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1. The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Author

Lakeman, Inge MM, van den Broek, Alexandra J, Vos, Juliën AM, Barnes, Daniel R, Adlard, Julian, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Arun, Banu K, Balmaña, Judith, Barrowdale, Daniel, Benitez, Javier, Borg, Ake, Caldés, Trinidad, Caligo, Maria A, Chung, Wendy K, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Couch, Fergus J, Daly, Mary B, Dennis, Joe, Dhawan, Mallika, Domchek, Susan M, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Feliubadaló, Lidia, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Gayther, Simon A, Gerdes, Anne-Marie, Godwin, Andrew K, Goldgar, David E, Hahnen, Eric, Hake, Christopher R, Hamann, Ute, Hogervorst, Frans BL, Hooning, Maartje J, Hopper, John L, Hulick, Peter J, Imyanitov, Evgeny N, OCGN Investigators, HEBON Investigators, KconFab Investigators, Isaacs, Claudine, Izatt, Louise, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, Jiao, Yue, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kets, Carolien M, Konstantopoulou, Irene, Kwong, Ava, Legrand, Clémentine, Leslie, Goska, Lesueur, Fabienne, Loud, Jennifer T, Lubiński, Jan, Manoukian, Siranoush, McGuffog, Lesley, Miller, Austin, Gomes, Denise Molina, Montagna, Marco, Mouret-Fourme, Emmanuelle, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Olah, Edith, Olopade, Olufunmilayo I, Park, Sue K, Parsons, Michael T, Peterlongo, Paolo, Piedmonte, Marion, Radice, Paolo, Rantala, Johanna, Rennert, Gad, Risch, Harvey A, Schmutzler, Rita K, Sharma, Priyanka, Simard, Jacques, Singer, Christian F, Stadler, Zsofia, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Teulé, Alex, Thomassen, Mads, and Thull, Darcy L

Subjects
GEMO Study Collaborators, EMBRACE Collaborators, OCGN Investigators, HEBON Investigators, KconFab Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Risk Factors, Retrospective Studies, Heterozygote, Mutation, Adult, Female, Prevention, Cancer, Aging, Breast Cancer, 2.1 Biological and endogenous factors, Genetics & Heredity, Genetics, Clinical Sciences
Abstract

PurposeTo evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.MethodsWe included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.ResultsFor BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

Published
2021

2. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O'Mara, Tracy A, Dennis, Joe, Tyrer, Jonathan P, Barnes, Daniel R, McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K, Adank, Muriel A, Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Conroy, Don M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, He, Wei, Hogervorst, Frans BL, Hollestelle, Antoinette, and Hopper, John L

Subjects
GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Cancer
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

Published
2021

3. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O'Mara, Tracy A, Dennis, Joe, Tyrer, Jonathan P, Barnes, Daniel R, McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K, Adank, Muriel A, Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heiko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Conroy, Don M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, He, Wei, Hogervorst, Frans BL, Hollestelle, Antoinette, and Hopper, John L

Subjects
GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Risk Factors, Genotype, Linkage Disequilibrium, Mutation, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Adult, Middle Aged, Female, Genome-Wide Association Study, Breast Cancer, Prevention, Cancer, Genetic Testing, Human Genome, Genetics, 2.1 Biological and endogenous factors
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P

Published
2021

4. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author

Barnes, Daniel R, Rookus, Matti A, McGuffog, Lesley, Leslie, Goska, Mooij, Thea M, Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L, Arnold, Norbert, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M, Blok, Marinus J, Bonanni, Bernardo, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Bradbury, Angela R, Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K, Claes, Kathleen BM, Colas, Chrystelle, Collonge-Rame, Marie-Agnès, Cook, Jackie, Daly, Mary B, Davidson, Rosemarie, de la Hoya, Miguel, de Putter, Robin, Delnatte, Capucine, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dorfling, Cecilia M, Dumont, Martine, Eeles, Ros, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hentschel, Julia, Hogervorst, Frans BL, Hooning, Maartje J, Horvath, Judit, Hu, Chunling, Hulick, Peter J, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kast, Karin, Koudijs, Marco, Kruse, Torben A, Kwong, Ava, Laitman, Yael, Lasset, Christine, and Lazaro, Conxi

Subjects
Clinical Research, Cancer, Ovarian Cancer, Prevention, Rare Diseases, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Ovarian Neoplasms, Prospective Studies, Retrospective Studies, Risk Factors, BRCA1, 2, breast cancer, ovarian cancer, PRS, genetics, GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Consortium of Investigators of Modifiers of BRCA and BRCA2, BRCA1/2, Genetics, Clinical Sciences, Genetics & Heredity
Abstract

PurposeWe assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.MethodsRetrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.ResultsThe ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar.ConclusionPopulation-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Published
2020

5. Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status

Author

Feng, Helian, Gusev, Alexander, Pasaniuc, Bogdan, Wu, Lang, Long, Jirong, Abu‐full, Zomoroda, Aittomäki, Kristiina, Andrulis, Irene L, Anton‐Culver, Hoda, Antoniou, Antonis C, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canisius, Sander, Campa, Daniele, Carter, Brian D, Carter, Jonathan, Castelao, Jose E, Chang‐Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Collaborators, GEMO Study, Collaborators, EMBRACE, Collaborators, GC‐HBOC study, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, De Leeneer, Kim, Dennis, Joe, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, dos‐Santos‐Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García‐Closas, Montserrat, García‐Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González‐Neira, Anna, and Greene, Mark H

Subjects
Biological Sciences, Health Sciences, Genetics, Cancer, Biotechnology, Prevention, Clinical Research, Human Genome, Estrogen, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Estrogens, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Receptors, Estrogen, Risk Assessment, Transcriptome, Vesicular Transport Proteins, breast cancer subtype, causal gene, GWAS, TWAS, GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Public Health and Health Services, Epidemiology
Abstract

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

Published
2020

6. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author

Zhang, Haoyu, Ahearn, Thomas U, Lecarpentier, Julie, Barnes, Daniel, Beesley, Jonathan, Qi, Guanghao, Jiang, Xia, O'Mara, Tracy A, Zhao, Ni, Bolla, Manjeet K, Dunning, Alison M, Dennis, Joe, Wang, Qin, Ful, Zumuruda Abu, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auer, Paul L, Azzollini, Jacopo, Barrowdale, Daniel, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bialkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Bondavalli, Davide, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byers, Helen, Caldés, Trinidad, Caligo, Maria A, Calvello, Mariarosaria, Campa, Daniele, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiaens, Melissa, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Foretova, Lenka, Fostira, Florentia, Friedman, Eitan, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Häberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hake, Christopher R, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, and Hillemanns, Peter

Subjects
kConFab Investigators, ABCTB Investigators, EMBRACE Study, GEMO Study Collaborators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, Case-Control Studies, Linkage Disequilibrium, Mutation, Female, Genome-Wide Association Study, Triple Negative Breast Neoplasms, Human Genome, Cancer, Prevention, Genetics, Breast Cancer, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P

Published
2020

7. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author

Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Allen, Jamie, Kar, Siddhartha, Pooley, Karen A, Dennis, Joe, Michailidou, Kyriaki, Turman, Constance, Soucy, Penny, Lemaçon, Audrey, Lush, Michael, Tyrer, Jonathan P, Ghoussaini, Maya, Moradi Marjaneh, Mahdi, Jiang, Xia, Agata, Simona, Aittomäki, Kristiina, Alonso, M Rosario, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auber, Bernd, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Amie M, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Bosse, Kristin, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brock, Ian W, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Camp, Nicola J, Campbell, Ian, Canzian, Federico, Carroll, Jason S, Carter, Brian D, Castelao, Jose E, Chiquette, Jocelyne, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Droit, Arnaud, Dubois, Stéphane, Dumont, Martine, Duran, Mercedes, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Floris, Giuseppe, and Flyger, Henrik

Subjects
GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Bayes Theorem, Risk Factors, Chromosome Mapping, Regulatory Sequences, Nucleic Acid, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Female, Genome-Wide Association Study, Biomarkers, Tumor, Genetic Testing, Prevention, Genetics, Cancer, Breast Cancer, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Published
2020

8. Publisher Correction: Shared heritability and functional enrichment across six solid cancers.

Author

Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, deFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, and Ganz, Patricia A

Subjects
MD Multidisciplinary
Abstract

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

Published
2019

9. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Author

Qian, Frank, Rookus, Matti A, Leslie, Goska, Risch, Harvey A, Greene, Mark H, Aalfs, Cora M, Adank, Muriel A, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arnold, Norbert, Arun, Banu K, Ausems, Margreet GEM, Azzollini, Jacopo, Barrowdale, Daniel, Barwell, Julian, Benitez, Javier, Białkowska, Katarzyna, Bonadona, Valérie, Borde, Julika, Borg, Ake, Bradbury, Angela R, Brunet, Joan, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Carter, Jonathan, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Collée, J Margriet, Collonge-Rame, Marie-Agnès, Couch, Fergus J, Daly, Mary B, Delnatte, Capucine, Diez, Orland, Domchek, Susan M, Dorfling, Cecilia M, Eason, Jacqueline, Easton, Douglas F, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Feliubadaló, Lidia, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Garcia-Barberan, Vanesa, Gehrig, Andrea, Glendon, Gord, Godwin, Andrew K, Gómez Garcia, Encarna B, Hamann, Ute, Hauke, Jan, Hopper, John L, Hulick, Peter J, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Jakubowska, Anna, Janavicius, Ramunas, John, Esther M, Karlan, Beth Y, Kets, Carolien M, Laitman, Yael, Lázaro, Conxi, Leroux, Dominique, Lester, Jenny, Lesueur, Fabienne, Loud, Jennifer T, Lubiński, Jan, Łukomska, Alicja, McGuffog, Lesley, Mebirouk, Noura, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Miller, Austin, Montagna, Marco, Mooij, Thea M, Mouret-Fourme, Emmanuelle, Nathanson, Katherine L, Nehoray, Bita, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, Offit, Kenneth, Olah, Edith, Ong, Kai-ren, Oosterwijk, Jan C, Ottini, Laura, Parsons, Michael T, Peterlongo, Paolo, Pfeiler, Georg, and Pradhan, Nisha

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Prevention, Ovarian Cancer, Breast Cancer, Genetics, Aging, Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Body Height, Body Mass Index, Female, Genes, BRCA1, Genes, BRCA2, Heterozygote, Humans, Mendelian Randomization Analysis, Menopause, Middle Aged, Mutation, Ovarian Neoplasms, Proportional Hazards Models, KConFab Investigators, HEBON Investigators, GEMO Study Collaborators, EMBRACE Collaborators, CIMBA, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundHeight and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.MethodsWe applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models.ResultsObserved height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction

Published
2019

10. Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

Author

Shu, Xiang, Wu, Lang, Khankari, Nikhil K, Shu, Xiao-Ou, Wang, Thomas J, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Milne, Roger L, Schmidt, Marjanka K, Pharoah, Paul DP, Andrulis, Irene L, Hunter, David J, Simard, Jacques, Easton, Douglas F, Zheng, Wei, Alicia, Beeghly-Fadiel J, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beane Freeman, Laura E, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, David Cheng, Ting-Yuan, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dunning, Alison M, Dwek, Miriam, Earp, H Shelton, Eccles, Diana M, Heather Eliassen, A, Engel, Christoph, Eriksson, Mikael, Gareth Evans, D, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, He, Wei, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hogervorst, Frans B, Hollestelle, Antoinette, and Hoover, Robert N

Subjects
Clinical Research, Diabetes, Prevention, Nutrition, Obesity, Cancer, Aging, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Blood Glucose, Body Mass Index, Breast Neoplasms, Diabetes Mellitus, Type 2, Female, Humans, Insulin, Mendelian Randomization Analysis, Middle Aged, Obesity, Abdominal, Waist-Hip Ratio, Breast cancer, insulin, glucose, obesity, genetics, Mendelian randomization analysis, Breast Cancer Association Consortium, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundIn addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.MethodsWe conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.ResultsAll sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.ConclusionsWe confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

Published
2019

11. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Author

Ferreira, Manuel A, Gamazon, Eric R, Al-Ejeh, Fares, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Azzollini, Jacopo, Balmaña, Judith, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Campbell, Ian, Canzian, Federico, Carter, Jonathan, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, Dennis, Joe, Devilee, Peter, Diez, Orland, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, and BCFR Investigators

Subjects
EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Gene Expression Profiling, Quantitative Trait Loci, Female, Genome-Wide Association Study, Prevention, Cancer, Human Genome, Aging, Breast Cancer, Genetics, Biotechnology, 2.1 Biological and endogenous factors
Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Published
2019

12. Genome-wide association study of germline variants and breast cancer-specific mortality.

Author

Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, and Holleczek, Bernd

Subjects
NBCS Collaborators, Chromosomes, Human, Pair 7, Humans, Breast Neoplasms, Receptors, Estrogen, Prognosis, Proportional Hazards Models, Bayes Theorem, Female, Genetic Variation, Genome-Wide Association Study, White People, Genetics, Breast Cancer, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).ResultsWe did not find any variant associated with breast cancer-specific mortality at P

Published
2019

13. Shared heritability and functional enrichment across six solid cancers.

Author

Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, deFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, and Ganz, Patricia A

Subjects
Humans, Breast Neoplasms, Colorectal Neoplasms, Ovarian Neoplasms, Head and Neck Neoplasms, Lung Neoplasms, Prostatic Neoplasms, Genetic Predisposition to Disease, Neoplasm Proteins, Case-Control Studies, Smoking, Mental Disorders, Inheritance Patterns, Phenotype, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Prevention, Cancer, Breast Cancer, Genetics, Rare Diseases, Lung Cancer, Human Genome, Colo-Rectal Cancer, Digestive Diseases, Lung, MD Multidisciplinary
Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Published
2019

14. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author

Figlioli, Gisella, Bogliolo, Massimo, Catucci, Irene, Caleca, Laura, Lasheras, Sandra Viz, Pujol, Roser, Kiiski, Johanna I, Muranen, Taru A, Barnes, Daniel R, Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K, Leslie, Goska, Aalfs, Cora M, Adank, Muriel A, Adlard, Julian, Agata, Simona, Cadoo, Karen, Agnarsson, Bjarni A, Ahearn, Thomas, Aittomäki, Kristiina, Ambrosone, Christine B, Andrews, Lesley, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auber, Bernd, Auvinen, Päivi, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Beane Freeman, Laura E, Beauparlant, Charles Joly, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Berger, Raanan, Bermisheva, Marina, Blanco, Amie M, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brady, Angela F, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caliebe, Almuth, Caligo, Maria A, Campa, Daniele, Campbell, Ian G, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Claes, Kathleen BM, Clarke, Christine L, Collavoli, Anita, Conner, Thomas A, Cox, David G, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S, Ditsch, Nina, Domchek, Susan M, Dorfling, Cecilia M, dos-Santos-Silva, Isabel, Durda, Katarzyna, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Foulkes, William D, Friebel, Tara M, Friedman, Eitan, Gabrielson, Marike, Gaddam, Pragna, and Gago-Dominguez, Manuela

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Genetics, Breast Cancer, Cancer, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, ABCTB Investigators, GEMO Study Collaborators, KConFab, Cancer genetics, Clinical sciences, Oncology and carcinogenesis, Epidemiology
Abstract

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

Published
2019

15. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author

Møller, Pål, Seppälä, Toni, Dowty, James G., Haupt, Saskia, Dominguez-Valentin, Mev, Sunde, Lone, Bernstein, Inge, Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John-Paul, Sijmons, Rolf, Laghi, Luigi, Valle, Adriana Della, Heinimann, Karl, Half, Elizabeth, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Scott, Rodney J., Katz, Lior, Laish, Ido, Vainer, Elez, Vaccaro, Carlos Alberto, Carraro, Dirce Maria, Gluck, Nathan, Abu-Freha, Naim, Stakelum, Aine, Kennelly, Rory, Winter, Des, Rossi, Benedito Mauro, Greenblatt, Marc, Bohorquez, Mabel, Sheth, Harsh, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Horisberger, Karoline, Portenkirchner, Carmen, Nascimento, Ivana, Rossi, Norma Teresa, da Silva, Leandro Apolinário, Thomas, Huw, Zaránd, Attila, Mecklin, Jukka-Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Peltomäki, Päivi, Therkildsen, Christina, Lindberg, Lars Joachim, Thorlacius-Ussing, Ole, von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, de Vargas, Aída Falcón, Latchford, Andrew, Gerdes, Anne-Marie, Backman, Ann-Sofie, Guillén-Ponce, Carmen, Snyder, Carrie, Lautrup, Charlotte K., Amor, David, Palmero, Edenir, Stoffel, Elena, Duijkers, Floor, Hall, Michael J., Hampel, Heather, Williams, Heinric, Okkels, Henrik, Lubiński, Jan, Reece, Jeanette, Ngeow, Joanne, Guillem, Jose G., Arnold, Julie, Wadt, Karin, Monahan, Kevin, Senter, Leigha, Rasmussen, Lene J., van Hest, Liselotte P., Ricciardiello, Luigi, Kohonen-Corish, Maija R. J., Ligtenberg, Marjolijn J. L., Southey, Melissa, Aronson, Melyssa, Zahary, Mohd N., Samadder, N. Jewel, Poplawski, Nicola, Hoogerbrugge, Nicoline, Morrison, Patrick J., James, Paul, Lee, Grant, Chen-Shtoyerman, Rakefet, Ankathil, Ravindran, Pai, Rish, Ward, Robyn, Parry, Susan, Dębniak, Tadeusz, John, Thomas, van Overeem Hansen, Thomas, Caldés, Trinidad, Yamaguchi, Tatsuro, Barca-Tierno, Verónica, Garre, Pilar, Cavestro, Giulia Martina, Weitz, Jürgen, Redler, Silke, Büttner, Reinhard, Heuveline, Vincent, Hopper, John L., Win, Aung Ko, Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., ten Broeke, Sanne W., Hovig, Eivind, Nakken, Sigve, Pineda, Marta, Dueñas, Nuria, Brunet, Joan, Green, Kate, Lalloo, Fiona, Newton, Katie, Crosbie, Emma J., Mints, Miriam, Tjandra, Douglas, Neffa, Florencia, Esperon, Patricia, Kariv, Revital, Rosner, Guy, Pavicic, Walter Hernán, Kalfayan, Pablo, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia, Moslein, Gabriela, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., and Jenkins, Mark A.

Published
2022
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16. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author

Wu, Lang, Shi, Wei, Long, Jirong, Guo, Xingyi, Michailidou, Kyriaki, Beesley, Jonathan, Bolla, Manjeet K, Shu, Xiao-Ou, Lu, Yingchang, Cai, Qiuyin, Al-Ejeh, Fares, Rozali, Esdy, Wang, Qin, Dennis, Joe, Li, Bingshan, Zeng, Chenjie, Feng, Helian, Gusev, Alexander, Barfield, Richard T, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Burwinkel, Barbara, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, J Esteban, Chang-Claude, Jenny, Chen, Xiaoqing, Cheng, Ting-Yuan David, Christiansen, Hans, Clarke, Christine L, NBCS Collaborators, Collée, Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, David, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Eccles, Diana M, Eilber, Ursula, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, and Huang, Guanmengqian

Subjects
Biological Sciences, Genetics, Cancer, Breast Cancer, Human Genome, Prevention, Women's Health, Cancer Genomics, Biotechnology, 2.1 Biological and endogenous factors, Generic health relevance, Breast Neoplasms, Case-Control Studies, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk, Transcriptome, NBCS Collaborators, kConFab/AOCS Investigators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P

Published
2018

17. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author

Milne, Roger L, Kuchenbaecker, Karoline B, Michailidou, Kyriaki, Beesley, Jonathan, Kar, Siddhartha, Lindström, Sara, Hui, Shirley, Lemaçon, Audrey, Soucy, Penny, Dennis, Joe, Jiang, Xia, Rostamianfar, Asha, Finucane, Hilary, Bolla, Manjeet K, McGuffog, Lesley, Wang, Qin, Aalfs, Cora M, Adams, Marcia, Adlard, Julian, Agata, Simona, Ahmed, Shahana, Ahsan, Habibul, Aittomäki, Kristiina, Al-Ejeh, Fares, Allen, Jamie, Ambrosone, Christine B, Amos, Christopher I, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Auber, Bernd, Auer, Paul L, Ausems, Margreet GEM, Azzollini, Jacopo, Bacot, François, Balmaña, Judith, Barile, Monica, Barjhoux, Laure, Barkardottir, Rosa B, Barrdahl, Myrto, Barnes, Daniel, Barrowdale, Daniel, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Bignon, Yves-Jean, Blazer, Kathleen R, Blok, Marinus J, Blomqvist, Carl, Blot, William, Bobolis, Kristie, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Bozsik, Aniko, Bradbury, Angela R, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Bressac-de Paillerets, Brigitte, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Brunet, Joan, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byun, Jinyoung, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canzian, Federico, Caron, Olivier, Carracedo, Angel, Carter, Brian D, Castelao, J Esteban, Castera, Laurent, Caux-Moncoutier, Virginie, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Xiaoqing, Cheng, Ting-Yuan David, Chiquette, Jocelyne, Christiansen, Hans, Claes, Kathleen BM, Clarke, Christine L, Conner, Thomas, Conroy, Don M, and Cook, Jackie

Subjects
Biological Sciences, Genetics, Cancer, Human Genome, Prevention, Breast Cancer, Aging, Estrogen, 2.1 Biological and endogenous factors, Aetiology, BRCA1 Protein, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, White People, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab/AOCS Investigators, NBSC Collaborators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Published
2017

18. Association analysis identifies 65 new breast cancer risk loci

Author

Michailidou, Kyriaki, Lindström, Sara, Dennis, Joe, Beesley, Jonathan, Hui, Shirley, Kar, Siddhartha, Lemaçon, Audrey, Soucy, Penny, Glubb, Dylan, Rostamianfar, Asha, Bolla, Manjeet K, Wang, Qin, Tyrer, Jonathan, Dicks, Ed, Lee, Andrew, Wang, Zhaoming, Allen, Jamie, Keeman, Renske, Eilber, Ursula, French, Juliet D, Qing Chen, Xiao, Fachal, Laura, McCue, Karen, McCart Reed, Amy E, Ghoussaini, Maya, Carroll, Jason S, Jiang, Xia, Finucane, Hilary, Adams, Marcia, Adank, Muriel A, Ahsan, Habibul, Aittomäki, Kristiina, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Arun, Banu, Auer, Paul L, Bacot, François, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brand, Judith S, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brock, Ian W, Broeks, Annegien, Brooks-Wilson, Angela, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Butterbach, Katja, Cai, Qiuyin, Cai, Hui, Caldés, Trinidad, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chan, Tsun L, David Cheng, Ting-Yuan, Seng Chia, Kee, Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L, Collée, Margriet, Conroy, Don M, Cordina-Duverger, Emilie, Cornelissen, Sten, Cox, David G, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Elvira, Mingajeva, and Engel, Christoph

Subjects
Cancer, Asia, Asian People, Binding Sites, Breast Neoplasms, Computer Simulation, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Risk Assessment, Transcription Factors, White People, NBCS Collaborators, ABCTB Investigators, ConFab/AOCS Investigators, General Science & Technology
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Published
2017

19. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author

Win, Aung Ko, Dowty, James G., Reece, Jeanette C., Lee, Grant, Templeton, Allyson S., Plazzer, John-Paul, Buchanan, Daniel D., Akagi, Kiwamu, Aksoy, Seçil, Alonso, Angel, Alvarez, Karin, Amor, David J., Ankathil, Ravindran, Aretz, Stefan, Arnold, Julie L., Aronson, Melyssa, Austin, Rachel, Backman, Ann-Sofie, Bajwa-ten Broeke, Sanne W., Barca-Tierno, Verónica, Barwell, Julian, Bernstein, Inge, Berthet, Pascaline, Betz, Beate, Bignon, Yves-Jean, Boisjoli, Talya, Bonadona, Valérie, Briollais, Laurent, Brunet, Joan, Bucksch, Karolin, Buecher, Bruno, Buettner, Reinhard, Burn, John, Caldés, Trinidad, Capella, Gabriel, Caron, Olivier, Casey, Graham, Chew, Min H., Choi, Yun-hee, Church, James, Clendenning, Mark, Colas, Chrystelle, Cops, Elisa J., Coupier, Isabelle, Cruz-Correa, Marcia, de la Chapelle, Albert, de Wind, Niels, Dębniak, Tadeusz, Della Valle, Adriana, Delnatte, Capuccine, Dhooge, Marion, Dominguez-Valentin, Mev, Drouet, Youenn, Duijkers, Floor A., Engel, Christoph, Esperon, Patricia, Evans, D. Gareth, Falcón de Vargas, Aída, Figueiredo, Jane C, Foulkes, William, Fourme, Emmanuelle, Frebourg, Thierry, Gallinger, Steven, Garre, Pilar, Genuardi, Maurizio, Gerdes, Anne-Marie, Gima, Lauren M., Giraud, Sophie, Goodwin, Annabel, Görgens, Heike, Green, Kate, Guillem, Jose, Guillén-Ponce, Carmen, Guimbaud, Roselyne, Guindalini, Rodrigo S.C., Half, Elizabeth E., Hall, Michael J, Hampel, Heather, Hansen, Thomas V.O., Heinimann, Karl, Hes, Frederik J., Hill, James, Ho, Judy W.C., Holinski-Feder, Elke, Hoogerbrugge, Nicoline, Hüneburg, Robert, Huntley, Vanessa, James, Paul A., Jensen, Uffe B, John, Thomas, Juhari, Wan K.W., Kalady, Matthew, Kastrinos, Fay, Kloor, Matthias, Kohonen-Corish, Maija RJ, Krogh, Lotte N., Kupfer, Sonia S., Ladabaum, Uri, Lagerstedt-Robinson, Kristina, Lalloo, Fiona, Lasset, Christine, Latchford, Andrew, Laurent-Puig, Pierre, Lautrup, Charlotte K., Leggett, Barbara A., Lejeune, Sophie, LeMarchand, Loic, Ligtenberg, Marjolijn, Lindor, Noralane, Loeffler, Markus, Longy, Michel, Lopez, Francisco, Lowery, Jan, Lubiński, Jan, Lucassen, Anneke M, Lynch, Patrick M., Malińska, Karolina, Matsubara, Nagahide, Mecklin, Jukka-Pekka, Møller, Pål, Monahan, Kevin, Morrison, Patrick J., Nattermann, Jacob, Navarro, Matilde, Neffa, Florencia, Neklason, Deborah, Newcomb, Polly A., Ngeow, Joanne, Nichols, Cassandra, Nielsen, Maartje, Nixon, Dawn M., Nogues, Catherine, Okkels, Henrik, Olschwang, Sylviane, Pachter, Nicholas, Pai, Rish K., Palmero, Edenir I., Pande, Mala, Parry, Susan, Patel, Swati G., Pearlman, Rachel, Perne, Claudia, Pineda, Marta, Poplawski, Nicola K, Pylvänäinen, Kirsi, Qiu, Jay, Rahner, Nils, Ramesar, Raj, Rasmussen, Lene J., Redler, Silke, Reis, Rui M., Ricciardiello, Luigi, Rogoża-Janiszewska, Emilia, Rosty, Christophe, Samadder, N. Jewel, Sampson, Julian R., Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Schuster, Helène, Scott, Rodney, Senter, Leigha, Seppälä, Toni T, Shtoyerman, Rakefet, Sijmons, Rolf H., Snyder, Carrie, Solomon, Ilana B., Soto, Jose Luis, Southey, Melissa C., Spigelman, Allan, Spirandelli, Florencia, Spurdle, Amanda B., Steinke-Lange, Verena, Stoffel, Elena M., Strassburg, Christian P., Sunde, Lone, Susman, Rachel, Syngal, Sapna, Tanakaya, Kohji, Tezcan, Gülçin, Therkildsen, Christina, Thibodeau, Steve, Tomita, Naohiro, Tucker, Katherine M., Tunca, Berrin, Turchetti, Daniela, Uhrhammer, Nancy, Utsunomiya, Joji, Vaccaro, Carlos, van Duijnhoven, Fränzel J.B., van Wanzeele, Meghan J., Vangala, Deepak B., Vasen, Hans F.A., von Knebel Doeberitz, Magnus, von Salomé, Jenny, Wadt, Karin A.W., Ward, Robyn L., Weitz, Jürgen, Weitzel, Jeffrey N., Williams, Heinric, Winship, Ingrid, Wise, Paul E., Wods, Julie, Woods, Michael O., Yamaguchi, Tatsuro, Zachariae, Silke, Zahary, Mohd N., Hopper, John L., Haile, Robert W., Macrae, Finlay A., Möslein, Gabriela, and Jenkins, Mark A.

Published
2021
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20. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author

Maller, Pål, Seppälä, Toni, Dowty, James G., Haupt, Saskia, Dominguez-Valentin, Mev, Sunde, Lone, Bernstein, Inge, Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John-Paul, Sijmons, Rolf, Laghi, Luigi, Valle, Adriana Della, Heinimann, Karl, Half, Elizabeth, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Scott, Rodney J., Katz, Lior, Laish, Ido, Vainer, Elez, Vaccaro, Carlos Alberto, Carraro, Dirce Maria, Gluck, Nathan, Abu-Freha, Naim, Stakelum, Aine, Kennelly, Rory, Winter, Des, Rossi, Benedito Mauro, Greenblatt, Marc, Bohorquez, Mabel, Sheth, Harsh, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Horisberger, Karoline, Portenkirchner, Carmen, Nascimento, Ivana, Rossi, Norma Teresa, da Silva, Leandro Apolinário, Thomas, Huw, Zaránd, Attila, Mecklin, Jukka-Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Peltomäki, Päivi, Therkildsen, Christina, Lindberg, Lars Joachim, Thorlacius-Ussing, Ole, von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, de Vargas, Aída Falcón, Latchford, Andrew, Gerdes, Anne-Marie, Backman, Ann-Sofie, Guillén-Ponce, Carmen, Snyder, Carrie, Lautrup, Charlotte K., Amor, David, Palmero, Edenir, Stoffel, Elena, Duijkers, Floor, Hall, Michael J., Hampel, Heather, Williams, Heinric, Okkels, Henrik, LubiÅski, Jan, Reece, Jeanette, Ngeow, Joanne, Guillem, Jose G., Arnold, Julie, Wadt, Karin, Monahan, Kevin, Senter, Leigha, Rasmussen, Lene J., van Hest, Liselotte P., Ricciardiello, Luigi, Kohonen-Corish, Maija R. J., Ligtenberg, Marjolijn J. L., Southey, Melissa, Aronson, Melyssa, Zahary, Mohd N., Samadder, N. Jewel, Poplawski, Nicola, Hoogerbrugge, Nicoline, Morrison, Patrick J., James, Paul, Lee, Grant, Chen-Shtoyerman, Rakefet, Ankathil, Ravindran, Pai, Rish, Ward, Robyn, Parry, Susan, DÄbniak, Tadeusz, John, Thomas, van Overeem Hansen, Thomas, Caldés, Trinidad, Yamaguchi, Tatsuro, Barca-Tierno, Verónica, Garre, Pilar, Cavestro, Giulia Martina, Weitz, Jürgen, Redler, Silke, Büttner, Reinhard, Heuveline, Vincent, Hopper, John L., Win, Aung Ko, Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., ten Broeke, Sanne W., Hovig, Eivind, Nakken, Sigve, Pineda, Marta, Dueéas, Nuria, Brunet, Joan, Green, Kate, Lalloo, Fiona, Newton, Katie, Crosbie, Emma J., Mints, Miriam, Tjandra, Douglas, Neffa, Florencia, Esperon, Patricia, Kariv, Revital, Rosner, Guy, Pavicic, Walter Hernán, Kalfayan, Pablo, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia, Moslein, Gabriela, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., and Jenkins, Mark A.

Subjects
EPUB (Standard) -- Comparative analysis, Colonoscopy -- Comparative analysis, Colorectal cancer -- Comparative analysis, Health
Abstract

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so. Keywords: Lynch Syndrome, Epidemiology, Prevention, Penetrance, Colorectal cancer, Segregation analysis, Prospective, Incidence, Over-diagnosis, Colonoscopy, Author(s): Pål Maller[sup.1], Toni Seppälä[sup.2,3,4], James G. Dowty[sup.5], Saskia Haupt[sup.6,7], Mev Dominguez-Valentin[sup.1], Lone Sunde[sup.8,9], Inge Bernstein[sup.10,11], Christoph Engel[sup.12], Stefan Aretz[sup.13], Maartje Nielsen[sup.14], Gabriel Capella[sup.15], Dafydd Gareth Evans[sup.16], John Burn[sup.17], Elke [...]

Published
2022
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21. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

Author

Blanco, Ignacio, Kuchenbaecker, Karoline, Cuadras, Daniel, Wang, Xianshu, Barrowdale, Daniel, de Garibay, Gorka, Librado, Pablo, Sánchez-Gracia, Alejandro, Rozas, Julio, Bonifaci, Núria, McGuffog, Lesley, Pankratz, Vernon, Islam, Abul, Mateo, Francesca, Berenguer, Antoni, Petit, Anna, Català, Isabel, Brunet, Joan, Feliubadaló, Lidia, Tornero, Eva, Benítez, Javier, Osorio, Ana, Ramón y Cajal, Teresa, Nevanlinna, Heli, Aittomäki, Kristiina, Arun, Banu, Toland, Amanda, Karlan, Beth, Walsh, Christine, Lester, Jenny, Greene, Mark, Mai, Phuong, Nussbaum, Robert, Andrulis, Irene, Domchek, Susan, Nathanson, Katherine, Rebbeck, Timothy, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Claes, Kathleen, Van Maerken, Tom, Díez, Orland, Hansen, Thomas, Jønson, Lars, Gerdes, Anne-Marie, Ejlertsen, Bent, de la Hoya, Miguel, Caldés, Trinidad, Dunning, Alison, Oliver, Clare, Fineberg, Elena, Cook, Margaret, Peock, Susan, McCann, Emma, Murray, Alex, Jacobs, Chris, Pichert, Gabriella, Lalloo, Fiona, Chu, Carol, Dorkins, Huw, Paterson, Joan, Ong, Kai-Ren, Teixeira, Manuel, Hogervorst, Frans, van der Hout, Annemarie, Seynaeve, Caroline, van der Luijt, Rob, Ligtenberg, Marjolijn, Devilee, Peter, Wijnen, Juul, Rookus, Matti, Meijers-Heijboer, Hanne, Blok, Marinus, van den Ouweland, Ans, Aalfs, Cora, Rodriguez, Gustavo, Phillips, Kelly-Anne, Piedmonte, Marion, Nerenstone, Stacy, Bae-Jump, Victoria, OMalley, David, Ratner, Elena, Schmutzler, Rita, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, and Varon-Mateeva, Raymonda

Subjects
Aurora Kinase A, Breast Neoplasms, Carcinogenesis, Cell Cycle Proteins, Estrogen Receptor alpha, Evolution, Molecular, Extracellular Matrix Proteins, Female, Genes, BRCA1, Genes, BRCA2, Genetic Loci, Genetic Predisposition to Disease, Humans, Hyaluronan Receptors, Likelihood Functions, Mammary Glands, Human, Microtubule-Associated Proteins, Mutation, Nuclear Proteins, Polymorphism, Single Nucleotide, Retrospective Studies, Tubulin
Abstract

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Published
2015

22. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

Author

Maxwell, Christopher A, Benítez, Javier, Gómez-Baldó, Laia, Osorio, Ana, Bonifaci, Núria, Fernández-Ramires, Ricardo, Costes, Sylvain V, Guinó, Elisabet, Chen, Helen, Evans, Gareth JR, Mohan, Pooja, Català, Isabel, Petit, Anna, Aguilar, Helena, Villanueva, Alberto, Aytes, Alvaro, Serra-Musach, Jordi, Rennert, Gad, Lejbkowicz, Flavio, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Ripamonti, Carla B, Bonanni, Bernardo, Viel, Alessandra, Allavena, Anna, Bernard, Loris, Radice, Paolo, Friedman, Eitan, Kaufman, Bella, Laitman, Yael, Dubrovsky, Maya, Milgrom, Roni, Jakubowska, Anna, Cybulski, Cezary, Gorski, Bohdan, Jaworska, Katarzyna, Durda, Katarzyna, Sukiennicki, Grzegorz, Lubiński, Jan, Shugart, Yin Yao, Domchek, Susan M, Letrero, Richard, Weber, Barbara L, Hogervorst, Frans BL, Rookus, Matti A, Collee, J Margriet, Devilee, Peter, Ligtenberg, Marjolijn J, Luijt, Rob B van der, Aalfs, Cora M, Waisfisz, Quinten, Wijnen, Juul, Roozendaal, Cornelis EP van, HEBON, EMBRACE, Easton, Douglas F, Peock, Susan, Cook, Margaret, Oliver, Clare, Frost, Debra, Harrington, Patricia, Evans, D Gareth, Lalloo, Fiona, Eeles, Rosalind, Izatt, Louise, Chu, Carol, Eccles, Diana, Douglas, Fiona, Brewer, Carole, Nevanlinna, Heli, Heikkinen, Tuomas, Couch, Fergus J, Lindor, Noralane M, Wang, Xianshu, Godwin, Andrew K, Caligo, Maria A, Lombardi, Grazia, Loman, Niklas, Karlsson, Per, Ehrencrona, Hans, Wachenfeldt, Anna von, SWE-BRCA, Barkardottir, Rosa Bjork, Hamann, Ute, Rashid, Muhammad U, Lasa, Adriana, Caldés, Trinidad, Andrés, Raquel, Schmitt, Michael, Assmann, Volker, Stevens, Kristen, Offit, Kenneth, Curado, João, Tilgner, Hagen, Guigó, Roderic, Aiza, Gemma, Brunet, Joan, Castellsagué, Joan, and Martrat, Griselda

Subjects
HEBON, EMBRACE, SWE-BRCA, BCFR, GEMO Study Collaborators, kConFab, Breast, Cell Line, Tumor, Hela Cells, Microtubules, Epithelial Cells, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Protein-Serine-Threonine Kinases, BRCA1 Protein, BRCA2 Protein, Receptors, Estrogen, Extracellular Matrix Proteins, Cell Polarity, Genotype, Heterozygote, Genes, BRCA1, Genes, BRCA2, Female, Genetic Variation, Aurora Kinase A, Aurora Kinases, Hyaluronan Receptors, HeLa Cells, Cell Line, Tumor, Receptors, Estrogen, Genes, BRCA1, BRCA2, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Published
2011

23. Supplementary Figures and Table from BRIP1, a Gene Potentially Implicated in Familial Colorectal Cancer Type X

Author

Martín-Morales, Lorena, primary, Garre, Pilar, primary, Lorca, Víctor, primary, Cazorla, Marta, primary, Llovet, Patricia, primary, Bando, Inmaculada, primary, García-Barberan, Vanesa, primary, González-Morales, María Luisa, primary, Esteban-Jurado, Clara, primary, de la Hoya, Miguel, primary, Castellví-Bel, Sergi, primary, and Caldés, Trinidad, primary

Published
2023
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24. Data from BRIP1, a Gene Potentially Implicated in Familial Colorectal Cancer Type X

Author

Martín-Morales, Lorena, primary, Garre, Pilar, primary, Lorca, Víctor, primary, Cazorla, Marta, primary, Llovet, Patricia, primary, Bando, Inmaculada, primary, García-Barberan, Vanesa, primary, González-Morales, María Luisa, primary, Esteban-Jurado, Clara, primary, de la Hoya, Miguel, primary, Castellví-Bel, Sergi, primary, and Caldés, Trinidad, primary

Published
2023
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25. Supplementary Data from Analysis of the Oxidative Damage Repair Genes NUDT1, OGG1, and MUTYH in Patients from Mismatch Repair Proficient HNPCC Families (MSS-HNPCC)

Author

Garre, Pilar, primary, Briceño, Verónica, primary, Xicola, Rosa M., primary, Doyle, Brian J., primary, de la Hoya, Miguel, primary, Sanz, Julián, primary, Llovet, Patricia, primary, Pescador, Paula, primary, Puente, Javier, primary, Díaz-Rubio, Eduardo, primary, Llor, Xavier, primary, and Caldés, Trinidad, primary

Published
2023
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26. Data from Analysis of the Oxidative Damage Repair Genes NUDT1, OGG1, and MUTYH in Patients from Mismatch Repair Proficient HNPCC Families (MSS-HNPCC)

Author

Garre, Pilar, primary, Briceño, Verónica, primary, Xicola, Rosa M., primary, Doyle, Brian J., primary, de la Hoya, Miguel, primary, Sanz, Julián, primary, Llovet, Patricia, primary, Pescador, Paula, primary, Puente, Javier, primary, Díaz-Rubio, Eduardo, primary, Llor, Xavier, primary, and Caldés, Trinidad, primary

Published
2023
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27. Supplementary Methods from MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Author

Borràs, Ester, primary, Pineda, Marta, primary, Blanco, Ignacio, primary, Jewett, Ethan M., primary, Wang, Fei, primary, Teulé, Àlex, primary, Caldés, Trinidad, primary, Urioste, Miguel, primary, Martínez-Bouzas, Cristina, primary, Brunet, Joan, primary, Balmaña, Judith, primary, Torres, Asunción, primary, Ramón y Cajal, Teresa, primary, Sanz, Judit, primary, Pérez-Cabornero, Lucía, primary, Castellví-Bel, Sergi, primary, Alonso, Ángel, primary, Lanas, Ángel, primary, González, Sara, primary, Moreno, Víctor, primary, Gruber, Stephen B., primary, Rosenberg, Noah A., primary, Mukherjee, Bhramar, primary, Lázaro, Conxi, primary, and Capellá, Gabriel, primary

Published
2023
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28. Data from MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Author

Borràs, Ester, primary, Pineda, Marta, primary, Blanco, Ignacio, primary, Jewett, Ethan M., primary, Wang, Fei, primary, Teulé, Àlex, primary, Caldés, Trinidad, primary, Urioste, Miguel, primary, Martínez-Bouzas, Cristina, primary, Brunet, Joan, primary, Balmaña, Judith, primary, Torres, Asunción, primary, Ramón y Cajal, Teresa, primary, Sanz, Judit, primary, Pérez-Cabornero, Lucía, primary, Castellví-Bel, Sergi, primary, Alonso, Ángel, primary, Lanas, Ángel, primary, González, Sara, primary, Moreno, Víctor, primary, Gruber, Stephen B., primary, Rosenberg, Noah A., primary, Mukherjee, Bhramar, primary, Lázaro, Conxi, primary, and Capellá, Gabriel, primary

Published
2023
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29. Supplementary Figure 1 from MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Author

Borràs, Ester, primary, Pineda, Marta, primary, Blanco, Ignacio, primary, Jewett, Ethan M., primary, Wang, Fei, primary, Teulé, Àlex, primary, Caldés, Trinidad, primary, Urioste, Miguel, primary, Martínez-Bouzas, Cristina, primary, Brunet, Joan, primary, Balmaña, Judith, primary, Torres, Asunción, primary, Ramón y Cajal, Teresa, primary, Sanz, Judit, primary, Pérez-Cabornero, Lucía, primary, Castellví-Bel, Sergi, primary, Alonso, Ángel, primary, Lanas, Ángel, primary, González, Sara, primary, Moreno, Víctor, primary, Gruber, Stephen B., primary, Rosenberg, Noah A., primary, Mukherjee, Bhramar, primary, Lázaro, Conxi, primary, and Capellá, Gabriel, primary

Published
2023
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30. Supplementary Table 1 from MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Author

Borràs, Ester, primary, Pineda, Marta, primary, Blanco, Ignacio, primary, Jewett, Ethan M., primary, Wang, Fei, primary, Teulé, Àlex, primary, Caldés, Trinidad, primary, Urioste, Miguel, primary, Martínez-Bouzas, Cristina, primary, Brunet, Joan, primary, Balmaña, Judith, primary, Torres, Asunción, primary, Ramón y Cajal, Teresa, primary, Sanz, Judit, primary, Pérez-Cabornero, Lucía, primary, Castellví-Bel, Sergi, primary, Alonso, Ángel, primary, Lanas, Ángel, primary, González, Sara, primary, Moreno, Víctor, primary, Gruber, Stephen B., primary, Rosenberg, Noah A., primary, Mukherjee, Bhramar, primary, Lázaro, Conxi, primary, and Capellá, Gabriel, primary

Published
2023
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31. Supplementary Table 2 from MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Author

Borràs, Ester, primary, Pineda, Marta, primary, Blanco, Ignacio, primary, Jewett, Ethan M., primary, Wang, Fei, primary, Teulé, Àlex, primary, Caldés, Trinidad, primary, Urioste, Miguel, primary, Martínez-Bouzas, Cristina, primary, Brunet, Joan, primary, Balmaña, Judith, primary, Torres, Asunción, primary, Ramón y Cajal, Teresa, primary, Sanz, Judit, primary, Pérez-Cabornero, Lucía, primary, Castellví-Bel, Sergi, primary, Alonso, Ángel, primary, Lanas, Ángel, primary, González, Sara, primary, Moreno, Víctor, primary, Gruber, Stephen B., primary, Rosenberg, Noah A., primary, Mukherjee, Bhramar, primary, Lázaro, Conxi, primary, and Capellá, Gabriel, primary

Published
2023
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33. Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing

Author

Lorca, Víctor, Rueda, Daniel, Martín-Morales, Lorena, Fernández-Aceñero, María Jesús, Grolleman, Judith, Poves, Carmen, Llovet, Patricia, Tapial, Sandra, García-Barberán, Vanesa, Sanz, Julián, Pérez-Segura, Pedro, de Voer, Richarda M., Díaz-Rubio, Eduardo, de la Hoya, Miguel, Caldés, Trinidad, and Garre, Pilar

Published
2019
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35. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study

Author

de Juan, Inmaculada, Palanca, Sarai, Domenech, Asunción, Feliubadaló, Lidia, Segura, Ángel, Osorio, Ana, Chirivella, Isabel, de la Hoya, Miguel, Sánchez, Ana Beatriz, Infante, Mar, Tena, Isabel, Díez, Orland, Garcia-Casado, Zaida, Vega, Ana, Teulé, Àlex, Barroso, Alicia, Pérez, Pedro, Durán, Mercedes, Carrasco, Estela, Juan-Fita, Mª José, Murria, Rosa, Llop, Marta, Barragan, Eva, Izquierdo, Ángel, Benítez, Javier, Caldés, Trinidad, Salas, Dolores, and Bolufer, Pascual

Published
2015
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36. Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy

Author

Llovet, Patricia, Sastre, Javier, Ortega, Julián Sanz, Bando, Inmaculada, Ferrer, Milagros, García-Alfonso, Pilar, Donnay, Olga, Carrato, Alfredo, Jiménez, Ana, Aranda, Enrique, León, Ana, Grávalos, Cristina, Cámara, Juan Carlos, Feliú, Jaime, Sanchíz, Bárbara, Caldés, Trinidad, and Díaz-Rubio, Eduardo

Published
2015
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37. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author

Barnes, Daniel R, Silvestri, Valentina, Leslie, Goska, McGuffog, Lesley, Dennis, Joe, Yang, Xin, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Belotti, Muriel, Benitez, Javier, Berthet, Pascaline, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Brady, Angela F, Brennan, Paul, Brewer, Carole, Brunet, Joan, Bucalo, Agostino, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Cassingham, Hayley, Christensen, Lise Lotte, Cini, Giulia, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Cook, Jackie, Coppa, Anna, Cortesi, Laura, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Putter, Robin, Del Valle, Jesús, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Feliubadaló, Lidia, Fostira, Florentia, Frone, Megan, Frost, Debra, Gallagher, David, Gehrig, Andrea, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gregory, Helen, Gross, Eva, Hahnen, Eric, Hamann, Ute, Hansen, Thomas VO, Hanson, Helen, Hentschel, Julia, Horvath, Judit, KConFab Investigators, HEBON Investigators, Izatt, Louise, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, Johannsson, Oskar Th, John, Esther M, Kramer, Gero, Kroeldrup, Lone, Kruse, Torben A, Lautrup, Charlotte, Lazaro, Conxi, Lesueur, Fabienne, Lopez-Fernández, Adria, Mai, Phuong L, Manoukian, Siranoush, Matrai, Zoltan, Matricardi, Laura, Maxwell, Kara N, Mebirouk, Noura, Meindl, Alfons, Montagna, Marco, Monteiro, Alvaro N, Morrison, Patrick J, Muranen, Taru A, Murray, Alex, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nguyen-Dumont, Tu, Niederacher, Dieter, Olah, Edith, Olopade, Olufunmilayo I, Palli, Domenico, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth H, Pinto, Pedro, Porteous, Mary E, Pottinger, Caroline, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Robson, Mark, Rogers, Mark T, Rønlund, Karina, Rump, Andreas, Sánchez de Abajo, Ana María, Shah, Payal D, Sharif, Saba, Side, Lucy E, Singer, Christian F, Stadler, Zsofia, Steele, Linda, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tommasi, Stefania, Toss, Angela, Trainer, Alison H, Tripathi, Vishakha, Valentini, Virginia, van Asperen, Christi J, Venturelli, Marta, Viel, Alessandra, Vijai, Joseph, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Whaite, Anna, Zanna, Ines, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Ottini, Laura, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Barnes, Daniel R [0000-0002-3781-7570], Silvestri, Valentina [0000-0003-0712-9379], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Yang, Xin [0000-0003-0037-3790], Adlard, Julian [0000-0002-1693-0435], Agnarsson, Bjarni A [0000-0001-7721-9965], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barkardottir, Rosa B [0000-0003-0629-2772], Barrowdale, Daniel [0000-0003-1661-3939], Benitez, Javier [0000-0002-0923-7202], Boonen, Susanne E [0000-0002-7824-2080], Bozsik, Aniko [0000-0001-5410-9173], Brennan, Paul [0000-0003-1128-6254], Brunet, Joan [0000-0003-1945-3512], Bucalo, Agostino [0000-0003-3475-1067], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian [0000-0002-7773-4155], Cassingham, Hayley [0000-0001-9922-2321], Cini, Giulia [0000-0002-8696-8922], Claes, Kathleen BM [0000-0003-0841-7372], Coppa, Anna [0000-0001-9758-5444], Cortesi, Laura [0000-0001-8950-8561], Darder, Esther [0000-0002-7764-1397], de la Hoya, Miguel [0000-0002-8113-1410], de Putter, Robin [0000-0001-9410-8941], Del Valle, Jesús [0000-0003-3607-7045], Domchek, Susan M [0000-0002-5914-7272], Donaldson, Alan [0000-0001-9193-4172], Eason, Jacqueline [0000-0002-8711-8671], Engel, Christoph [0000-0002-7247-282X], Fostira, Florentia [0000-0003-2751-2332], Frone, Megan [0000-0001-8273-8866], Glendon, Gord [0000-0001-8630-6673], Godwin, Andrew K [0000-0002-3987-9580], Greene, Mark H [0000-0003-1852-9239], Hahnen, Eric [0000-0003-2448-7872], Hanson, Helen [0000-0002-3303-8713], Izatt, Louise [0000-0003-1258-4843], Izquierdo, Angel [0000-0003-2004-3246], James, Paul A [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Kroeldrup, Lone [0000-0003-3623-6536], Kruse, Torben A [0000-0002-2460-6483], Lazaro, Conxi [0000-0002-7198-5906], Lesueur, Fabienne [0000-0001-7404-4549], Matrai, Zoltan [0000-0001-8160-7100], Montagna, Marco [0000-0002-4929-2150], Monteiro, Alvaro N [0000-0002-8448-4801], Morrison, Patrick J [0000-0002-2823-1762], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Neuhausen, Susan L [0000-0001-5053-0390], Nevanlinna, Heli [0000-0002-0916-2976], Nguyen-Dumont, Tu [0000-0002-6217-0182], Niederacher, Dieter [0000-0001-6231-9226], Palli, Domenico [0000-0002-5558-2437], Parsons, Michael T [0000-0003-3242-8477], Perez-Segura, Pedro [0000-0001-5049-7199], Peterlongo, Paolo [0000-0001-6951-6855], Pinto, Pedro [0000-0001-6289-5792], Pottinger, Caroline [0000-0003-4233-882X], Radice, Paolo [0000-0001-6298-4111], Robson, Mark [0000-0002-3109-1692], Rump, Andreas [0000-0001-7116-6364], Sharif, Saba [0000-0002-9564-4890], Steele, Linda [0000-0003-3628-2022], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Teixeira, Manuel R [0000-0002-4896-5982], Thull, Darcy L [0000-0001-7999-2804], Tischkowitz, Marc [0000-0002-7880-0628], Toland, Amanda E [0000-0002-0271-1792], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], Tripathi, Vishakha [0000-0001-8118-8364], Valentini, Virginia [0000-0003-3393-7185], van Asperen, Christi J [0000-0002-1436-7650], Venturelli, Marta [0000-0003-0658-8004], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Whaite, Anna [0000-0003-4485-0341], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Chenevix-Trench, Georgia [0000-0002-1878-2587], Ottini, Laura [0000-0001-8030-0449], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, BRCA1 Protein, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases
Abstract

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

Published
2022

38. Additional file 1 of Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author

Møller, Pål, Seppälä, Toni, Dowty, James G., Haupt, Saskia, Dominguez-Valentin, Mev, Sunde, Lone, Bernstein, Inge, Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John-Paul, Sijmons, Rolf, Laghi, Luigi, Valle, Adriana Della, Heinimann, Karl, Half, Elizabeth, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Scott, Rodney J., Katz, Lior, Laish, Ido, Vainer, Elez, Vaccaro, Carlos Alberto, Carraro, Dirce Maria, Gluck, Nathan, Abu-Freha, Naim, Stakelum, Aine, Kennelly, Rory, Winter, Des, Rossi, Benedito Mauro, Greenblatt, Marc, Bohorquez, Mabel, Sheth, Harsh, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Horisberger, Karoline, Portenkirchner, Carmen, Nascimento, Ivana, Rossi, Norma Teresa, da Silva, Leandro Apolinário, Thomas, Huw, Zaránd, Attila, Mecklin, Jukka-Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Peltomäki, Päivi, Therkildsen, Christina, Lindberg, Lars Joachim, Thorlacius-Ussing, Ole, von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, de Vargas, Aída Falcón, Latchford, Andrew, Gerdes, Anne-Marie, Backman, Ann-Sofie, Guillén-Ponce, Carmen, Snyder, Carrie, Lautrup, Charlotte K., Amor, David, Palmero, Edenir, Stoffel, Elena, Duijkers, Floor, Hall, Michael J., Hampel, Heather, Williams, Heinric, Okkels, Henrik, Lubiński, Jan, Reece, Jeanette, Ngeow, Joanne, Guillem, Jose G., Arnold, Julie, Wadt, Karin, Monahan, Kevin, Senter, Leigha, Rasmussen, Lene J., van Hest, Liselotte P., Ricciardiello, Luigi, Kohonen-Corish, Maija R. J., Ligtenberg, Marjolijn J. L., Southey, Melissa, Aronson, Melyssa, Zahary, Mohd N., Samadder, N. Jewel, Poplawski, Nicola, Hoogerbrugge, Nicoline, Morrison, Patrick J., James, Paul, Lee, Grant, Chen-Shtoyerman, Rakefet, Ankathil, Ravindran, Pai, Rish, Ward, Robyn, Parry, Susan, Dębniak, Tadeusz, John, Thomas, van Overeem Hansen, Thomas, Caldés, Trinidad, Yamaguchi, Tatsuro, Barca-Tierno, Verónica, Garre, Pilar, Cavestro, Giulia Martina, Weitz, Jürgen, Redler, Silke, Büttner, Reinhard, Heuveline, Vincent, Hopper, John L., Win, Aung Ko, Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., ten Broeke, Sanne W., Hovig, Eivind, Nakken, Sigve, Pineda, Marta, Dueñas, Nuria, Brunet, Joan, Green, Kate, Lalloo, Fiona, Newton, Katie, Crosbie, Emma J., Mints, Miriam, Tjandra, Douglas, Neffa, Florencia, Esperon, Patricia, Kariv, Revital, Rosner, Guy, Pavicic, Walter Hernán, Kalfayan, Pablo, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia, Moslein, Gabriela, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., and Jenkins, Mark A.

Abstract

Additional file 1.

Published
2022
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40. Limited family structure and triple-negative breast cancer (TNBC) subtype as predictors of BRCA mutations in a genetic counseling cohort of early-onset sporadic breast cancers

Author

Zugazagoitia, Jon, Pérez-Segura, Pedro, Manzano, Arancha, Blanco, Ignacio, Vega, Ana, Custodio, Ana, Teulé, Alex, Fachal, Laura, Martínez, Beatriz, González-Sarmiento, Rogelio, Cruz-Hernández, Juan Jesús, Chirivella, Isabel, Garcés, Vicente, Garre, Pilar, Romero, Atocha, Caldés, Trinidad, Díaz-Rubio, Eduardo, and de la Hoya, Miguel

Published
2014
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43. Variation in the Risk of Colorectal Cancer for Lynch Syndrome: A retrospective family cohort study

Author

Win, Aung Ko, Dowty, James G., Reece, Jeanette C., Lee, Grant, Templeton, Allyson S., Plazzer, John-Paul, Buchanan, Daniel D., Akagi, Kiwamu, Aksoy, Seçil, Alonso, Angel, Alvarez, Karin, Amor, David J., Ankathil, Ravindran, Aretz, Stefan, Arnold, Julie L., Aronson, Melyssa, Austin, Rachel, Backman, Ann-Sofie, Bajwa–ten Broeke, Sanne W., Barca-Tierno, Verónica, Barwell, Julian, Bernstein, Inge, Berthet, Pascaline, Betz, Beate, Bignon, Yves-Jean, Boisjoli, Talya, Bonadona, Valérie, Briollais, Laurent, Brunet, Joan, Bucksch, Karolin, Buecher, Bruno, Buettner, Reinhard, Burn, John, Caldés, Trinidad, Capella, Gabriel, Caron, Olivier, Casey, Graham, Chew, Min H., Choi, Yun-hee, Church, James, Clendenning, Mark, Colas, Chrystelle, Cops, Elisa J., Coupier, Isabelle, Cruz-Correa, Marcia, de la Chapelle, Albert, de Wind, Niels, Dębniak, Tadeusz, Della Valle, Adriana, Delnatte, Capuccine, Dhooge, Marion, Dominguez-Valentin, Mev, Drouet, Youenn, Duijkers, Floor A., Engel, Christoph, Esperon, Patricia, Evans, D. Gareth, de Vargas, Aída Falcón, Figueiredo, Jane C, Foulkes, William, Fourme, Emmanuelle, Frebourg, Thierry, Gallinger, Steven, Garre, Pilar, Genuardi, Maurizio, Gerdes, Anne-Marie, Gima, Lauren M., Giraud, Sophie, Goodwin, Annabel, Görgens, Heike, Green, Kate, Guillem, Jose, Guillén-Ponce, Carmen, Guimbaud, Roselyne, Guindalini, Rodrigo S. C., Half, Elizabeth E., Hall, Michael J, Hampel, Heather, Hansen, Thomas V. O., Heinimann, Karl, Hes, Frederik J., Hill, James, Ho, Judy W.C., Holinski-Feder, Elke, Hoogerbrugge, Nicoline, Hüneburg, Robert, Huntley, Vanessa, James, Paul A., Jensen, Uffe B, John, Thomas, Juhari, Wan K.W., Kalady, Matthew, Kastrinos, Fay, Kloor, Matthias, Kohonen-Corish, Maija RJ, Krogh, Lotte N., Kupfer, Sonia S., Ladabaum, Uri, Lagerstedt-Robinson, Kristina, Lalloo, Fiona, Lasset, Christine, Latchford, Andrew, Laurent-Puig, Pierre, Lautrup, Charlotte K., Leggett, Barbara A., Lejeune, Sophie, LeMarchand, Loic, Ligtenberg, Marjolijn, Lindor, Noralane, Loeffler, Markus, Longy, Michel, Lopez, Francisco, Lowery, Jan, Lubiński, Jan, Lucassen, Anneke M, Lynch, Patrick M., Malińska, Karolina, Matsubara, Nagahide, Mecklin, Jukka-Pekka, Møller, Pål, Monahan, Kevin, Morrison, Patrick J., Nattermann, Jacob, Navarro, Matilde, Neffa, Florencia, Neklason, Deborah, Newcomb, Polly A., Ngeow, Joanne, Nichols, Cassandra, Nielsen, Maartje, Nixon, Dawn M., Nogues, Catherine, Okkels, Henrik, Olschwang, Sylviane, Pachter, Nicholas, Pai, Rish K., Palmero, Edenir I., Pande, Mala, Parry, Susan, Patel, Swati G., Pearlman, Rachel, Perne, Claudia, Pineda, Marta, Poplawski, Nicola K, Pylvänäinen, Kirsi, Qiu, Jay, Rahner, Nils, Ramesar, Raj, Rasmussen, Lene J., Redler, Silke, Reis, Rui M., Ricciardiello, Luigi, Rogoża-Janiszewska, Emilia, Rosty, Christophe, Samadder, N. Jewel, Sampson, Julian R., Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Schuster, Helène, Scott, Rodney, Senter, Leigha, Seppälä, Toni T, Shtoyerman, Rakefet, Sijmons, Rolf H., Snyder, Carrie, Solomon, Ilana B., Soto, Jose Luis, Southey, Melissa C., Spigelman, Allan, Spirandelli, Florencia, Spurdle, Amanda B., Steinke-Lange, Verena, Stoffel, Elena M., Strassburg, Christian P., Sunde, Lone, Susman, Rachel, Syngal, Sapna, Tanakaya, Kohji, Tezcan, Gülçin, Therkildsen, Christina, Thibodeau, Steve, Tomita, Naohiro, Tucker, Katherine M., Tunca, Berrin, Turchetti, Daniela, Uhrhammer, Nancy, Utsunomiya, Joji, Vaccaro, Carlos, van Duijnhoven, Fränzel J.B., van Wanzeele, Meghan J., Vangala, Deepak B., Vasen, Hans F.A., von Knebel Doeberitz, Magnus, von Salomé, Jenny, Wadt, Karin A. W., Ward, Robyn L., Weitz, Jürgen, Weitzel, Jeffrey N., Williams, Heinric, Winship, Ingrid, Wise, Paul E., Wods, Julie, Woods, Michael O., Yamaguchi, Tatsuro, Zachariae, Silke, Zahary, Mohd N., Hopper, John L., Haile, Robert W., Macrae, Finlay A., Möslein, Gabriela, and Jenkins, Mark A.

Subjects
Article
Abstract

BACKGROUND: Current clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the average age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate how much penetrance varies between carriers of pathogenic variants in the same gene by sex and continent of residence of the carrier. METHODS: We studied 79,809 relatives from 5,255 families, of at least three relatives, in which at least one was a confirmed carrier of a pathogenic or likely pathogenic variant in a mismatch repair gene (1,829 MLH1, 2,179 MSH2, 798 MSH6, 449 PMS2), recruited in 15 countries from North America, Europe and Australasia by the collaborative centres of the International Mismatch Repair Consortium. We used modified segregation analysis conditioned on ascertainment to estimate the average penetrance and modelled unmeasured polygenic factors to estimate the variation in penetrance of colorectal cancer. The existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested using a Wald p-value for the null hypothesis that the polygenic standard deviation is zero. FINDINGS: There was strong evidence of the existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was more prominent for MLH1 and MSH2 variant carriers; depending on gene, sex, and continent, with 7–56% of carriers having a risk of colorectal cancer to age 80 of less than 20%, and 9–44% having a risk of more than 80%, while only 10–19% had a risk of 40–60%. INTERPRETATION: Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessment for precision prevention and early detection of colorectal cancer for Lynch syndrome.

Published
2021

45. Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin

Author

Ruiz de Garibay, Gorka, Gutiérrez-Enríquez, Sara, Garre, Pilar, Bonache, Sandra, Romero, Atocha, Palomo, Laura, Sánchez de Abajo, Ana, Benítez, Javier, Balmaña, Judith, Pérez-Segura, Pedro, Díaz-Rubio, Eduardo, Díez, Orland, Caldés, Trinidad, and de la Hoya, Miguel

Published
2012
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48. Detection of a large rearrangement in PALB2 in Spanish breast cancer families with male breast cancer

Author

Blanco, Ana, de la Hoya, Miguel, Balmaña, Judith, Ramón y Cajal, Teresa, Teulé, Alex, Miramar, María-Dolores, Esteban, Eva, Infante, Mar, Benítez, Javier, Torres, Asunción, Tejada, María-Isabel, Brunet, Joan, Graña, Begoña, Balbín, Milagros, Pérez-Segura, Pedro, Osorio, Ana, Velasco, Eladio A., Chirivella, Isabel, Calvo, María-Teresa, Feliubadaló, Lidia, Lasa, Adriana, Díez, Orland, Carracedo, Angel, Caldés, Trinidad, and Vega, Ana

Published
2012
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49. Evidence for a link between TNFRSF11A and risk of breast cancer

Author

Bonifaci, Núria, Palafox, Marta, Pellegrini, Pasquale, Osorio, Ana, Benítez, Javier, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Roversi, Gaia, Barile, Monica, Viel, Alessandra, Mariette, Frederique, Bernard, Loris, Radice, Paolo, Kaufman, Bella, Laitman, Yael, Milgrom, Roni, Friedman, Eitan, Sáez, María E., Climent, Fina, Soler, María Teresa, Diez, Orland, Balmaña, Judith, Lasa, Adriana, Ramón y Cajal, Teresa, Miramar, María-Dolores, de la Hoya, Miguel, Pérez-Segura, Pedro, Caldés, Trinidad, Moreno, Víctor, Urruticoechea, Ander, Brunet, Joan, Lázaro, Conxi, Blanco, Ignacio, Pujana, Miguel Angel, and González-Suárez, Eva

Published
2011
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