Author: "Southey, Melissa" / Database: eScholarship - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Southey, Melissa"' showing total 133 results

Start Over Author "Southey, Melissa" Database eScholarship

133 results on '"Southey, Melissa"'

1. Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel

Author: Parsons, Michael T, de la Hoya, Miguel, Richardson, Marcy E, Tudini, Emma, Anderson, Michael, Berkofsky-Fessler, Windy, Caputo, Sandrine M, Chan, Raymond C, Cline, Melissa S, Feng, Bing-Jian, Fortuno, Cristina, Gomez-Garcia, Encarna, Hadler, Johanna, Hiraki, Susan, Holdren, Megan, Houdayer, Claude, Hruska, Kathleen, James, Paul, Karam, Rachid, Leong, Huei San, Martins, Alexandra, Mensenkamp, Arjen R, Monteiro, Alvaro N, Nathan, Vaishnavi, O'Connor, Robert, Pedersen, Inge Sokilde, Pesaran, Tina, Radice, Paolo, Schmidt, Gunnar, Southey, Melissa, Tavtigian, Sean, Thompson, Bryony A, Toland, Amanda E, Turnbull, Clare, Vogel, Maartje J, Weyandt, Jamie, Wiggins, George AR, Zec, Lauren, Couch, Fergus J, Walker, Logan C, Vreeswijk, Maaike PG, Goldgar, David E, and Spurdle, Amanda B
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Women's Health, Breast Cancer, Ovarian Cancer, Cancer, Rare Diseases, Good Health and Well Being, ACMG/AMP variant curation guidelines, BRCA1, BRCA2, ClinGen, ClinVar, VCEP, Humans, BRCA2 Protein, BRCA1 Protein, Female, Genetic Variation, Breast Neoplasms, Genomics, Databases, Genetic, Ovarian Neoplasms, Genetic Predisposition to Disease, Genetic Testing, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.
Published: 2024

2. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

Author: Wang, Anqi, Shen, Jiayi, Rodriguez, Alex, Saunders, Edward, Chen, Fei, Janivara, Rohini, Darst, Burcu, Sheng, Xin, Xu, Yili, Chou, Alisha, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark, Plym, Anna, Sahimi, Ali, Hoffman, Thomas, 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, Schleutker, Johanna, Tammela, Teuvo, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham, Southey, Melissa, MacInnis, Robert, Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Rentsch, Christopher, Cho, Kelly, Mcmahon, Benjamin, Neal, David, Donovan, Jenny, Hamdy, Freddie, Martin, Richard, Nordestgaard, Borge, Nielsen, Sune, Weischer, Maren, Bojesen, Stig, Røder, Andreas, Stroomberg, Hein, Batra, Jyotsna, Chambers, Suzanne, Horvath, Lisa, Clements, Judith, Tilly, Wayne, Risbridger, Gail, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordstrom, Tobias, Pashayan, Nora, Dunning, Alison, Ghoussaini, Maya, Travis, Ruth, Key, Tim, Riboli, Elio, Park, Jong, Sellers, Thomas, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie, Cook, Michael, Mucci, Lorelei, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David, Penney, Kathryn, Turman, Constance, Tangen, Catherine, Goodman, Phyllis, Thompson, Ian, Hamilton, Robert, Fleshner, Neil, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet, Ostrander, Elaine, Koutros, Stella, Beane Freeman, Laura, Stampfer, Meir, Wolk, Alicja, and Håkansson, Niclas
Subjects: Humans, Male, Black People, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic or Latino, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Factors, White People, Asian People
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

3. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Author: O’Mahony, Denise G, Ramus, Susan J, Southey, Melissa C, Meagher, Nicola S, Hadjisavvas, Andreas, John, Esther M, Hamann, Ute, Imyanitov, Evgeny N, Andrulis, Irene L, Sharma, Priyanka, Daly, Mary B, Hake, Christopher R, Weitzel, Jeffrey N, Jakubowska, Anna, Godwin, Andrew K, Arason, Adalgeir, Bane, Anita, Simard, Jacques, Soucy, Penny, Caligo, Maria A, Mai, Phuong L, Claes, Kathleen BM, Teixeira, Manuel R, Chung, Wendy K, Lazaro, Conxi, Hulick, Peter J, Toland, Amanda E, Pedersen, Inge Sokilde, Neuhausen, Susan L, Vega, Ana, de la Hoya, Miguel, Nevanlinna, Heli, Dhawan, Mallika, Zampiga, Valentina, Danesi, Rita, Varesco, Liliana, Gismondi, Viviana, Vellone, Valerio Gaetano, James, Paul A, Janavicius, Ramunas, Nikitina-Zake, Liene, Nielsen, Finn Cilius, van Overeem Hansen, Thomas, Pejovic, Tanja, Borg, Ake, Rantala, Johanna, Offit, Kenneth, Montagna, Marco, Nathanson, Katherine L, Domchek, Susan M, Osorio, Ana, García, María J, Karlan, Beth Y, De Fazio, Anna, Bowtell, David, McGuffog, Lesley, Leslie, Goska, Parsons, Michael T, Dörk, Thilo, Speith, Lisa-Marie, dos Santos, Elizabeth Santana, da Costa, Alexandre André BA, Radice, Paolo, Peterlongo, Paolo, Papi, Laura, Engel, Christoph, Hahnen, Eric, Schmutzler, Rita K, Wappenschmidt, Barbara, Easton, Douglas F, Tischkowitz, Marc, Singer, Christian F, Tan, Yen Yen, Whittemore, Alice S, Sieh, Weiva, Brenton, James D, Yannoukakos, Drakoulis, Fostira, Florentia, Konstantopoulou, Irene, Soukupova, Jana, Vocka, Michal, Chenevix-Trench, Georgia, Pharoah, Paul DP, Antoniou, Antonis C, Goldgar, David E, Spurdle, Amanda B, and Michailidou, Kyriaki
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Breast Cancer, Genetics, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Female, Virulence, BRCA1 Protein, BRCA2 Protein, Ovarian Neoplasms, Genetic Predisposition to Disease, Breast Neoplasms, HEBON Investigators, GEMO Study Collaborators, AOCS Group, CZECANCA Consortium, Consortium of Investigators of Modifiers of BRCA1/2, Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundThe distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.MethodsData for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).ResultsNo histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.ConclusionsWe provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
Published: 2023

4. Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies

Author: Jung, Audrey Y, Ahearn, Thomas U, Behrens, Sabine, Middha, Pooja, Bolla, Manjeet K, Wang, Qin, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Freeman, Laura E Beane, Becher, Heiko, Brenner, Hermann, Canzian, Federico, Carey, Lisa A, Consortium, CTS, Czene, Kamila, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine D, Fritschi, Lin, Gabrielson, Marike, Giles, Graham G, Guénel, Pascal, Hadjisavvas, Andreas, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Hunter, David J, Hüsing, Anika, Kaaks, Rudolf, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Lacey, James V, Le Marchand, Loic, Lissowska, Jolanta, Loizidou, Maria A, Mannermaa, Arto, Maurer, Tabea, Murphy, Rachel A, Olshan, Andrew F, Olsson, Håkan, Patel, Alpa V, Perou, Charles M, Rennert, Gad, Shibli, Rana, Shu, Xiao-Ou, Southey, Melissa C, Stone, Jennifer, Tamimi, Rulla M, Teras, Lauren R, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wang, Sophia S, Wolk, Alicja, Wu, Anna H, Yang, Xiaohong R, Zheng, Wei, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Milne, Roger L, Chatterjee, Nilanjan, Schmidt, Marjanka K, García-Closas, Montserrat, and Chang-Claude, Jenny
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Aging, Reproductive health and childbirth, Female, Humans, Breast Neoplasms, Receptor, ErbB-2, Receptors, Progesterone, Receptors, Estrogen, Triple Negative Breast Neoplasms, Case-Control Studies, Risk Factors, Biomarkers, Tumor, CTS Consortium, Receptor, erbB-2, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.
Published: 2022

5. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author: Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Yie, Joanne Ngeow Yuen, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Women's Health, Digestive Diseases, Breast Cancer, Ovarian Cancer, Pancreatic Cancer, Prevention, Cancer, Urologic Diseases, Rare Diseases, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Breast Neoplasms, Male, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Ovarian Neoplasms, Pancreatic Neoplasms, Risk, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.
Published: 2022

6. 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 JC, 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 KE, 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 LR, 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
Subjects: Human Genome, Genetics, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Mental health, Generic health relevance, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Social Science Genetic Association Consortium, Within Family Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
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

7. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients

Author: Giardiello, Daniele, Hooning, Maartje J, Hauptmann, Michael, Keeman, Renske, Heemskerk-Gerritsen, BAM, Becher, Heiko, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Camp, Nicola J, Czene, Kamila, Devilee, Peter, Eccles, Diana M, Fasching, Peter A, Figueroa, Jonine D, Flyger, Henrik, García-Closas, Montserrat, Haiman, Christopher A, Hamann, Ute, Hopper, John L, Jakubowska, Anna, Leeuwen, Floor E, Lindblom, Annika, Lubiński, Jan, Margolin, Sara, Martinez, Maria Elena, Nevanlinna, Heli, Nevelsteen, Ines, Pelders, Saskia, Pharoah, Paul DP, Siesling, Sabine, Southey, Melissa C, van der Hout, Annemieke H, van Hest, Liselotte P, Chang-Claude, Jenny, Hall, Per, Easton, Douglas F, Steyerberg, Ewout W, and Schmidt, Marjanka K
Subjects: Genetics, Breast Cancer, Prevention, Cancer, Humans, Female, Breast Neoplasms, Mastectomy, Prophylactic Mastectomy, Germ-Line Mutation, Risk Factors, Contralateral breast cancer, Risk prediction, Contralateral preventive mastectomy, Clinical decision-making, Breast cancer genetic predisposition, Breast Cancer Association Consortium, BCAC, Prediction performance, BRCA1/2 germline mutation, Polygenic risk score, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: BackgroundPrediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors.MethodsWe included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models.ResultsThe discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.ConclusionsAdditional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
Published: 2022

8. Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

Author: Wang, Xiaoliang, Kapoor, Pooja Middha, Auer, Paul L, Dennis, Joe, Dunning, Alison M, Wang, Qin, Lush, Michael, Michailidou, Kyriaki, Bolla, Manjeet K, Aronson, Kristan J, Murphy, Rachel A, Brooks-Wilson, Angela, Lee, Derrick G, Cordina-Duverger, Emilie, Guénel, Pascal, Truong, Thérèse, Mulot, Claire, Teras, Lauren R, Patel, Alpa V, Dossus, Laure, Kaaks, Rudolf, Hoppe, Reiner, Lo, Wing-Yee, Brüning, Thomas, Hamann, Ute, Czene, Kamila, Gabrielson, Marike, Hall, Per, Eriksson, Mikael, Jung, Audrey, Becher, Heiko, Couch, Fergus J, Larson, Nicole L, Olson, Janet E, Ruddy, Kathryn J, Giles, Graham G, MacInnis, Robert J, Southey, Melissa C, Le Marchand, Loic, Wilkens, Lynne R, Haiman, Christopher A, Olsson, Håkan, Augustinsson, Annelie, Krüger, Ute, Wagner, Philippe, Scott, Christopher, Winham, Stacey J, Vachon, Celine M, Perou, Charles M, Olshan, Andrew F, Troester, Melissa A, Hunter, David J, Eliassen, Heather A, Tamimi, Rulla M, Brantley, Kristen, Andrulis, Irene L, Figueroa, Jonine, Chanock, Stephen J, Ahearn, Thomas U, García-Closas, Montserrat, Evans, Gareth D, Newman, William G, van Veen, Elke M, Howell, Anthony, Wolk, Alicja, Håkansson, Niclas, Anton-Culver, Hoda, Ziogas, Argyrios, Jones, Michael E, Orr, Nick, Schoemaker, Minouk J, Swerdlow, Anthony J, Kitahara, Cari M, Linet, Martha, Prentice, Ross L, Easton, Douglas F, Milne, Roger L, Kraft, Peter, Chang-Claude, Jenny, and Lindström, Sara
Subjects: Genetics, Cancer, Aging, Human Genome, Breast Cancer, Prevention, Estrogen, 2.1 Biological and endogenous factors, Aetiology, Breast, Breast Neoplasms, Estrogen Replacement Therapy, Female, Hormone Replacement Therapy, Humans, Male, Menopause, Risk Factors
Abstract: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values
Published: 2022

9. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author: McCartney, Daniel L, Min, Josine L, Richmond, Rebecca C, Lu, Ake T, Sobczyk, Maria K, Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R, Mishra, Pashupati P, Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M, Ratliff, Scott M, Richardson, Tom G, Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D, Walker, Rosie M, Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R, Gieger, Christian, de Geus, Eco JC, Harris, Sarah E, Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon LR, Kresovich, Jacob K, Li, Shengxu, Lunetta, Kathryn L, Mangino, Massimo, Mason, Dan, McIntosh, Andrew M, Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M, Ollikainen, Miina, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Polidoro, Silvia, Porteous, David J, Raitakari, Olli, Rich, Stephen S, Sandler, Dale P, Sillanpää, Elina, Smith, Alicia K, Southey, Melissa C, Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G, Van Den Berg, David J, van Dongen, Jenny, Wilson, James G, Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T, Binder, Alexandra M, Boomsma, Dorret I, Chen, Wei, Christensen, Kaare, Conneely, Karen N, Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A, Lehtimäki, Terho, Lohoff, Falk W, Milani, Lili, Milne, Roger L, Probst-Hensch, Nicole, Reiner, Alex P, Ritz, Beate, and Rotter, Jerome I
Subjects: Prevention, Nutrition, Aging, Human Genome, Genetics, Generic health relevance, Inflammatory and immune system, Good Health and Well Being, Adiposity, Biomarkers, C-Reactive Protein, CpG Islands, DNA Methylation, Educational Status, Epigenesis, Genetic, Genetic Loci, Genetic Markers, Genome, Human, Genome-Wide Association Study, Granulocytes, Humans, Immunity, Innate, Lipid Metabolism, Multifactorial Inheritance, Plasminogen Activator Inhibitor 1, DNA methylation, GWAS, Epigenetic clock, Genetics of DNA Methylation Consortium, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract: BackgroundBiological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.ResultsLeveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.ConclusionThis study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Published: 2021

10. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.

Author: Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Easton, Douglas F, Ekici, Arif B, Eliassen, A Heather, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Geisler, Jürgen, Giles, Graham G, Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hunter, David J, Jacot, William, Jakubowska, Anna, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A, Nevanlinna, Heli, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Pharoah, Paul DP, Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Christopher, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Teras, Lauren R, Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Wang, Qin, Winqvist, Robert, and Wolk, Alicja
Subjects: kConFab/AOCS Investigators, Cancer, Genetics, Breast Cancer, Prevention, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021

11. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Author: McCartney, Daniel L, Min, Josine L, Richmond, Rebecca C, Lu, Ake T, Sobczyk, Maria K, Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R, Mishra, Pashupati P, Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M, Ratliff, Scott M, Richardson, Tom G, Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D, Walker, Rosie M, Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R, Gieger, Christian, Genetics of DNA Methylation Consortium, de Geus, Eco JC, Harris, Sarah E, Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon LR, Kresovich, Jacob K, Li, Shengxu, Lunetta, Kathryn L, Mangino, Massimo, Mason, Dan, McIntosh, Andrew M, Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Ollikainen, Miina, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Polidoro, Silvia, Porteous, David J, Raitakari, Olli, Rich, Stephen S, Sandler, Dale P, Sillanpää, Elina, Smith, Alicia K, Southey, Melissa C, Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G, Van Den Berg, David J, van Dongen, Jenny, Wilson, James G, Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T, Binder, Alexandra M, Boomsma, Dorret I, Chen, Wei, Christensen, Kaare, Conneely, Karen N, Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A, Lehtimäki, Terho, Lohoff, Falk W, Milani, Lili, Milne, Roger L, Probst-Hensch, Nicole, and Reiner, Alex P
Subjects: Genetics of DNA Methylation Consortium, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, DNA methylation, Epigenetic clock, GWAS, Bioinformatics, Environmental Sciences, Biological Sciences, Information and Computing Sciences
Abstract: BackgroundBiological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.ResultsLeveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.ConclusionThis study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Published: 2021

12. Genome-Wide Interaction Analysis of Menopausal Hormone Therapy Use and Breast Cancer Risk Among 62,370 Women

Author: Wang, Xiaoliang, Kapoor, Pooja Middha, Auer, Paul L, Dennis, Joe, Dunning, Alison M, Wang, Qin, Lush, Michael, Michailidou, Kyriaki, Bolla, Manjeet K, Aronson, Kristan J, Murphy, Rachel A, Brooks-Wilson, Angela, Lee, Derrick G, Cordina-Duverger, Emilie, Guénel, Pascal, Truong, Thérèse, Mulot, Claire, Teras, Lauren R, Patel, Alpa V, Dossus, Laure, Kaaks, Rudolf, Hoppe, Reiner, Lo, Wing-Yee, Brüning, Thomas, Hamann, Ute, Czene, Kamila, Gabrielson, Marike, Hall, Per, Eriksson, Mikael, Jung, Audrey, Becher, Heiko, Couch, Fergus J, Larson, Nicole L, Olson, Janet E, Ruddy, Kathryn J, Giles, Graham G, MacInnis, Robert J, Southey, Melissa C, Marchand, Loic Le, Wilkens, Lynne R, Haiman, Christopher A, Olsson, Håkan, Augustinsson, Annelie, Krüger, Ute, Wagner, Philippe, Scott, Christopher, Winham, Stacey J, Vachon, Celine M, Perou, Charles M, Olshan, Andrew F, Troester, Melissa A, Hunter, David J, Eliassen, A Heather, Tamimi, Rulla M, Brantley, Kristen, Andrulis, Irene L, Figueroa, Jonine, Chanock, Stephen J, Ahearn, Thomas U, García-Closas, Montserrat, Evans, Gareth D, Newman, William G, Veen, Elke M van, Howell, Anthony, Wolk, Alicja, Håkansson, Niclas, Anton-Culver, Hoda, Ziogas, Argyrios, Jones, Michael E, Orr, Nick, Schoemaker, Minouk J, Swerdlow, Anthony J, Kitahara, Cari M, Linet, Martha, Prentice, Ross L, Easton, Douglas F, Milne, Roger L, Kraft, Peter, Chang-Claude, Jenny, and Lindström, Sara
Subjects: Cancer, Prevention, Breast Cancer, Genetics, Human Genome, Aging, Estrogen, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being
Abstract: Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values
Published: 2021

13. Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer.

Author: Schaid, Daniel, McDonnell, Shannon, FitzGerald, Liesel, DeRycke, Lissa, Fogarty, Zachary, Giles, Graham, MacInnis, Robert, Southey, Melissa, Nguyen-Dumont, Tu, Cancel-Tassin, Geraldine, Cussenot, Oliver, Whittemore, Alice, Sieh, Weiva, Hsieh, Chih-Lin, Stanford, Janet, Schleutker, Johanna, Cropp, Cheryl, Carpten, John, Hoegel, Josef, Eeles, Rosalind, Kote-Jarai, Zsofia, Ackerman, Michael, Klein, Christopher, Mandal, Diptasri, Cooney, Kathleen, Bailey-Wilson, Joan, Helfand, Brian, Catalona, William, Wiklund, Fredrick, Riska, Shaun, Bahetti, Saurabh, Larson, Melissa, Cannon Albright, Lisa, Teerlink, Craig, Xu, Jianfeng, Isaacs, William, Ostrander, Elaine, Thibodeau, Stephen, and Ioannidis, Nilah
Subjects: Custom-capture sequencing, Familial prostate cancer, Genetic risk variants, Whole-exome sequencing, Genes, BRCA2, Guanine Nucleotide Exchange Factors, Humans, Male, Neoplasm Grading, Prostatic Neoplasms, Protein Serine-Threonine Kinases, Trypsin, Exome Sequencing
Abstract: BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.
Published: 2021

14. Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Author: Park, JooYong, Choi, Ji-Yeob, Choi, Jaesung, Chung, Seokang, Song, Nan, Park, Sue K, Han, Wonshik, Noh, Dong-Young, Ahn, Sei-Hyun, Lee, Jong Won, Kim, Mi Kyung, Jee, Sun Ha, Wen, Wanqing, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Shah, Mitul, Conroy, Don M, Harrington, Patricia A, Mayes, Rebecca, Czene, Kamila, Hall, Per, Teras, Lauren R, Patel, Alpa V, Couch, Fergus J, Olson, Janet E, Sawyer, Elinor J, Roylance, Rebecca, Bojesen, Stig E, Flyger, Henrik, Lambrechts, Diether, Baten, Adinda, Matsuo, Keitaro, Ito, Hidemi, Guénel, Pascal, Truong, Thérèse, Keeman, Renske, Schmidt, Marjanka K, Wu, Anna H, Tseng, Chiu-Chen, Cox, Angela, Cross, Simon S, kConFab Investigators, Andrulis, Irene L, Hopper, John L, Southey, Melissa C, Wu, Pei-Ei, Shen, Chen-Yang, Fasching, Peter A, Ekici, Arif B, Muir, Kenneth, Lophatananon, Artitaya, Brenner, Hermann, Arndt, Volker, Jones, Michael E, Swerdlow, Anthony J, Hoppe, Reiner, Ko, Yon-Dschun, Hartman, Mikael, Li, Jingmei, Mannermaa, Arto, Hartikainen, Jaana M, Benitez, Javier, González-Neira, Anna, Haiman, Christopher A, Dörk, Thilo, Bogdanova, Natalia V, Teo, Soo Hwang, Mohd Taib, Nur Aishah, Fletcher, Olivia, Johnson, Nichola, Grip, Mervi, Winqvist, Robert, Blomqvist, Carl, Nevanlinna, Heli, Lindblom, Annika, Wendt, Camilla, Kristensen, Vessela N, Nbcs Collaborators, Tollenaar, Rob AEM, Heemskerk-Gerritsen, Bernadette AM, Radice, Paolo, Bonanni, Bernardo, Hamann, Ute, Manoochehri, Mehdi, Lacey, James V, Martinez, Maria Elena, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Yoo, Keun-Young, and Kang, Daehee
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Estrogen, Prevention, Aging, Genetics, Women's Health, Clinical Research, Cancer, Breast Cancer, 2.1 Biological and endogenous factors, breast cancer, estrogen, gene-environment interaction, Oncology and carcinogenesis
Abstract: In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
Published: 2021

15. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Easton, Douglas F, Ekici, Arif B, Eliassen, A Heather, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Geisler, Jürgen, Giles, Graham G, Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hunter, David J, Jacot, William, Jakubowska, Anna, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A, Nevanlinna, Heli, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Pharoah, Paul DP, Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Christopher, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Teras, Lauren R, Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Wang, Qin, Winqvist, Robert, and Wolk, Alicja
Subjects: Cancer, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Biomarkers, Tumor, Breast Neoplasms, Cancer Survivors, Female, Genetic Predisposition to Disease, Genetic Variation, Germ Cells, Germ-Line Mutation, Humans, Kaplan-Meier Estimate, Polymorphism, Single Nucleotide, kConFab/AOCS Investigators
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021

16. Genetic overlap between autoimmune diseases and non‐Hodgkin lymphoma subtypes

Author: Din, Lennox, Sheikh, Mohammad, Kosaraju, Nikitha, Smedby, Karin Ekstrom, Bernatsky, Sasha, Berndt, Sonja I, Skibola, Christine F, Nieters, Alexandra, Wang, Sophia, McKay, James D, Cocco, Pierluigi, Maynadié, Marc, Foretová, Lenka, Staines, Anthony, Mack, Thomas M, de Sanjosé, Silvia, Vyse, Timothy J, Padyukov, Leonid, Monnereau, Alain, Arslan, Alan A, Moore, Amy, Brooks‐Wilson, Angela R, Novak, Anne J, Glimelius, Bengt, Birmann, Brenda M, Link, Brian K, Stewart, Carolyn, Vajdic, Claire M, Haioun, Corinne, Magnani, Corrado, Conti, David V, Cox, David G, Casabonne, Delphine, Albanes, Demetrius, Kane, Eleanor, Roman, Eve, Muzi, Giacomo, Salles, Gilles, Giles, Graham G, Adami, Hans‐Olov, Ghesquières, Hervé, De Vivo, Immaculata, Clavel, Jacqueline, Cerhan, James R, Spinelli, John J, Hofmann, Jonathan, Vijai, Joseph, Curtin, Karen, Costenbader, Karen H, Onel, Kenan, Offit, Kenneth, Teras, Lauren R, Morton, Lindsay, Conde, Lucia, Miligi, Lucia, Melbye, Mads, Ennas, Maria Grazia, Liebow, Mark, Purdue, Mark P, Glenn, Martha, Southey, Melissa C, Din, Morris, Rothman, Nathaniel, Camp, Nicola J, Doo, Nicole Wong, Becker, Nikolaus, Pradhan, Nisha, Bracci, Paige M, Boffetta, Paolo, Vineis, Paolo, Brennan, Paul, Kraft, Peter, Lan, Qing, Severson, Richard K, Vermeulen, Roel CH, Milne, Roger L, Kaaks, Rudolph, Travis, Ruth C, Weinstein, Stephanie J, Chanock, Stephen J, Ansell, Stephen M, Slager, Susan L, Zheng, Tongzhang, Zhang, Yawei, Benavente, Yolanda, Taub, Zachary, Madireddy, Lohith, Gourraud, Pierre‐Antoine, Oksenberg, Jorge R, Cozen, Wendy, Hjalgrim, Henrik, and Khankhanian, Pouya
Subjects: Biological Sciences, Genetics, Lymphoma, Arthritis, Neurodegenerative, Brain Disorders, Autoimmune Disease, Cancer, Human Genome, Rare Diseases, Hematology, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Alleles, Autoimmune Diseases, Female, Genetic Predisposition to Disease, HLA Antigens, Humans, Lymphoma, Non-Hodgkin, Male, Middle Aged, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Risk Factors, autoimmune disease, genome-wide association study, meta-analysis, non-Hodgkin lymphoma, Public Health and Health Services, Epidemiology
Abstract: Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.
Published: 2019

17. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Author: Kelemen, Linda E, Earp, Madalene, Fridley, Brooke L, Chenevix-Trench, Georgia, Australian Ovarian Cancer Study Group, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Lambrechts, Diether, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Behrens, Sabine, Moysich, Kirsten B, Cannioto, Rikki, Lele, Shashikant, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Thompson, Pamela J, Wilkens, Lynne R, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Hillemanns, Peter, Runnebaum, Ingo B, du Bois, Andreas, Harter, Philipp, Heitz, Florian, Schwaab, Ira, Butzow, Ralf, Pelttari, Liisa M, Nevanlinna, Heli, Modugno, Francesmary, Edwards, Robert P, Kelley, Joseph L, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Kjaer, Susanne K, Jensen, Allan, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Bruinsma, Fiona, Southey, Melissa C, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen, Wu, Xifeng, Sellers, Thomas A, Levine, Douglas A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Olson, Sara H, Orlow, Irene, Vestrheim Thomsen, Liv Cecilie, Bjorge, Line, Krakstad, Camilla, Tangen, Ingvild L, Kiemeney, Lambertus A, Aben, Katja KH, Massuger, Leon FAG, van Altena, Anne M, Pejovic, Tanja, Bean, Yukie, Kellar, Melissa, Cook, Linda S, Le, Nhu D, Brooks-Wilson, Angela, Gronwald, Jacek, Cybulski, Cezary, Jakubowska, Anna, Lubiński, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Hogdall, Estrid, Engelholm, Svend Aage, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Pharoah, Paul DP, Dicks, Ed, Song, Honglin, Tyrer, Jonathan P, McNeish, Iain, Siddiqui, Nadeem, and Carty, Karen
Subjects: Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Adenocarcinoma, Mucinous, Ovarian Neoplasms, Hydro-Lyases, Thymidylate Synthase, Proteins, RNA, Antisense, Logistic Models, Odds Ratio, Risk, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Middle Aged, Female, Genetic Association Studies, consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Ovarian Cancer, Rare Diseases, Biotechnology, Cancer, Digestive Diseases, Genetics, Chemical Physics, Other Chemical Sciences, Other Biological Sciences
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

18. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Author: Schumacher, Fredrick R, Al Olama, Ali Amin, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Saunders, Edward J, Dadaev, Tokhir, Leongamornlert, Daniel, Anokian, Ezequiel, Cieza-Borrella, Clara, Goh, Chee, Brook, Mark N, Sheng, Xin, Fachal, Laura, Dennis, Joe, Tyrer, Jonathan, Muir, Kenneth, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Håkansson, Niclas, West, Catharine ML, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei A, Giovannucci, Edward, Andriole, Gerald L, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Beane Freeman, Laura E, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry S, Kerns, Sarah L, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Stanford, Janet L, and Cybulski, Cezary
Subjects: Cancer, Aging, Prostate Cancer, Genetics, Urologic Diseases, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk, Profile Study, Australian Prostate Cancer BioResource, IMPACT Study, Canary PASS Investigators, Breast and Prostate Cancer Cohort Consortium, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Cancer of the Prostate in Sweden, Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci, Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
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 C, p.Pro1054Arg) in ATM and 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.
Published: 2018

19. The BRCA2 c.68‐7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Author: Colombo, Mara, Lòpez‐Perolio, Irene, Meeks, Huong D, Caleca, Laura, Parsons, Michael T, Li, Hongyan, Vecchi, Giovanna, Tudini, Emma, Foglia, Claudia, Mondini, Patrizia, Manoukian, Siranoush, Behar, Raquel, Garcia, Encarna B Gómez, Meindl, Alfons, Montagna, Marco, Niederacher, Dieter, Schmidt, Ane Y, Varesco, Liliana, Wappenschmidt, Barbara, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Wang, Qin, Aittomäki, Kristiina, Andrulis, Irene L, Anton‐Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly‐Fadel, Alicia, Benitez, Javier, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Chang‐Claude, Jenny, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, García‐Closas, Montserrat, Giles, Graham G, González‐Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hollestelle, Antoinette, Hopper, John L, Jakubowska, Anna, Jung, Audrey, Kosma, Veli‐Matti, Lambrechts, Diether, Le Marchand, Loid, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Miao, Hui, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Olson, Janet E, Peterlongo, Paolo, Peto, Julian, Pylkäs, Katri, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, See, Mee Hoong, Southey, Melissa C, Swerdlow, Anthony, Teo, Soo H, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Asperen, Christi J, Ouweland, Ans MW den, der Kolk, Lizet E, Winqvist, Robert, Yannoukakos, Drakoulis, Zheng, Wei, Investigators, kConFab AOCS, Dunning, Alison M, and Easton, Douglas F
Subjects: Cancer, Genetics, Clinical Research, Prevention, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, BRCA2 Protein, Base Sequence, Calibration, Cell Line, Exons, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Mitomycin, Models, Genetic, RNA Splicing, RNA, Messenger, kConFab/AOCS Investigators, BRCA2, digital PCR, multifactorial likelihood analysis, quantitative real-time PCR, spliceogenic variants, Clinical Sciences, Genetics & Heredity
Abstract: Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2018

20. The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Author: Colombo, Mara, Lòpez-Perolio, Irene, Meeks, Huong D, Caleca, Laura, Parsons, Michael T, Li, Hongyan, De Vecchi, Giovanna, Tudini, Emma, Foglia, Claudia, Mondini, Patrizia, Manoukian, Siranoush, Behar, Raquel, Garcia, Encarna B Gómez, Meindl, Alfons, Montagna, Marco, Niederacher, Dieter, Schmidt, Ane Y, Varesco, Liliana, Wappenschmidt, Barbara, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Wang, Qin, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadel, Alicia, Benitez, Javier, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Chang-Claude, Jenny, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hollestelle, Antoinette, Hopper, John L, Jakubowska, Anna, Jung, Audrey, Kosma, Veli-Matti, Lambrechts, Diether, Le Marchand, Loid, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Miao, Hui, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Olson, Janet E, Peterlongo, Paolo, Peto, Julian, Pylkäs, Katri, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, See, Mee Hoong, Southey, Melissa C, Swerdlow, Anthony, Teo, Soo H, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, van Asperen, Christi J, van den Ouweland, Ans MW, van der Kolk, Lizet E, Winqvist, Robert, Yannoukakos, Drakoulis, Zheng, Wei, kConFab/AOCS Investigators, Dunning, Alison M, and Easton, Douglas F
Subjects: kConFab/AOCS Investigators, Cell Line, Humans, Genetic Predisposition to Disease, Mitomycin, BRCA2 Protein, RNA, Messenger, Calibration, RNA Splicing, Base Sequence, Exons, Models, Genetic, Female, Genetic Variation, BRCA2, digital PCR, multifactorial likelihood analysis, quantitative real-time PCR, spliceogenic variants, RNA, Messenger, Models, Genetic, Genetics & Heredity, Genetics, Clinical Sciences
Abstract: Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2018

21. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Prevention, Genetics, Ovarian Cancer, Women's Health, Cancer, 2.1 Biological and endogenous factors, Adolescent, Adult, Aged, Aged, 80 and over, Body Height, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Geography, Humans, Mendelian Randomization Analysis, Middle Aged, Ovarian Neoplasms, Risk Factors, Young Adult, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundObservational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.MethodsWe pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.ResultsGreater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.ConclusionsWomen with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
Published: 2018

22. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study.

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S
Subjects: Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Ovarian Neoplasms, Genetic Predisposition to Disease, Body Height, Risk Factors, Case-Control Studies, Geography, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Young Adult, Mendelian Randomization Analysis, Carcinoma, Ovarian Epithelial, Genetics, Clinical Research, Rare Diseases, Ovarian Cancer, Cancer, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
Abstract: BackgroundObservational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.MethodsWe pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.ResultsGreater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.ConclusionsWomen with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
Published: 2018

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

Author: Dadaev, Tokhir, Saunders, Edward J, Newcombe, Paul J, Anokian, Ezequiel, Leongamornlert, Daniel A, Brook, Mark N, Cieza-Borrella, Clara, Mijuskovic, Martina, Wakerell, Sarah, Olama, Ali Amin Al, Schumacher, Fredrick R, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Goh, Chee, Sheng, Xin, Zhang, Zhuo, Muir, Kenneth, Govindasami, Koveela, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis, Thompson, Ian M, 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 LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Hakansson, Niclas, West, Catharine, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei, Giovannucci, Edward, Andriole, Gerald, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Freeman, Laura E Beane, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry, Kerns, Sarah, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, and Sellers, Thomas A
Subjects: Genetics, Aging, Urologic Diseases, Prostate Cancer, Prevention, Human Genome, Cancer, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Algorithms, Bayes Theorem, Black People, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Molecular Sequence Annotation, Multivariate Analysis, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Risk, White People, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium
Abstract: Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
Published: 2018

24. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Kelemen, Linda E, Earp, Madalene, Fridley, Brooke L, Chenevix-Trench, Georgia, Group, on behalf of Australian Ovarian Cancer Study, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Lambrechts, Diether, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Behrens, Sabine, Moysich, Kirsten B, Cannioto, Rikki, Lele, Shashikant, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Thompson, Pamela J, Wilkens, Lynne R, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Hillemanns, Peter, Runnebaum, Ingo B, du Bois, Andreas, Harter, Philipp, Heitz, Florian, Schwaab, Ira, Butzow, Ralf, Pelttari, Liisa M, Nevanlinna, Heli, Modugno, Francesmary, Edwards, Robert P, Kelley, Joseph L, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Kjaer, Susanne K, Jensen, Allan, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Bruinsma, Fiona, Southey, Melissa C, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen, Wu, Xifeng, Sellers, Thomas A, Levine, Douglas A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Olson, Sara H, Orlow, Irene, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Krakstad, Camilla, Tangen, Ingvild L, Kiemeney, Lambertus A, Aben, Katja KH, Massuger, Leon FAG, van Altena, Anne M, Pejovic, Tanja, Bean, Yukie, Kellar, Melissa, Cook, Linda S, Le, Nhu D, Brooks-Wilson, Angela, Gronwald, Jacek, Cybulski, Cezary, Jakubowska, Anna, Lubiński, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Hogdall, Estrid, Engelholm, Svend Aage, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Pharoah, Paul DP, Dicks, Ed, Song, Honglin, Tyrer, Jonathan P, McNeish, Iain, Siddiqui, Nadeem, and Carty, Karen
Subjects: Biochemistry and Cell Biology, Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Microbiology, Digestive Diseases, Cancer, Genetics, Rare Diseases, Biotechnology, Ovarian Cancer, Adenocarcinoma, Mucinous, Case-Control Studies, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Humans, Hydro-Lyases, Logistic Models, Middle Aged, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Proteins, Quantitative Trait Loci, RNA, Antisense, Risk, Signal Transduction, Thymidylate Synthase, consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Other Chemical Sciences, Other Biological Sciences, Chemical Physics, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

25. PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Author: Jiao, Xiang, Aravidis, Christos, Marikkannu, Rajeshwari, Rantala, Johanna, Picelli, Simone, Adamovic, Tatjana, Liu, Tao, Maguire, Paula, Kremeyer, Barbara, Luo, Liping, von Holst, Susanna, Kontham, Vinaykumar, Thutkawkorapin, Jessada, Margolin, Sara, Du, Quan, Lundin, Johanna, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Beckmann, Matthias W, Blomqvist, Carl, Blot, William, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Chang-Claude, Jenny, Couch, Fergus J, Cox, Angela, Cross, Simon S, Deming-Halverson, Sandra L, Devilee, Peter, dos-Santos-Silva, Isabel, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Guo, Qi, Gündert, Melanie, Haiman, Christopher A, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hooning, Maartje J, Hopper, John L, Huang, Guanmengqian, Jakubowska, Anna, Jones, Michael E, Kerin, Michael J, Kosma, Veli-Matti, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Lubinski, Jan, Mannermaa, Arto, Martens, John WM, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Peto, Julian, Pylkäs, Katri, Radice, Paolo, Rhenius, Valerie, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Southey, Melissa C, Swerdlow, Anthony J, Truong, Thérèse, Wendt, Camilla, Winqvist, Robert, Zheng, Wei, Benitez, Javier, Dunning, Alison M, and Pharoah, Paul DP
Subjects: Cancer, Prevention, Breast Cancer, Genetics, Human Genome, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, familial breast cancer, linkage analysis, risk haplotype, sequencing, NBCS Collaborators, kConFab/AOCS Investigators, Oncology and Carcinogenesis
Abstract: Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
Published: 2017

26. PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1.

Author: Jiao, Xiang, Aravidis, Christos, Marikkannu, Rajeshwari, Rantala, Johanna, Picelli, Simone, Adamovic, Tatjana, Liu, Tao, Maguire, Paula, Kremeyer, Barbara, Luo, Liping, von Holst, Susanna, Kontham, Vinaykumar, Thutkawkorapin, Jessada, Margolin, Sara, Du, Quan, Lundin, Johanna, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Beckmann, Matthias W, Blomqvist, Carl, Blot, William, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Chang-Claude, Jenny, NBCS Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Deming-Halverson, Sandra L, Devilee, Peter, Dos-Santos-Silva, Isabel, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Guo, Qi, Gündert, Melanie, Haiman, Christopher A, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hooning, Maartje J, Hopper, John L, Huang, Guanmengqian, Jakubowska, Anna, Jones, Michael E, Kerin, Michael J, Kosma, Veli-Matti, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Lubinski, Jan, Mannermaa, Arto, Martens, John WM, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Peto, Julian, Pylkäs, Katri, Radice, Paolo, Rhenius, Valerie, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Southey, Melissa C, Swerdlow, Anthony J, Truong, Thérèse, Wendt, Camilla, Winqvist, Robert, Zheng, Wei, kConFab/AOCS Investigators, and Benitez, Javier
Subjects: NBCS Collaborators, kConFab/AOCS Investigators, familial breast cancer, linkage analysis, risk haplotype, sequencing, Oncology and Carcinogenesis
Abstract: Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
Published: 2017

27. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Author: Muranen, Taru A, Greco, Dario, Blomqvist, Carl, Aittomäki, Kristiina, Khan, Sofia, Hogervorst, Frans, Verhoef, Senno, Pharoah, Paul DP, Dunning, Alison M, Shah, Mitul, Luben, Robert, Bojesen, Stig E, Nordestgaard, Børge G, Schoemaker, Minouk, Swerdlow, Anthony, García-Closas, Montserrat, Figueroa, Jonine, Dörk, Thilo, Bogdanova, Natalia V, Hall, Per, Li, Jingmei, Khusnutdinova, Elza, Bermisheva, Marina, Kristensen, Vessela, Borresen-Dale, Anne-Lise, Investigators, NBCS, Peto, Julian, dos Santos Silva, Isabel, Couch, Fergus J, Olson, Janet E, Hillemans, Peter, Park-Simon, Tjoung-Won, Brauch, Hiltrud, Hamann, Ute, Burwinkel, Barbara, Marme, Frederik, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Cross, Simon S, Sawyer, Elinor J, Tomlinson, Ian, Lambrechts, Diether, Moisse, Matthieu, Lindblom, Annika, Margolin, Sara, Hollestelle, Antoinette, Martens, John WM, Fasching, Peter A, Beckmann, Matthias W, Andrulis, Irene L, Knight, Julia A, Investigators, kConFab AOCS, Anton-Culver, Hoda, Ziogas, Argyrios, Giles, Graham G, Milne, Roger L, Brenner, Hermann, Arndt, Volker, Mannermaa, Arto, Kosma, Veli-Matti, Chang-Claude, Jenny, Rudolph, Anja, Devilee, Peter, Seynaeve, Caroline, Hopper, John L, Southey, Melissa C, John, Esther M, Whittemore, Alice S, Bolla, Manjeet K, Wang, Qin, Michailidou, Kyriaki, Dennis, Joe, Easton, Douglas F, Schmidt, Marjanka K, and Nevanlinna, Heli
Subjects: Cancer, Prevention, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Checkpoint Kinase 2, Female, Genes, Modifier, Genetic Predisposition to Disease, Humans, Odds Ratio, Penetrance, Sequence Deletion, breast cancer, Breast Cancer Association Consortium, CHEK2*1100delC, common variants, polygenic risk score, NBCS Investigators, kConFab/AOCS Investigators, Genetics, Clinical Sciences, Genetics & Heredity
Abstract: PurposeCHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).MethodsUsing genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.ResultsThe PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.ConclusionOur results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
Published: 2017

28. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

Author: Muranen, Taru A, Greco, Dario, Blomqvist, Carl, Aittomäki, Kristiina, Khan, Sofia, Hogervorst, Frans, Verhoef, Senno, Pharoah, Paul DP, Dunning, Alison M, Shah, Mitul, Luben, Robert, Bojesen, Stig E, Nordestgaard, Børge G, Schoemaker, Minouk, Swerdlow, Anthony, García-Closas, Montserrat, Figueroa, Jonine, Dörk, Thilo, Bogdanova, Natalia V, Hall, Per, Li, Jingmei, Khusnutdinova, Elza, Bermisheva, Marina, Kristensen, Vessela, Borresen-Dale, Anne-Lise, NBCS Investigators, Peto, Julian, Dos Santos Silva, Isabel, Couch, Fergus J, Olson, Janet E, Hillemans, Peter, Park-Simon, Tjoung-Won, Brauch, Hiltrud, Hamann, Ute, Burwinkel, Barbara, Marme, Frederik, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Cross, Simon S, Sawyer, Elinor J, Tomlinson, Ian, Lambrechts, Diether, Moisse, Matthieu, Lindblom, Annika, Margolin, Sara, Hollestelle, Antoinette, Martens, John WM, Fasching, Peter A, Beckmann, Matthias W, Andrulis, Irene L, Knight, Julia A, kConFab/AOCS Investigators, Anton-Culver, Hoda, Ziogas, Argyrios, Giles, Graham G, Milne, Roger L, Brenner, Hermann, Arndt, Volker, Mannermaa, Arto, Kosma, Veli-Matti, Chang-Claude, Jenny, Rudolph, Anja, Devilee, Peter, Seynaeve, Caroline, Hopper, John L, Southey, Melissa C, John, Esther M, Whittemore, Alice S, Bolla, Manjeet K, Wang, Qin, Michailidou, Kyriaki, Dennis, Joe, Easton, Douglas F, Schmidt, Marjanka K, and Nevanlinna, Heli
Subjects: NBCS Investigators, kConFab/AOCS Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Odds Ratio, Sequence Deletion, Penetrance, Female, Genes, Modifier, Checkpoint Kinase 2, breast cancer, Breast Cancer Association Consortium, CHEK2*1100delC, common variants, polygenic risk score, Genes, Modifier, Prevention, Cancer, Breast Cancer, 2.1 Biological and endogenous factors, Genetics & Heredity, Genetics, Clinical Sciences
Abstract: PurposeCHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).MethodsUsing genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.ResultsThe PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.ConclusionOur results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
Published: 2017

29. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

Author: Hamdi, Yosr, Soucy, Penny, Adoue, Véronique, Michailidou, Kyriaki, Canisius, Sander, Lemaçon, Audrey, Droit, Arnaud, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Baynes, Caroline, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Chang-Claude, Jenny, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, García-Closas, Montserrat, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Grenaker-Alnæs, Grethe, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Hamann, Ute, Hallberg, Emily, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jones, Michael, Kabisch, Maria, Kataja, Vesa, Lambrechts, Diether, Marchand, Loic Le, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Maranian, Mel, Margolin, Sara, Marme, Frederik, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olswold, Curtis, Peto, Julian, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Radice, Paolo, Rudolph, Anja, Sawyer, Elinor J, Schmidt, Marjanka K, Shu, Xiao-Ou, Southey, Melissa C, Swerdlow, Anthony, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Vachon, Celine, Van Den Ouweland, Ans MW, Wang, Qin, Winqvist, Robert, Investigators, kConFab AOCS, Zheng, Wei, Benitez, Javier, Chenevix-Trench, Georgia, Dunning, Alison M, Pharoah, Paul DP, Kristensen, Vessela, Hall, Per, Easton, Douglas F, Pastinen, Tomi, Nord, Silje, and Simard, Jacques
Subjects: Human Genome, Cancer, Breast Cancer, Prevention, Genetics, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Tumor, Breast Neoplasms, Canada, Carrier Proteins, Case-Control Studies, Chromosomes, Human, Pair 4, DNA Helicases, Europe, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Mitochondrial Proteins, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Assessment, Risk Factors, breast cancer, genetic susceptibility, association studies, differential allelic expression, cis-regulatory variants, NBCS Collaborators, kConFab/AOCS Investigators, Oncology and Carcinogenesis
Abstract: There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
Published: 2016

30. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

Author: Hamdi, Yosr, Soucy, Penny, Adoue, Véronique, Michailidou, Kyriaki, Canisius, Sander, Lemaçon, Audrey, Droit, Arnaud, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Baynes, Caroline, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Chang-Claude, Jenny, NBCS Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, García-Closas, Montserrat, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Grenaker-Alnæs, Grethe, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Hamann, Ute, Hallberg, Emily, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jones, Michael, Kabisch, Maria, Kataja, Vesa, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Maranian, Mel, Margolin, Sara, Marme, Frederik, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olswold, Curtis, Peto, Julian, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Radice, Paolo, Rudolph, Anja, Sawyer, Elinor J, Schmidt, Marjanka K, Shu, Xiao-Ou, Southey, Melissa C, Swerdlow, Anthony, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Vachon, Celine, Van Den Ouweland, Ans MW, Wang, Qin, Winqvist, Robert, kConFab/AOCS Investigators, Zheng, Wei, Benitez, Javier, Chenevix-Trench, Georgia, Dunning, Alison M, Pharoah, Paul DP, Kristensen, Vessela, Hall, Per, Easton, Douglas F, Pastinen, Tomi, Nord, Silje, and Simard, Jacques
Subjects: NBCS Collaborators, kConFab/AOCS Investigators, Chromosomes, Human, Pair 4, Humans, Breast Neoplasms, Genetic Predisposition to Disease, DNA Helicases, Carrier Proteins, Mitochondrial Proteins, Odds Ratio, Risk Assessment, Risk Factors, Case-Control Studies, Gene Frequency, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Canada, Europe, Female, Genetic Association Studies, Biomarkers, Tumor, association studies, breast cancer, cis-regulatory variants, differential allelic expression, genetic susceptibility, Oncology and Carcinogenesis
Abstract: There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
Published: 2016

31. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author: Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen BM, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Group, Australian Ovarian Cancer Study, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, and Zheng, Wei
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Ovarian Cancer, Aging, Breast Cancer, Cancer, Women's Health, Rare Diseases, Prevention, Urologic Diseases, Aetiology, 2.1 Biological and endogenous factors, Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Fanconi Anemia Complementation Group N Protein, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mutation, Nuclear Proteins, Ovarian Neoplasms, Prostatic Neoplasms, Risk, Tumor Suppressor Proteins, Australian Ovarian Cancer Study Group, Cancer: breast, Cancer: ovary, Cancer: prostate, cancer predisposition, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract: BackgroundThe rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.MethodsWe genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.ResultsFor European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.ConclusionsThis report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Published: 2016

32. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Author: Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen Bm, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Australian Ovarian Cancer Study Group, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, and Zheng, Wei
Subjects: Australian Ovarian Cancer Study Group, Humans, Breast Neoplasms, Ovarian Neoplasms, Prostatic Neoplasms, Genetic Predisposition to Disease, Tumor Suppressor Proteins, Nuclear Proteins, Risk, Case-Control Studies, Mutation, Female, Male, Genetic Association Studies, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2, Fanconi Anemia Complementation Group N Protein, Cancer: breast, Cancer: ovary, Cancer: prostate, Genetics, cancer predisposition, Cancer, Breast Cancer, Clinical Research, 2.1 Biological and endogenous factors, Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract: BackgroundThe rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.MethodsWe genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.ResultsFor European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.ConclusionsThis report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Published: 2016

33. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women.

Author: Rebbeck, Timothy R, Friebel, Tara M, Mitra, Nandita, Wan, Fei, Chen, Stephanie, Andrulis, Irene L, Apostolou, Paraskevi, Arnold, Norbert, Arun, Banu K, Barrowdale, Daniel, Benitez, Javier, Berger, Raanan, Berthet, Pascaline, Borg, Ake, Buys, Saundra S, Caldes, Trinidad, Carter, Jonathan, Chiquette, Jocelyne, Claes, Kathleen BM, Couch, Fergus J, Cybulski, Cezary, Daly, Mary B, de la Hoya, Miguel, Diez, Orland, Domchek, Susan M, Nathanson, Katherine L, Durda, Katarzyna, Ellis, Steve, EMBRACE, Evans, D Gareth, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Glendon, Gord, Godwin, Andrew K, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Hallberg, Emily, Hamann, Ute, Hansen, Thomas VO, HEBON, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, John, Esther M, Karlan, Beth Y, Kaufman, Bella, Investigators, KConFab, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Loman, Niklas, Lubinski, Jan, Manoukian, Siranoush, Mitchell, Gillian, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Park, Sue Kyung, Piedmonte, Marion, Radice, Paolo, Rappaport-Fuerhauser, Christine, Rookus, Matti A, Seynaeve, Caroline, Simard, Jacques, Singer, Christian F, Soucy, Penny, Southey, Melissa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Szabo, Csilla I, Tancredi, Mariella, Teixeira, Manuel R, Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Toloczko-Grabarek, Aleksandra, Tung, Nadine, van Rensburg, Elizabeth J, Villano, Danylo, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Zidan, Jamal, and Zorn, Kristin K
Subjects: EMBRACE, HEBON, Humans, Breast Neoplasms, Population Surveillance, Heterozygote, Phenotype, Loss of Heterozygosity, Germ-Line Mutation, Alleles, Genes, BRCA1, Genes, BRCA2, Exons, Female, Promoter Regions, Genetic, BRCA1, BRCA2, Hereditary breast and ovarian cancer, Transheterozygosity, Genes, Promoter Regions, Genetic, Clinical Research, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: BackgroundMost BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.MethodsFrom 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.ResultsThe majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p
Published: 2016

34. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women.

Author: Rebbeck, Timothy R, Friebel, Tara M, Mitra, Nandita, Wan, Fei, Chen, Stephanie, Andrulis, Irene L, Apostolou, Paraskevi, Arnold, Norbert, Arun, Banu K, Barrowdale, Daniel, Benitez, Javier, Berger, Raanan, Berthet, Pascaline, Borg, Ake, Buys, Saundra S, Caldes, Trinidad, Carter, Jonathan, Chiquette, Jocelyne, Claes, Kathleen BM, Couch, Fergus J, Cybulski, Cezary, Daly, Mary B, de la Hoya, Miguel, Diez, Orland, Domchek, Susan M, Nathanson, Katherine L, Durda, Katarzyna, Ellis, Steve, EMBRACE, Evans, D Gareth, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Glendon, Gord, Godwin, Andrew K, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Hallberg, Emily, Hamann, Ute, Hansen, Thomas VO, HEBON, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, John, Esther M, Karlan, Beth Y, Kaufman, Bella, Investigators, KConFab, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Loman, Niklas, Lubinski, Jan, Manoukian, Siranoush, Mitchell, Gillian, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Park, Sue Kyung, Piedmonte, Marion, Radice, Paolo, Rappaport-Fuerhauser, Christine, Rookus, Matti A, Seynaeve, Caroline, Simard, Jacques, Singer, Christian F, Soucy, Penny, Southey, Melissa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Szabo, Csilla I, Tancredi, Mariella, Teixeira, Manuel R, Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Toloczko-Grabarek, Aleksandra, Tung, Nadine, van Rensburg, Elizabeth J, Villano, Danylo, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Zidan, Jamal, and Zorn, Kristin K
Subjects: EMBRACE, HEBON, Humans, Breast Neoplasms, Population Surveillance, Heterozygote, Phenotype, Loss of Heterozygosity, Germ-Line Mutation, Alleles, Genes, BRCA1, Genes, BRCA2, Exons, Female, Promoter Regions, Genetic, BRCA1, BRCA2, Hereditary breast and ovarian cancer, Transheterozygosity, Clinical Research, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, Aetiology, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: BackgroundMost BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.MethodsFrom 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.ResultsThe majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p
Published: 2016

35. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Author: Ghoussaini, Maya, French, Juliet D, Michailidou, Kyriaki, Nord, Silje, Beesley, Jonathan, Canisus, Sander, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, Marjaneh, Moradi, Lee, Jason S, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Milne, Roger L, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, Benitez, Javier, González-Neira, Anna, Alonso, M Rosario, Pita, Guillermo, Neuhausen, Susan L, Anton-Culver, Hoda, Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Tessier, Daniel C, Vincent, Daniel, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Dörk, Thilo, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Investigators, kConFab AOCS, Wu, Anna H, Van Den Berg, David, Lambrechts, Diether, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Barile, Monica, Couch, Fergus J, Hallberg, Emily, Giles, Graham G, Haiman, Christopher A, Le Marchand, Loic, Goldberg, Mark S, Teo, Soo H, Yip, Cheng Har, Borresen-Dale, Anne-Lise, Collaborators, NBCS, Zheng, Wei, Cai, Qiuyin, Winqvist, Robert, Pylkäs, Katri, Andrulis, Irene L, Devilee, Peter, Tollenaar, Rob AEM, García-Closas, Montserrat, Figueroa, Jonine, Hall, Per, Czene, Kamila, Brand, Judith S, Darabi, Hatef, Eriksson, Mikael, Hooning, Maartje J, Koppert, Linetta B, Li, Jingmei, Shu, Xiao-Ou, Zheng, Ying, Cox, Angela, Cross, Simon S, Shah, Mitul, and Rhenius, Valerie
Subjects: Prevention, Genetics, Cancer, Breast Cancer, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosomes, Human, Pair 5, Enhancer Elements, Genetic, Fibroblast Growth Factor 10, Genetic Predisposition to Disease, Haplotypes, Humans, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, kConFab/AOCS Investigators, NBCS Collaborators, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
Published: 2016

36. Fine‐scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author: Shi, Jiajun, Zhang, Yanfeng, Zheng, Wei, Michailidou, Kyriaki, Ghoussaini, Maya, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Milne, Roger L, Shu, Xiao‐Ou, Beesley, Jonathan, Kar, Siddhartha, Andrulis, Irene L, Anton‐Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Zhao, Zhiguo, Guo, Xingyi, Benitez, Javier, Beeghly‐Fadiel, Alicia, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Hui, Canisius, Sander, Chang‐Claude, Jenny, Choi, Ji‐Yeob, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Droit, Arnaud, Dork, Thilo, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gaborieau, Valerie, García‐Closas, Montserrat, Giles, Graham G, Grip, Mervi, Guenel, Pascal, Haiman, Christopher A, Hamann, Ute, Hartman, Mikael, Miao, Hui, Hollestelle, Antoinette, Hopper, John L, Hsiung, Chia‐Ni, Investigators, kConFab, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Torres, Diana, Kabisch, Maria, Kang, Daehee, Khan, Sofia, Knight, Julia A, Kosma, Veli‐Matti, Lambrechts, Diether, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McLean, Catriona, Meindl, Alfons, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Nord, Silje, Børresen‐Dale, Anne‐Lise, Olson, Janet E, Orr, Nick, van den Ouweland, Ans MW, Peterlongo, Paolo, Putti, Thomas Choudary, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shen, Chen‐Yang, Hou, Ming‐Feng, Shrubsole, Matha J, and Southey, Melissa C
Subjects: Genetics, Cancer, Breast Cancer, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Alleles, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 8, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, White People, breast cancer, genetic susceptibility, 8q24, fine-mapping, single nucleotide polymorphism, Mervi Grip, kConFab Investigators, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
Published: 2016

37. Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs).

Author: Darabi, Hatef, Beesley, Jonathan, Droit, Arnaud, Kar, Siddhartha, Nord, Silje, Moradi Marjaneh, Mahdi, Soucy, Penny, Michailidou, Kyriaki, Ghoussaini, Maya, Fues Wahl, Hanna, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Alonso, M Rosario, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Benitez, Javier, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Chang-Claude, Jenny, Choi, Ji-Yeob, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Easton, Douglas F, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Galle, Eva, García-Closas, Montserrat, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hallberg, Emily, Hamann, Ute, Hartman, Mikael, Hollestelle, Antoinette, Hopper, John L, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Kang, Daehee, Khan, Sofia, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Lambrechts, Diether, Le Marchand, Loic, Lee, Soo Chin, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Mayes, Rebecca, McKay, James, Meindl, Alfons, Milne, Roger L, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Olswold, Curtis, Orr, Nick, Peterlongo, Paolo, Pita, Guillermo, Pylkäs, Katri, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C, Stram, Daniel O, Surowy, Harald, Swerdlow, Anthony, Teo, Soo H, Tessier, Daniel C, Tomlinson, Ian, Torres, Diana, and Truong, Thérèse
Abstract: Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
Published: 2016

38. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Author: Guo, Yan, Warren Andersen, Shaneda, Shu, Xiao-Ou, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Garcia-Closas, Montserrat, Milne, Roger L, Schmidt, Marjanka K, Chang-Claude, Jenny, Dunning, Allison, Bojesen, Stig E, Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bogdanova, Natalia V, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dumont, Martine, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham G, Guénel, Pascal, Haiman, Christopher A, Hamann, Ute, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jasmine, Farzana, Jenkins, Mark, John, Esther M, Johnson, Nichola, Jones, Michael E, Kabisch, Maria, Kibriya, Muhammad, Knight, Julia A, Koppert, Linetta B, Kosma, Veli-Matti, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Luben, Robert, Lubinski, Jan, Malone, Kathi E, Mannermaa, Arto, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olson, Janet E, Perez, Jose IA, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Shrubsole, Martha J, Southey, Melissa C, Swerdlow, Anthony J, Toland, Amanda E, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Ursin, Giske, Van Der Luijt, Rob B, and Verhoef, Senno
Subjects: Humans, Breast Neoplasms, Genetic Predisposition to Disease, Body Mass Index, Models, Statistical, Risk Factors, Menopause, Polymorphism, Single Nucleotide, Middle Aged, European Continental Ancestry Group, Female, Mendelian Randomization Analysis, Models, Statistical, Polymorphism, Single Nucleotide, Genetics, Prevention, Breast Cancer, Nutrition, Clinical Research, Cancer, Aging, Human Genome, 2.1 Biological and endogenous factors, General & Internal Medicine, Medical and Health Sciences
Abstract: BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p
Published: 2016

39. Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Author: Schmidt, Marjanka K, Hogervorst, Frans, van Hien, Richard, Cornelissen, Sten, Broeks, Annegien, Adank, Muriel A, Meijers, Hanne, Waisfisz, Quinten, Hollestelle, Antoinette, Schutte, Mieke, van den Ouweland, Ans, Hooning, Maartje, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Antoniou, Antonis C, Arndt, Volker, Bermisheva, Marina, Bogdanova, Natalia V, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dunning, Alison M, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Galle, Eva, García-Closas, Montserrat, Giles, Graham G, Haeberle, Lothar, Hall, Per, Hillemanns, Peter, Hopper, John L, Jakubowska, Anna, John, Esther M, Jones, Michael, Khusnutdinova, Elza, Knight, Julia A, Kosma, Veli-Matti, Kristensen, Vessela, Lee, Andrew, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Meindl, Alfons, Milne, Roger L, Muranen, Taru A, Newcomb, Polly A, Offit, Kenneth, Park-Simon, Tjoung-Won, Peto, Julian, Pharoah, Paul DP, Robson, Mark, Rudolph, Anja, Sawyer, Elinor J, Schmutzler, Rita K, Seynaeve, Caroline, Soens, Julie, Southey, Melissa C, Spurdle, Amanda B, Surowy, Harald, Swerdlow, Anthony, Tollenaar, Rob AEM, Tomlinson, Ian, Trentham-Dietz, Amy, Vachon, Celine, Wang, Qin, Whittemore, Alice S, Ziogas, Argyrios, van der Kolk, Lizet, Nevanlinna, Heli, Dörk, Thilo, Bojesen, Stig, and Easton, Douglas F
Subjects: Clinical Research, Genetics, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Middle Aged, Odds Ratio, Receptors, Estrogen, Receptors, Progesterone, Risk Assessment, Sequence Deletion, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: PurposeCHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.Patients and methodsCHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.ResultsProportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.ConclusionThese CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
Published: 2016

40. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Author: Wyszynski, Asaf, Hong, Chi-Chen, Lam, Kristin, Michailidou, Kyriaki, Lytle, Christian, Yao, Song, Zhang, Yali, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Nordestgaard, BÃ¸rge G, Gonzalez-Neira, Anna, Benitez, Javier, Neuhausen, Susan L, Brenner, Hermann, Dieffenbach, Aida Karina, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, DÃ¶rk, Thilo, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Wu, Anna H, Van Den Berg, David, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Peterlongo, Paolo, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Henderson, Brian E, Dumont, Martine, Teo, Soo Hwang, Wong, Tien Y, Kristensen, Vessela, Zheng, Wei, Long, Jirong, Winqvist, Robert, Pylkäs, Katri, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, García-Closas, Montserrat, Figueroa, Jonine, Klevebring, Daniel, Czene, Kamila, Hooning, Maartje J, van den Ouweland, Ans M. W., Darabi, Hatef, Shu, Xiao-Ou, Gao, Yu-Tang, Cox, Angela, Blot, William, Signorello, Lisa B, Shah, Mitul, Kang, Daehee, Choi, Ji-Yeob, Hartman, Mikael, Miao, Hui, Hamann, Ute, Jakubowska, Anna, Lubinski, Jan, Sangrajrang, Suleeporn, McKay, James, Toland, Amanda E, Yannoukakos, Drakoulis, Shen, Chen-Yang, Wu, Pei-Ei, Swerdlow, Anthony, and Orr, Nick
Published: 2016

41. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Author: Arndt, Volker, Beckmann, Matthias, Beeghly-Fadiel, Alicia, Benitez, Javier, Blomqvist, Carl, Bogdanova, Natalia, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Cai, Qiuyin, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus, Cox, Angela, Cross, Simon, Czene, Kamila, Dörk, Thilo, Dumont, Martine, Fasching, Peter, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham, Guénel, Pascal, Haiman, Christopher, Hamann, Ute, Harrington, Patricia, Hartman, Mikael, Hooning, Maartje, Hopper, John, Jakubowska, Anna, Jasmine, Farzana, John, Esther, Johnson, Nichola, Kabisch, Maria, Khan, Sofia, Kibriya, Muhammad, Knight, Julia, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert, Lubinski, Jan, Malone, Kathleen, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Miao, Hui, Muir, Kenneth, Neuhausen, Susan, Nevanlinna, Heli, Neven, Patrick, Olson, Janet, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor, Schmutzler, Rita, Schoemaker, Minouk, Shah, Mitul, Shrubsole, Martha, Southey, Melissa, Swerdlow, Anthony, Toland, Amanda, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Ursin, Giske, Van Der Luijt, Rob, Verhoef, Senno, Wang-Gohrke, Shan, Whittemore, Alice, Winqvist, Robert, Pilar Zamora, M, Zhao, Hui, Dunning, Alison, Simard, Jacques, Hall, Per, Kraft, Peter, Pharoah, Paul, Hunter, David, Easton, Douglas, and Zheng, Wei
Subjects: Breast cancer, Epidemiology, GWAS, Genetic susceptibility, Type 2 diabetes, Breast Neoplasms, Case-Control Studies, Diabetes Mellitus, Type 2, Ethnicity, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, White People
Abstract: PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. RESULTS: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04). CONCLUSIONS: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
Published: 2016

42. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

Author: Zhao, Zhiguo, Wen, Wanqing, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Zhang, Ben, Long, Jirong, Shu, Xiao-Ou, Schmidt, Marjanka K, Milne, Roger L, García-Closas, Montserrat, Chang-Claude, Jenny, Lindstrom, Sara, Bojesen, Stig E, Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Blomqvist, Carl, Bogdanova, Natalia V, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Cai, Qiuyin, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Dumont, Martine, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham G, Guénel, Pascal, Haiman, Christopher A, Hamann, Ute, Harrington, Patricia, Hartman, Mikael, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jasmine, Farzana, John, Esther M, Johnson, Nichola, Kabisch, Maria, Khan, Sofia, Kibriya, Muhammad, Knight, Julia A, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert, Lubinski, Jan, Malone, Kathleen E, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Miao, Hui, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olson, Janet E, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk, Shah, Mitul, Shrubsole, Martha, Southey, Melissa C, Swerdlow, Anthony J, Toland, Amanda E, and Tomlinson, Ian
Subjects: Genetics, Breast Cancer, Prevention, Diabetes, Aging, Cancer, Clinical Research, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, Diabetes Mellitus, Type 2, Ethnicity, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, White People, Type 2 diabetes, Genetic susceptibility, GWAS, Breast cancer, Epidemiology, Oncology and Carcinogenesis, Public Health and Health Services
Abstract: PurposeType 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.MethodsWe constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.ResultsThe T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).ConclusionsWe have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
Published: 2016

43. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

Author: Easton, Douglas F, Lesueur, Fabienne, Decker, Brennan, Michailidou, Kyriaki, Li, Jun, Allen, Jamie, Luccarini, Craig, Pooley, Karen A, Shah, Mitul, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahmad, Jamil, Thompson, Ella R, Damiola, Francesca, Pertesi, Maroulio, Voegele, Catherine, Mebirouk, Noura, Robinot, Nivonirina, Durand, Geoffroy, Forey, Nathalie, Luben, Robert N, Ahmed, Shahana, Aittomäki, Kristiina, Anton-Culver, Hoda, Arndt, Volker, Australian Ovarian Cancer Study Group, Baynes, Caroline, Beckman, Matthias W, Benitez, Javier, Van Den Berg, David, Blot, William J, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Chang-Claude, Jenny, Chia, Kee Seng, Choi, Ji-Yeob, Conroy, Don M, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fostira, Florentia, García-Closas, Montserrat, Giles, Graham G, Glendon, Gord, González-Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hart, Steven N, Hartman, Mikael, Hooning, Maartje J, Hsiung, Chia-Ni, Ito, Hidemi, Jakubowska, Anna, James, Paul A, John, Esther M, Johnson, Nichola, Jones, Michael, Kabisch, Maria, Kang, Daehee, kConFab Investigators, Kosma, Veli-Matti, Kristensen, Vessela, Lambrechts, Diether, Li, Na, Lifepool Investigators, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Meindl, Alfons, Mitchell, Gillian, Muir, Kenneth, NBCS Investigators, Nevelsteen, Ines, van den Ouweland, Ans, Peterlongo, Paolo, Phuah, Sze Yee, Pylkäs, Katri, Rowley, Simone M, Sangrajrang, Suleeporn, Schmutzler, Rita K, Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony, and Teo, Soo H
Subjects: Australian Ovarian Cancer Study Group, kConFab Investigators, Lifepool Investigators, NBCS Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, RNA Helicases, DNA-Binding Proteins, Risk, Cohort Studies, Mutation, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Fanconi Anemia Complementation Group Proteins, Genetic Association Studies, Cancer: breast, Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract: BACKGROUND:BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS:We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS:The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS:These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
Published: 2016

44. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Author: Zhao, Zhiguo, Wen, Wanqing, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Zhang, Ben, Long, Jirong, Shu, Xiao-Ou, Schmidt, Marjanka K, Milne, Roger L, García-Closas, Montserrat, Chang-Claude, Jenny, Lindstrom, Sara, Bojesen, Stig E, Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Blomqvist, Carl, Bogdanova, Natalia V, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Cai, Qiuyin, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Dumont, Martine, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham G, Guénel, Pascal, Haiman, Christopher A, Hamann, Ute, Harrington, Patricia, Hartman, Mikael, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jasmine, Farzana, John, Esther M, Johnson, Nichola, Kabisch, Maria, Khan, Sofia, Kibriya, Muhammad, Knight, Julia A, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert, Lubinski, Jan, Malone, Kathleen E, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Miao, Hui, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olson, Janet E, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk, Shah, Mitul, Shrubsole, Martha, Southey, Melissa C, Swerdlow, Anthony J, Toland, Amanda E, and Tomlinson, Ian
Subjects: Humans, Breast Neoplasms, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Odds Ratio, Risk Factors, Case-Control Studies, Polymorphism, Single Nucleotide, Middle Aged, European Continental Ancestry Group, Ethnic Groups, Female, Genetic Variation, Breast cancer, Epidemiology, GWAS, Genetic susceptibility, Type 2 diabetes, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Prevention, Diabetes, Aging, Clinical Research, Breast Cancer, Human Genome, Cancer, Genetics, 2.1 Biological and endogenous factors, Public Health and Health Services, Oncology and Carcinogenesis
Abstract: PurposeType 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.MethodsWe constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.ResultsThe T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).ConclusionsWe have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
Published: 2016

45. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes

Author: Machiela, Mitchell J, Lan, Qing, Slager, Susan L, Vermeulen, Roel CH, Teras, Lauren R, Camp, Nicola J, Cerhan, James R, Spinelli, John J, Wang, Sophia S, Nieters, Alexandra, Vijai, Joseph, Yeager, Meredith, Wang, Zhaoming, Ghesquières, Hervé, McKay, James, Conde, Lucia, de Bakker, Paul IW, Cox, David G, Burdett, Laurie, Monnereau, Alain, Flowers, Christopher R, De Roos, Anneclaire J, Brooks-Wilson, Angela R, Giles, Graham G, Melbye, Mads, Gu, Jian, Jackson, Rebecca D, Kane, Eleanor, Purdue, Mark P, Vajdic, Claire M, Albanes, Demetrius, Kelly, Rachel S, Zucca, Mariagrazia, Bertrand, Kimberly A, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Hutchinson, Amy, Zhi, Degui, Habermann, Thomas M, Link, Brian K, Novak, Anne J, Dogan, Ahmet, Asmann, Yan W, Liebow, Mark, Thompson, Carrie A, Ansell, Stephen M, Witzig, Thomas E, Tilly, Hervé, Haioun, Corinne, Molina, Thierry J, Hjalgrim, Henrik, Glimelius, Bengt, Adami, Hans-Olov, Roos, Göran, Bracci, Paige M, Riby, Jacques, Smith, Martyn T, Holly, Elizabeth A, Cozen, Wendy, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Tinker, Lesley F, North, Kari E, Becker, Nikolaus, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, Lightfoot, Tracy, Crouch, Simon, Smith, Alex, Roman, Eve, Diver, W Ryan, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Villano, Danylo J, Zheng, Tongzhang, Zhang, Yawei, Holford, Theodore R, Turner, Jenny, Southey, Melissa C, Clavel, Jacqueline, Virtamo, Jarmo, Weinstein, Stephanie, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Boeing, Heiner, Tjønneland, Anne, Angelucci, Emanuele, Di Lollo, Simonetta, Rais, Marco, De Vivo, Immaculata, Giovannucci, Edward, Kraft, Peter, and Huang, Jinyan
Subjects: Clinical Research, Rare Diseases, Genetics, Cancer, Hematology, Lymphoma, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Lymphoma, B-Cell, Male, Middle Aged, Prospective Studies, Telomere, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
Published: 2016

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

Author: Gusev, Alexander, Shi, Huwenbo, Kichaev, Gleb, Pomerantz, Mark, Li, Fugen, Long, Henry W, Ingles, Sue A, Kittles, Rick A, Strom, Sara S, Rybicki, Benjamin A, Nemesure, Barbara, Isaacs, William B, Zheng, Wei, Pettaway, Curtis A, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P, John, Esther M, Murphy, Adam B, Signorello, Lisa B, Carpten, John, Leske, M Cristina, Wu, Suh-Yuh, Hennis, Anslem JM, Neslund-Dudas, Christine, Hsing, Ann W, Chu, Lisa, Goodman, Phyllis J, Klein, Eric A, Witte, John S, Casey, Graham, Kaggwa, Sam, Cook, Michael B, Stram, Daniel O, Blot, William J, Eeles, Rosalind A, Easton, Douglas, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G, Southey, Melissa C, Fitzgerald, Liesel M, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E, Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo LJ, Nordestgaard, Børge G, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Stanford, Janet L, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Teerlink, Craig, Brenner, Hermann, Dieffenbach, Aida K, Arndt, Volker, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Spurdle, Amanda, Clements, Judith A, Teixeira, Manuel R, Pandha, Hardev, Michael, Agnieszka, Paulo, Paula, Maia, Sofia, Kierzek, Andrzej, PRACTICAL consortium, Conti, David V, and Albanes, Demetrius
Subjects: PRACTICAL consortium, Cell Line, Tumor, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Histones, Epigenesis, Genetic, Acetylation, Inheritance Patterns, Linkage Disequilibrium, Polymorphism, Single Nucleotide, African Americans, European Continental Ancestry Group, Male, Atlases as Topic, Genome-Wide Association Study, Genetic Loci, Cell Line, Tumor, Epigenesis, Genetic, Polymorphism, Single Nucleotide
Abstract: Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
Published: 2016

47. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Author: Dunning, Alison M, Michailidou, Kyriaki, Kuchenbaecker, Karoline B, Thompson, Deborah, French, Juliet D, Beesley, Jonathan, Healey, Catherine S, Kar, Siddhartha, Pooley, Karen A, Lopez-Knowles, Elena, Dicks, Ed, Barrowdale, Daniel, Sinnott-Armstrong, Nicholas A, Sallari, Richard C, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, Moradi Marjaneh, Mahdi, Lee, Jason S, Hills, Margaret, Jarosz, Monika, Drury, Suzie, Canisius, Sander, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Hopper, John L, Southey, Melissa C, Broeks, Annegien, Schmidt, Marjanka K, Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W, Fasching, Peter A, Dos-Santos-Silva, Isabel, Peto, Julian, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, González-Neira, Anna, Perez, Jose IA, Anton-Culver, Hoda, Eunjung, Lee, Arndt, Volker, Brenner, Hermann, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Aittomäki, Kristiina, Blomqvist, Carl, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natasha, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-Chen, Wu, Anna H, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Henderson, Brian E, Goldberg, Mark S, Teo, Soo H, Yip, Cheng Har, Nord, Silje, Borresen-Dale, Anne-Lise, Kristensen, Vessela, Long, Jirong, Zheng, Wei, Pylkäs, Katri, Winqvist, Robert, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, Figueroa, Jonine, Sherman, Mark E, Czene, Kamila, Darabi, Hatef, Hollestelle, Antoinette, van den Ouweland, Ans MW, Humphreys, Keith, Gao, Yu-Tang, and Shu, Xiao-Ou
Subjects: EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators, Chromosomes, Human, Pair 6, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Carrier Proteins, Cell Cycle Proteins, Estrogen Receptor alpha, Risk Factors, Gene Expression, Gene Expression Regulation, Neoplastic, Base Sequence, Protein Binding, Phenotype, Polymorphism, Single Nucleotide, Female, Genetic Association Studies, Cancer, Clinical Research, Breast Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Published: 2016

48. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Author: Dunning, Alison M, Michailidou, Kyriaki, Kuchenbaecker, Karoline B, Thompson, Deborah, French, Juliet D, Beesley, Jonathan, Healey, Catherine S, Kar, Siddhartha, Pooley, Karen A, Lopez-Knowles, Elena, Dicks, Ed, Barrowdale, Daniel, Sinnott-Armstrong, Nicholas A, Sallari, Richard C, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, Moradi Marjaneh, Mahdi, Lee, Jason S, Hills, Margaret, Jarosz, Monika, Drury, Suzie, Canisius, Sander, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Hopper, John L, Southey, Melissa C, Broeks, Annegien, Schmidt, Marjanka K, Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W, Fasching, Peter A, Dos-Santos-Silva, Isabel, Peto, Julian, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, González-Neira, Anna, Perez, Jose IA, Anton-Culver, Hoda, Eunjung, Lee, Arndt, Volker, Brenner, Hermann, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Aittomäki, Kristiina, Blomqvist, Carl, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natasha, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-Chen, Wu, Anna H, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Henderson, Brian E, Goldberg, Mark S, Teo, Soo H, Yip, Cheng Har, Nord, Silje, Borresen-Dale, Anne-Lise, Kristensen, Vessela, Long, Jirong, Zheng, Wei, Pylkäs, Katri, Winqvist, Robert, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, Figueroa, Jonine, Sherman, Mark E, Czene, Kamila, Darabi, Hatef, Hollestelle, Antoinette, van den Ouweland, Ans MW, Humphreys, Keith, Gao, Yu-Tang, and Shu, Xiao-Ou
Subjects: EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators, Chromosomes, Human, Pair 6, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Carrier Proteins, Cell Cycle Proteins, Estrogen Receptor alpha, Risk Factors, Gene Expression, Gene Expression Regulation, Neoplastic, Base Sequence, Protein Binding, Phenotype, Polymorphism, Single Nucleotide, Female, Genetic Association Studies, Cancer, Genetics, Breast Cancer, Clinical Research, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Published: 2016

49. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

Author: Meeks, Huong D, Song, Honglin, Michailidou, Kyriaki, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Barrowdale, Daniel, Frost, Debra, EMBRACE, McGuffog, Lesley, Ellis, Steve, Feng, Bingjian, Buys, Saundra S, Hopper, John L, Southey, Melissa C, Tesoriero, Andrea, kConFab Investigators, James, Paul A, Bruinsma, Fiona, Campbell, Ian G, Australia Ovarian Cancer Study Group, Broeks, Annegien, Schmidt, Marjanka K, Hogervorst, Frans BL, HEBON, Beckman, Matthias W, Fasching, Peter A, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Riboli, Elio, Banerjee, Susana, Menon, Usha, Tomlinson, Ian, Burwinkel, Barbara, Hamann, Ute, Marme, Frederik, Rudolph, Anja, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Garber, Judy, Cramer, Daniel, Terry, Kathryn L, Poole, Elizabeth M, Tworoger, Shelley S, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Godwin, Andrew K, Guénel, Pascal, Truong, Thérèse, GEMO Study Collaborators, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Mazoyer, Sylvie, Sinilnikova, Olga M, Isaacs, Claudine, Maugard, Christine, Bojesen, Stig E, Flyger, Henrik, Gerdes, Anne-Marie, Hansen, Thomas VO, Jensen, Allen, Kjaer, Susanne K, Hogdall, Claus, Hogdall, Estrid, Pedersen, Inge Sokilde, Thomassen, Mads, Benitez, Javier, González-Neira, Anna, Osorio, Ana, Hoya, Miguel de la, Segura, Pedro Perez, Diez, Orland, Lazaro, Conxi, Brunet, Joan, Anton-Culver, Hoda, Eunjung, Lee, John, Esther M, Neuhausen, Susan L, Ding, Yuan Chun, Castillo, Danielle, Weitzel, Jeffrey N, Ganz, Patricia A, Nussbaum, Robert L, Chan, Salina B, Karlan, Beth Y, Lester, Jenny, Wu, Anna, Gayther, Simon, Ramus, Susan J, Sieh, Weiva, Whittermore, Alice S, Monteiro, Alvaro NA, Phelan, Catherine M, Terry, Mary Beth, Piedmonte, Marion, Offit, Kenneth, Robson, Mark, and Levine, Douglas
Subjects: EMBRACE, kConFab Investigators, Australia Ovarian Cancer Study Group, HEBON, GEMO Study Collaborators, OCGN, PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome, Humans, Breast Neoplasms, Ovarian Neoplasms, Prostatic Neoplasms, Neoplasm Invasiveness, Genetic Predisposition to Disease, Lysine, BRCA2 Protein, Codon, Terminator, Logistic Models, Odds Ratio, Risk Assessment, Risk Factors, Heterozygote, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Clinical Research, Prevention, Cancer, Prostate Cancer, Aging, Urologic Diseases, Breast Cancer, Ovarian Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
Published: 2016

50. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

Author: Meeks, Huong D, Song, Honglin, Michailidou, Kyriaki, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Barrowdale, Daniel, Frost, Debra, EMBRACE, McGuffog, Lesley, Ellis, Steve, Feng, Bingjian, Buys, Saundra S, Hopper, John L, Southey, Melissa C, Tesoriero, Andrea, kConFab Investigators, James, Paul A, Bruinsma, Fiona, Campbell, Ian G, Australia Ovarian Cancer Study Group, Broeks, Annegien, Schmidt, Marjanka K, Hogervorst, Frans BL, HEBON, Beckman, Matthias W, Fasching, Peter A, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Riboli, Elio, Banerjee, Susana, Menon, Usha, Tomlinson, Ian, Burwinkel, Barbara, Hamann, Ute, Marme, Frederik, Rudolph, Anja, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Garber, Judy, Cramer, Daniel, Terry, Kathryn L, Poole, Elizabeth M, Tworoger, Shelley S, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Godwin, Andrew K, Guénel, Pascal, Truong, Thérèse, GEMO Study Collaborators, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Mazoyer, Sylvie, Sinilnikova, Olga M, Isaacs, Claudine, Maugard, Christine, Bojesen, Stig E, Flyger, Henrik, Gerdes, Anne-Marie, Hansen, Thomas VO, Jensen, Allen, Kjaer, Susanne K, Hogdall, Claus, Hogdall, Estrid, Pedersen, Inge Sokilde, Thomassen, Mads, Benitez, Javier, González-Neira, Anna, Osorio, Ana, Hoya, Miguel de la, Segura, Pedro Perez, Diez, Orland, Lazaro, Conxi, Brunet, Joan, Anton-Culver, Hoda, Eunjung, Lee, John, Esther M, Neuhausen, Susan L, Ding, Yuan Chun, Castillo, Danielle, Weitzel, Jeffrey N, Ganz, Patricia A, Nussbaum, Robert L, Chan, Salina B, Karlan, Beth Y, Lester, Jenny, Wu, Anna, Gayther, Simon, Ramus, Susan J, Sieh, Weiva, Whittermore, Alice S, Monteiro, Alvaro NA, Phelan, Catherine M, Terry, Mary Beth, Piedmonte, Marion, Offit, Kenneth, Robson, Mark, and Levine, Douglas
Subjects: EMBRACE, kConFab Investigators, Australia Ovarian Cancer Study Group, HEBON, GEMO Study Collaborators, OCGN, PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome, Humans, Breast Neoplasms, Ovarian Neoplasms, Prostatic Neoplasms, Neoplasm Invasiveness, Genetic Predisposition to Disease, Lysine, BRCA2 Protein, Codon, Terminator, Logistic Models, Odds Ratio, Risk Assessment, Risk Factors, Heterozygote, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Clinical Research, Aging, Cancer, Prevention, Prostate Cancer, Ovarian Cancer, Breast Cancer, Urologic Diseases, Rare Diseases, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: BackgroundThe K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.MethodsUsing weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.ResultsThe K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.ConclusionsOur study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
Published: 2016

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

133 results on '"Southey, Melissa"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources