pollard, Katherine S, Easton, Douglas F, Tung, Joyce Y, Chang-Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M, Stefansson, Kari, Ong, Ken K, and Perry, John R B

Abstract

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

Published
2017
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12. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Author

Haycock, Philip C., Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N., Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J., Evans, David M., Willeit, Peter, Aviv, Abraham, Gaunt, Tom R., Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M., Pooley, Karen A., Eeles, Rosalind A., Lee, Jeffrey E., Fang, Shenying, Chen, Wei V., Law, Matthew H., Bowdler, Lisa M., Iles, Mark M., Yang, Qiong, Worrall, Bradford B., Markus, Hugh Stephen, Hung, Rayjean J., Amos, Chris I., Spurdle, Amanda B., Thompson, Deborah J., O’Mara, Tracy A., Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N. Charlotte, Lund, Eiliv, Duell, Eric J., Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J., Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F., Bown, Matthew J., Samani, Nilesh J., van t’Hof, Femke N.G., Tromp, Gerard, Jones, Gregory T., Kuivaniemi, Helena, Elmore, James R., Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M., Neale, Rachel E., Olson, Sara H., Gallinger, Steven, Li, Donghui, Petersen, Gloria M., Risch, Harvey A., Klein, Alison P., Han, Jiali, Abnet, Christian C., Freedman, Neal D., Taylor, Philip R., Maris, John M., Aben, Katja K., Kiemeney, Lambertus A., Vermeulen, Sita H., Wiencke, John K., Walsh, Kyle M., Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R., SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T., Montgomery, Grant W., Nyholt, Dale R., van Heel, David A., Hunt, Karen, Arking, Dan E., Ashar, Foram N., Sotoodehnia, Nona, Woo, Daniel, Rosand, Jonathan, Comeau, Mary E., Brown, W. Mark, Silverman, Edwin K., Hokanson, John E., Cho, Michael H., Hui, Jennie, Ferreira, Manuel A., Thompson, Philip J., Morrison, Alanna C., Felix, Janine F., Smith, Nicholas L., Christiano, Angela M, Petukhova, Lynn, Betz, Regina C., Fan, Xing, Zhang, Xuejun, Zhu, Caihong, Langefeld, Carl D., Thompson, Susan D., Wang, Feijie, Lin, Xu, Schwartz, David A., Fingerlin, Tasha, Rotter, Jerome I., Cotch, Mary Frances, Jensen, Richard A., Munz, Matthias, Dommisch, Henrik, Schaefer, Arne S., Han, Fang, Ollila, Hanna M., Hillary, Ryan P., Albagha, Omar, Ralston, Stuart H., Zeng, Chenjie, Zheng, Wei, Shu, Xiao-Ou, Reis, Andre, Uebe, Steffen, Hüffmeier, Ulrike, Kawamura, Yoshiya, Otowa, Takeshi, Sasaki, Tsukasa, Hibberd, Martin Lloyd, Davila, Sonia, Xie, Gang, Siminovitch, Katherine, Bei, Jin-Xin, Zeng, Yi-Xin, Försti, Asta, Chen, Bowang, Landi, Stefano, Franke, Andre, Fischer, Annegret, Ellinghaus, David, Flores, Carlos, Noth, Imre, Ma, Shwu-Fan, Foo, Jia Nee, Liu, Jianjun, Kim, Jong-Won, Cox, David G., Delattre, Olivier, Mirabeau, Olivier, Skibola, Christine F., Tang, Clara S., Garcia-Barcelo, Merce, Chang, Kai-Ping, Su, Wen-Hui, Chang, Yu-Sun, Martin, Nicholas G., Gordon, Scott, Wade, Tracey D., Lee, Chaeyoung, Kubo, Michiaki, Cha, Pei-Chieng, Nakamura, Yusuke, Levy, Daniel, Kimura, Masayuki, Hwang, Shih-Jen, Hunt, Steven, Spector, Tim, Soranzo, Nicole, Manichaikul, Ani W., Barr, R. Graham, Kahali, Bratati, Speliotes, Elizabeth, Yerges-Armstrong, Laura M., Cheng, Ching-Yu, Jonas, Jost B., Wong, Tien Yin, Fogh, Isabella, Lin, Kuang, Powell, John F., Rice, Kenneth, Relton, Caroline L., Martin, Richard M., and Davey Smith, George

Abstract

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017
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13. Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers

Author

Walker, Logan C, Marquart, Louise, Pearson, John F, Wiggins, George A R, O'Mara, Tracy A, Parsons, Michael T, Barrowdale, Daniel, McGuffog, Lesley, Dennis, Joe, Benitez, Javier, Slavin, Thomas P, Radice, Paolo, Frost, Debra, Godwin, Andrew K, Meindl, Alfons, Schmutzler, Rita Katharina, Isaacs, Claudine, Peshkin, Beth N, Caldes, Trinidad, Hogervorst, Frans BL, Lazaro, Conxi, Jakubowska, Anna, Montagna, Marco, Chen, Xiaoqing, Offit, Kenneth, Hulick, Peter J, Andrulis, Irene L, Lindblom, Annika, Nussbaum, Robert L, Nathanson, Katherine L, Chenevix-Trench, Georgia, Antoniou, Antonis C, Couch, Fergus J, and Spurdle, Amanda B

Abstract

Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.

Published
2017
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15. Five endometrial cancer risk loci identified through genome-wide association analysis

Author

Cheng, Timothy H T, Thompson, Deborah J, O'Mara, Tracy A, Painter, Jodie N, Glubb, Dylan M, Flach, Susanne, Lewis, Annabelle, French, Juliet D, Freeman-Mills, Luke, Church, David, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley, Webb, Penelope M, Attia, John, Holliday, Elizabeth G, McEvoy, Mark, Scott, Rodney J, Henders, Anjali K, Martin, Nicholas G, Montgomery, Grant W, Nyholt, Dale R, Ahmed, Shahana, Healey, Catherine S, Shah, Mitul, Dennis, Joe, Fasching, Peter A, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Hall, Per, Czene, Kamila, Darabi, Hatef, Li, Jingmei, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo, Amant, Frederic, Schrauwen, Stefanie, Zhao, Hui, Lambrechts, Diether, Depreeuw, Jeroen, Dowdy, Sean C, Goode, Ellen L, Fridley, Brooke L, Winham, Stacey J, Njølstad, Tormund S, Salvesen, Helga B, Trovik, Jone, Werner, Henrica M J, Ashton, Katie, Otton, Geoffrey, Proietto, Tony, Liu, Tao, Mints, Miriam, Tham, Emma, Li, Mulin Jun, Yip, Shun H, Wang, Junwen, Bolla, Manjeet K, Michailidou, Kyriaki, Wang, Qin, Tyrer, Jonathan P, Dunlop, Malcolm, Houlston, Richard, Palles, Claire, Hopper, John L, Peto, Julian, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Cunningham, Julie M, Pharoah, Paul D P, Dunning, Alison M, Edwards, Stacey L, Easton, Douglas F, Tomlinson, Ian, and Spurdle, Amanda B

Abstract

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2= 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

Published
2016
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16. Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer.

Author

Jirong Long, Wei Zheng, Yong-Bing Xiang, Lose, Felicity, Thompson, Deborah, Tomlinson, Ian, Yu, Herbert, Wentzensen, Nicolas, Lambrechts, Diether, Dörk, Thilo, Dubrowinskaja, Natalia, Goodman, Marc T., Salvesen, Helga B., Fasching, Peter A., Scott, Rodney J., Delahanty, Ryan, Ying Zheng, O'Mara, Tracy, Healey, Catherine S., and Hodgson, Shirley

Abstract

The article presents a genome-wide association study highlighting a possible genetic locus for endometrial cancer. The study reveals chromosome 1q42.2 as a potential endometrial cancer susceptibility locus as it showed consistent association with the cancer. It encourages functional analyses of the CAPN9 gene to determine its role in endometrial carcinogenesis.

Published
2012
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17. No Association between FTO or HHEX and Endometrial Cancer Risk.

Author

Gaudet, Mia M., Yang, Hannah P., Bosquet, Jesus Gonzalez, Healey, Catherine S., Ahmed, Shahana, Dunning, Alison M., Easton, Doug F., Spurdle, Amanda B., Ferguson, Kaltin, O'Mara, Tracy, Lambrechts, Diether, Despierre, Evelyn, Vergote, Ignace, Amant, Frederic, Lacey Jr., James V., Lissowska, Jola, Peplonska, Beata, Brinton, Louise A., Chanock, Stephen, and Garcia-Closas, Montserrat

Abstract

The article discusses a study which evaluated the hypothesis that the genetic risk factors of obesity and diabetes and the risk of endometrial cancer. The authors genotyped tag-single nucleotide polymorphisms (SNP) and candidate SNPs in fat mass and obesity-associated gene (FTO) and hematopoietically-expressed homeobox protein (HHEX) in a primary set of 417 endometrial cancer cases. It was found that there was no association between endometrial cancer and the phenotypes.

Published
2010
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18. Kallikrein-Related Peptidase 10 (KLK10) Expression and Single Nucleotide Polymorphisms in Ovarian Cancer Survival.

Author

Batra, Jyotsna, Tan, Olivia L., O'Mara, Tracy, Zammit, Rebecca, Nagle, Christina M., Clements, Judith A., Kedda, Mary-Anne, and Spurdle, Amanda B.

Abstract

Kallikrein-related peptidase 10 (KLK10) overexpression is a predictor of poor disease outcome in women with late-stage ovarian cancer. We aimed to identify whether KLK10 overexpression could be attributed to genetic variants, in particular, in hormone response elements or transcription factor binding sites.Cox regression analysis was used to assess the association between 2 tag and 1 exonic KLK10 single nucleotide polymorphisms (SNPs) and the survival of 319 patients with ovarian cancer. Four different ovarian cancer cell lines were investigated for KLK10 expression after hormone stimulation, and sequence variation in the 3.6-Kb upstream of the KLK10 start site. In silico analyses of SNPs in cell lines and from published databases were undertaken to identify further research novel and potentially functional SNPs that are not covered by tag SNPs.The KLK10 SNPs investigated were not associated with ovarian cancer survival. However, steroid hormone treatment of ovarian cell lines showed KLK10 up-regulation in response to estrogen and estrogen plus progesterone treatments in the aggressive cell line PEO1 and affirmed a role for KLK10 in aggressive ovarian cancer. Potentially functional KLK10 SNPs were identified by cell line sequencing and bioinformatic analysis.Potentially functional candidate KLK10 SNPs require investigation in future association studies of ovarian cancer risk and survival, including rs3760738 identified in aggressive ovarian cancer cell lines and predicted to affect transcription factor binding sites. [ABSTRACT FROM AUTHOR]

Published
2010
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19. The Use of Predictive or Prognostic Genetic Biomarkers in Endometrial and Other Hormone-Related Cancers: Justification for Extensive Candidate Gene Single Nucleotide Polymorphism Studies of the Matrix Metalloproteinase Family and their Inhibitors.

Author

O'Mara, Tracy A., Clements, Judith A., and Spurdle, Amanda B.

Abstract

The article offers an overview of the evidence for matrix metalloproteinases (MMPs) and single nucleotide polymorphism (SNP) in endometrial and hormonal cancers to render justification for MMP SNPs as cancer markers. It mentions that genome-wide association studies have speed up the discovery of SNP associated with susceptibility to complex diseases. It notes that the MMP family of proteases are engaged in various cell processes and differences in gene and protein expression linked to cancer.

Published
2009
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21. Correction: Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers

Author

Walker, Logan, Marquart, Louise, Pearson, John, Wiggins, George, O’Mara, Tracy, Parsons, Michael, Barrowdale, Daniel, McGuffog, Lesley, Dennis, Joe, Benitez, Javier, Slavin, Thomas, Radice, Paolo, Frost, Debra, Godwin, Andrew, Meindl, Alfons, Schmutzler, Rita, Isaacs, Claudine, Peshkin, Beth, Caldes, Trinidad, Hogervorst, Frans, Lazaro, Conxi, Jakubowska, Anna, Montagna, Marco, Chen, Xiaoqing, Offit, Kenneth, Hulick, Peter, Andrulis, Irene, Lindblom, Annika, Nussbaum, Robert, Nathanson, Katherine, Chenevix-Trench, Georgia, Antoniou, Antonis, Couch, Fergus, and Spurdle, Amanda

Abstract

This Article was originally published under a CC BY-NC-SA 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Published
2019
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22. Non-coding RNAs underlie genetic predisposition to breast cancer

Author

Moradi Marjaneh, Mahdi, Beesley, Jonathan, O’Mara, Tracy A., Mukhopadhyay, Pamela, Koufariotis, Lambros T., Kazakoff, Stephen, Hussein, Nehal, Fachal, Laura, Bartonicek, Nenad, Hillman, Kristine M., Kaufmann, Susanne, Sivakumaran, Haran, Smart, Chanel E., McCart Reed, Amy E., Ferguson, Kaltin, Saunus, Jodi M., Lakhani, Sunil R., Barnes, Daniel R., Antoniou, Antonis C., Dinger, Marcel E., Waddell, Nicola, Easton, Douglas F., Dunning, Alison M., Chenevix-Trench, Georgia, Edwards, Stacey L., and French, Juliet D.

Abstract

Background: Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. Results: Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. Conclusions: We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.

Published
2020
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