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2. BRCA-DIRECT digital pathway for diagnostic germline genetic testing within a UK breast oncology setting: a randomised, non-inferiority trial

Author

Torr, Bethany, Jones, Christopher, Kavanaugh, Grace, Hamill, Monica, Allen, Sophie, Choi, Subin, Garrett, Alice, Valganon-Petrizan, Mikel, MacMahon, Suzanne, Yuan, Lina, Way, Rosalind, Harder, Helena, Gold, Rochelle, Taylor, Amy, Gabe, Rhian, Lucassen, Anneke, Manchanda, Ranjit, Fallowfield, Lesley, Jenkins, Valerie, Gandhi, Ashu, Evans, D. Gareth, George, Angela, Hubank, Michael, Kemp, Zoe, Bremner, Stephen, and Turnbull, Clare

Published
2024
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4. A Likelihood Ratio Approach for Utilizing Case‐Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author

Zanti, Maria, O′Mahony, Denise G, Parsons, Michael T, Li, Hongyan, Dennis, Joe, Aittomäkkiki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Brown, Melissa A, Buys, Saundra S, Canzian, Federico, Caputo, Sandrine M, Castelao, Jose E, Chang-Claude, Jenny, Collaborators, GC-HBOC study, Czene, Kamila, Daly, Mary B, De Nicolo, Arcangela, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Gentry-Maharaj, Aleksandra, Giele, Willemina RR Geurts-, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Garcia, Encarna B Gómez, Güendert, Melanie, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Houdayer, Claude, Houlston, Richard S, Howell, Anthony, Investigators, ABCTB, Jakimovska, Milena, Jakubowska, Anna, Jernström, Helena, John, Esther M, Kaaks, Rudolf, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Lacey, James V, Lambrechts, Diether, Léoné, Melanie, Lindblom, Annika, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Menon, Usha, Milne, Roger L, Monteiro, Alvaro N, Murphy, Rachel A, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Offit, Kenneth, Park, Sue K, James, Paul, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Punie, Kevin, Radice, Paolo, Rashid, Muhammad U, Rennert, Gad, Romero, Atocha, Rosenberg, Efraim H, Saloustros, Emmanouil, Sandler, Dale P, Schmidt, Marjanka K, Schmutzler, Rita K, and Shu, Xiao-Ou

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Biotechnology, Genetic Testing, Prevention, Cancer, Human Genome, Women's Health, Breast Cancer, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Case-Control Studies, BRCA2 Protein, Genetic Predisposition to Disease, Female, BRCA1 Protein, Breast Neoplasms, Likelihood Functions, Genetic Variation, Penetrance, GC-HBOC study Collaborators, ABCTB Investigators, ACMG/AMP, BRCA, PS4, VUS, case-control, likelihood ratio, variant classification, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Published
2023

5. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes

Author

Møller, Pål, Haupt, Saskia, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., Sunde, Lone, Seppälä, Toni, Burn, John, Bernstein, Inge, Capella, Gabriel, Evans, D. Gareth, Lindblom, Annika, Winship, Ingrid, Macrae, Finlay, Katz, Lior, Laish, Ido, Vainer, Elez, Monahan, Kevin, Half, Elizabeth, Horisberger, Karoline, da Silva, Leandro Apolinário, Heuveline, Vincent, Therkildsen, Christina, Lautrup, Charlotte, Klarskov, Louise L, Cavestro, Giulia Martina, Möslein, Gabriela, Hovig, Eivind, and Dominguez-Valentin, Mev

Published
2024
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9. Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol

Author

Dixon-Zegeye, Miriam, Shaw, Rachel, Collins, Linda, Perez-Smith, Kendra, Ooms, Alexander, Qiao, Maggie, Pantziarka, Pan, Izatt, Louise, Tischkowitz, Marc, Harrison, Rachel E., George, Angela, Woodward, Emma R., Lord, Simon, Hawkes, Lara, Evans, D. Gareth, Franklin, James, Hanson, Helen, and Blagden, Sarah P.

Published
2024
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10. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival

Author

Morra, Anna, Schreurs, Maartje AC, Andrulis, Irene L, Anton‐Culver, Hoda, Augustinsson, Annelie, Beckmann, Matthias W, Behrens, Sabine, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Broeks, Annegien, Buys, Saundra S, Camp, Nicola J, Castelao, Jose E, Cessna, Melissa H, Chang‐Claude, Jenny, Chung, Wendy K, Sahlberg, Kristine K, Børresen‐Dale, Anne‐Lise, Gram, Inger Torhild, Olsen, Karina Standahl, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, OSBREAC, Alnæs, Grethe I Grenaker, Colonna, Sarah V, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fehm, Tanja N, Figueroa, Jonine D, Flyger, Henrik, Gabrielson, Marike, Gago‐Dominguez, Manuela, García‐Closas, Montserrat, García‐Sáenz, José A, Genkinger, Jeanine, Grassmann, Felix, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Hamann, Ute, Harrington, Patricia A, Hartikainen, Jaana M, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, J Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Cao, Michelle, Chakrabarti, Anannya, Chauhan, Deepa, Chauhan, Manisha, Chenevix‐Trench, Georgia, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Courtney, Eliza, Cummings, Margaret, and Dawson, Sarah‐Jane

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Breast Cancer, Clinical Research, Prevention, Cancer, Female, Humans, Breast Neoplasms, Checkpoint Kinase 2, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Proportional Hazards Models, CHEK2 c.1100delC germline genetic variant, contralateral breast cancer risk, radiotherapy, survival, systemic treatment, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Biochemistry and Cell Biology, Oncology and carcinogenesis
Abstract

BackgroundBreast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.AimTo assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.MethodsAnalyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.ResultsThere was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].ConclusionSystemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Published
2023

11. Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival

Author

Lopes Cardozo, Josephine MN, Andrulis, Irene L, Bojesen, Stig E, Dörk, Thilo, Eccles, Diana M, Fasching, Peter A, Hooning, Maartje J, Keeman, Renske, Nevanlinna, Heli, Rutgers, Emiel JT, Easton, Douglas F, Hall, Per, Pharoah, Paul DP, van 't Veer, Laura J, Schmidt, Marjanka K, Ahearn, Thomas U, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bolla, Manjeet K, Bonanni, Bernardo, Boyle, Terry, Brenner, Hermann, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Camp, Nicola J, Canzian, Federico, Cardoso, Fatima, Castelao, Jose E, Cessna, Melissa H, Chan, Tsun L, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Colonna, Sarah V, Copson, Ellen, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Drukker, Caroline A, Dunning, Alison M, Dwek, Miriam, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Figueroa, Jonine D, Fletcher, Olivia, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Genkinger, Jeanine, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hartman, Mikael, Heemskerk-Gerritsen, Bernadette AM, Hein, Alexander, Ho, Weang-Kee, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Ito, Hidemi, Jakubowska, Anna, Jernström, Helena, John, Esther M, Johnson, Nichola, Jones, Michael E, Joseph, Vijai, Kaaks, Rudolf, Kang, Daehee, Kim, Sung-Won, Kitahara, Cari M, Koppert, Linetta B, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, and Koutros, Stella

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Good Health and Well Being, Female, Humans, Breast Neoplasms, Risk Factors, Prognosis, Proportional Hazards Models, Breast, Breast Cancer Association Consortium and MINDACT Collaborators, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeA polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer.MethodsWomen with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment.ResultsThe PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent.ConclusionAn increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.

Published
2023

12. The effect of variable labels on deep learning models trained to predict breast density

Author

Squires, Steven, Harkness, Elaine F., Evans, D. Gareth, and Astley, Susan M.

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

Purpose: High breast density is associated with reduced efficacy of mammographic screening and increased risk of developing breast cancer. Accurate and reliable automated density estimates can be used for direct risk prediction and passing density related information to further predictive models. Expert reader assessments of density show a strong relationship to cancer risk but also inter-reader variation. The effect of label variability on model performance is important when considering how to utilise automated methods for both research and clinical purposes. Methods: We utilise subsets of images with density labels to train a deep transfer learning model which is used to assess how label variability affects the mapping from representation to prediction. We then create two end-to-end deep learning models which allow us to investigate the effect of label variability on the model representation formed. Results: We show that the trained mappings from representations to labels are altered considerably by the variability of reader scores. Training on labels with distribution variation removed causes the Spearman rank correlation coefficients to rise from $0.751\pm0.002$ to either $0.815\pm0.006$ when averaging across readers or $0.844\pm0.002$ when averaging across images. However, when we train different models to investigate the representation effect we see little difference, with Spearman rank correlation coefficients of $0.846\pm0.006$ and $0.850\pm0.006$ showing no statistically significant difference in the quality of the model representation with regard to density prediction. Conclusions: We show that the mapping between representation and mammographic density prediction is significantly affected by label variability. However, the effect of the label variability on the model representation is limited.

Published
2022

13. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author

Middha, Pooja, Wang, Xiaoliang, Behrens, Sabine, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baert, Thaïs, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Benitez, Javier, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dossus, Laure, Dugué, Pierre-Antoine, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine D, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Giles, Graham G, González-Neira, Anna, Grassmann, Felix, Grundy, Anne, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan E, Harkness, Elaine F, Holleczek, Bernd, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Ingvar, Christian, Isaksson, Karolin, Jernström, Helena, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Larsson, Susanna, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Shuai, Linet, Martha, Lissowska, Jolanta, Martinez, Maria Elena, Maurer, Tabea, Mulligan, Anna Marie, Mulot, Claire, Murphy, Rachel A, Newman, William G, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, O’Brien, Katie M, Olson, Janet E, Patel, Alpa V, Prentice, Ross, Rees-Punia, Erika, Rennert, Gad, Rhenius, Valerie, Ruddy, Kathryn J, and Sandler, Dale P

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer Genomics, Human Genome, Estrogen, Cancer, Women's Health, Genetics, Prevention, Aging, Breast Cancer, 2.1 Biological and endogenous factors, Adult, Female, Humans, Gene-Environment Interaction, Genetic Predisposition to Disease, Breast Neoplasms, Bayes Theorem, Genome-Wide Association Study, Risk Factors, Polymorphism, Single Nucleotide, Case-Control Studies, Breast cancer, Gene-environment interactions, Genetic epidemiology, European ancestry, CTS Consortium, ABCTB Investigators, kConFab Investigators, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundGenome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.MethodsAnalyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.ResultsAssuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

Published
2023

14. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author

Mueller, Stefanie H, Lai, Alvina G, Valkovskaya, Maria, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Abu-Ful, Zomoruda, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baert, Thais, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Brucker, Sara Y, Buys, Saundra S, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Chung, Wendy K, Colonna, Sarah V, Cornelissen, Sten, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Yu-Tang, García-Closas, Montserrat, García-Sáenz, José A, Genkinger, Jeanine, Gentry-Maharaj, Aleksandra, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Harkness, Elaine F, Harrington, Patricia A, Hartikainen, Jaana M, Hartman, Mikael, Hein, Alexander, Ho, Weang-Kee, Hooning, Maartje J, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Khusnutdinova, Elza K, Kim, Sung-Won, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, Lacey, James V, Lambrechts, Diether, and Le Marchand, Loic

Subjects
Breast Cancer, Genetics, Clinical Research, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Breast Neoplasms, Genetic Predisposition to Disease, Black People, Genetic Testing, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Formins, Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, NBCS Collaborators, CTS Consortium, ABCTB Investigators, Clinical Sciences
Abstract

BackgroundLow-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.MethodsWe evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.ResultsIn European ancestry samples, 14 genes were significantly associated (q

Published
2023

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

Author

Jung, Audrey Y, Ahearn, Thomas U, Behrens, Sabine, Middha, Pooja, Bolla, Manjeet K, Wang, Qin, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Freeman, Laura E Beane, Becher, Heiko, Brenner, Hermann, Canzian, Federico, Carey, Lisa A, Consortium, CTS, Czene, Kamila, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine D, Fritschi, Lin, Gabrielson, Marike, Giles, Graham G, Guénel, Pascal, Hadjisavvas, Andreas, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Hunter, David J, Hüsing, Anika, Kaaks, Rudolf, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Lacey, James V, Le Marchand, Loic, Lissowska, Jolanta, Loizidou, Maria A, Mannermaa, Arto, Maurer, Tabea, Murphy, Rachel A, Olshan, Andrew F, Olsson, Håkan, Patel, Alpa V, Perou, Charles M, Rennert, Gad, Shibli, Rana, Shu, Xiao-Ou, Southey, Melissa C, Stone, Jennifer, Tamimi, Rulla M, Teras, Lauren R, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wang, Sophia S, Wolk, Alicja, Wu, Anna H, Yang, Xiaohong R, Zheng, Wei, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Milne, Roger L, Chatterjee, Nilanjan, Schmidt, Marjanka K, García-Closas, Montserrat, and Chang-Claude, Jenny

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Aging, Reproductive health and childbirth, Female, Humans, Breast Neoplasms, Receptor, ErbB-2, Receptors, Progesterone, Receptors, Estrogen, Triple Negative Breast Neoplasms, Case-Control Studies, Risk Factors, Biomarkers, Tumor, CTS Consortium, Receptor, erbB-2, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Published
2022

16. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author

Hakkaart, Christopher, Pearson, John F, Marquart, Louise, Dennis, Joe, Wiggins, George AR, Barnes, Daniel R, Robinson, Bridget A, Mace, Peter D, Aittomäki, Kristiina, Andrulis, Irene L, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Belhadj, Sami, Berger, Lieke, Blok, Marinus J, Boonen, Susanne E, Borde, Julika, Bradbury, Angela R, Brunet, Joan, Buys, Saundra S, Caligo, Maria A, Campbell, Ian, Chung, Wendy K, Claes, Kathleen BM, Collonge-Rame, Marie-Agnès, Cook, Jackie, Cosgrove, Casey, Couch, Fergus J, Daly, Mary B, Dandiker, Sita, Davidson, Rosemarie, de la Hoya, Miguel, de Putter, Robin, Delnatte, Capucine, Dhawan, Mallika, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Easton, Douglas F, Ehrencrona, Hans, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Feliubadaló, Lidia, Fostira, Florentia, Friedman, Eitan, Frone, Megan, Frost, Debra, Garber, Judy, Gayther, Simon A, Gehrig, Andrea, Gesta, Paul, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Hahnen, Eric, Hake, Christopher R, Hamann, Ute, Hansen, Thomas VO, Hauke, Jan, Hentschel, Julia, Herold, Natalie, Honisch, Ellen, 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, Kemp, Zoe, Kirk, Judy, Konstantopoulou, Irene, Koudijs, Marco, Kwong, Ava, Laitman, Yael, Lalloo, Fiona, Lasset, Christine, Lautrup, Charlotte, Lazaro, Conxi, Legrand, Clémentine, Leslie, Goska, Lesueur, Fabienne, Mai, Phuong L, Manoukian, Siranoush, Mari, Véronique, Martens, John WM, McGuffog, Lesley, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, and Montagna, Marco

Subjects
Human Genome, Prevention, Breast Cancer, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Heterozygote, Humans, RNA, Messenger, GEMO Study Collaborators, EMBRACE Collaborators, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators
Abstract

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Published
2022

17. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author

Dixon-Suen, Suzanne C, Lewis, Sarah J, Martin, Richard M, English, Dallas R, Boyle, Terry, Giles, Graham G, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Investigators, ABCTB, Ahearn, Thomas U, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Auvinen, Päivi, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Brüning, Thomas, Buys, Saundra S, Camp, Nicola J, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Cessna, Melissa H, Chang-Claude, Jenny, Chanock, Stephen J, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Goldberg, Mark S, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Häberle, Lothar, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hart, Steven N, Harvie, Michelle, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J, Hoppe, Reiner, Hopper, John, Howell, Anthony, Hunter, David J, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Loibl, Sibylle, Lubiński, Jan, Mannermaa, Arto, and Manoochehri, Mehdi

Subjects
Aging, Genetics, Breast Cancer, Clinical Research, Cancer, Prevention, Female, Humans, Breast Neoplasms, Exercise, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Factors, Sedentary Behavior, Breast Cancer Association Consortium, Breast, Physical activity, Sedentary Behaviour, Engineering, Medical and Health Sciences, Education, Sport Sciences
Abstract

ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

Published
2022

18. Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Author

Grootes, Isabelle, Keeman, Renske, Blows, Fiona M, Milne, Roger L, Giles, Graham G, Swerdlow, Anthony J, Fasching, Peter A, Abubakar, Mustapha, Andrulis, Irene L, Anton-Culver, Hoda, Beckmann, Matthias W, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Briceno, Ignacio, Burwinkel, Barbara, Camp, Nicola J, Castelao, Jose E, Choi, Ji-Yeob, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Eriksson, Mikael, Ernst, Kristina, Evans, D Gareth, Figueroa, Jonine D, Fink, Visnja, Floris, Giuseppe, Fox, Stephen, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Sáenz, José A, González-Neira, Anna, Haeberle, Lothar, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hartman, Mikael, Hein, Alexander, Hooning, Maartje J, Hou, Ming-Feng, Howell, Sacha J, Investigators, ABCTB, Investigators, kConFab, Ito, Hidemi, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kang, Daehee, Kristensen, Vessela N, Kwong, Ava, Lambrechts, Diether, Li, Jingmei, Lubiński, Jan, Manoochehri, Mehdi, Margolin, Sara, Matsuo, Keitaro, Taib, Nur Aishah Mohd, Mulligan, Anna Marie, Nevanlinna, Heli, Newman, William G, Offit, Kenneth, Osorio, Ana, Park, Sue K, Park-Simon, Tjoung-Won, Patel, Alpa V, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rennert, Gad, Romero, Atocha, Saloustros, Emmanouil, Sawyer, Elinor J, Schneeweiss, Andreas, Schochter, Fabienne, Schoemaker, Minouk J, Shen, Chen-Yang, Shibli, Rana, Sinn, Peter, Tapper, William J, Tawfiq, Essa, Teo, Soo Hwang, Teras, Lauren R, Torres, Diana, Vachon, Celine M, van Deurzen, Carolien HM, Wendt, Camilla, and Williams, Justin A

Subjects
Cancer, Breast Cancer, Breast Neoplasms, Female, Humans, Progesterone, Prognosis, Receptor, ErbB-2, Receptors, Progesterone, PREDICT Breast, breast cancer, Progesterone receptor, ABCTB Investigators, kConFab Investigators, Receptor, erbB-2, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundPredict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).MethodThe prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.ResultsHaving a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.ConclusionThe inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.

Published
2022

21. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Author

Pagnamenta, Alistair T., Yu, Jing, Walker, Susan, Noble, Alexandra J., Lord, Jenny, Dutta, Prasun, Hashim, Mona, Camps, Carme, Green, Hannah, Devaiah, Smrithi, Nashef, Lina, Parr, Jason, Fratter, Carl, Ibnouf Hussein, Rana, Lindsay, Sarah J., Lalloo, Fiona, Banos-Pinero, Benito, Evans, David, Mallin, Lucy, Waite, Adrian, Evans, Julie, Newman, Andrew, Allen, Zoe, Perez-Becerril, Cristina, Ryan, Gavin, Hart, Rachel, Taylor, John, Bedenham, Tina, Clement, Emma, Blair, Ed, Hay, Eleanor, Forzano, Francesca, Higgs, Jenny, Canham, Natalie, Majumdar, Anirban, McEntagart, Meriel, Lahiri, Nayana, Stewart, Helen, Smithson, Sarah, Calpena, Eduardo, Jackson, Adam, Banka, Siddharth, Titheradge, Hannah, McGowan, Ruth, Rankin, Julia, Shaw-Smith, Charles, Evans, D. Gareth, Burghel, George J., Smith, Miriam J., Anderson, Emily, Madhu, Rajesh, Firth, Helen, Ellard, Sian, Brennan, Paul, Anderson, Claire, Taupin, Doug, Rogers, Mark T., Cook, Jackie A., Durkie, Miranda, East, James E., Fowler, Darren, Wilson, Louise, Igbokwe, Rebecca, Gardham, Alice, Tomlinson, Ian, Baralle, Diana, Uhlig, Holm H., and Taylor, Jenny C.

Published
2024
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22. Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement

Author

Møller, Pal, Seppälä, Toni T., Ahadova, Aysel, Crosbie, Emma J., Holinski-Feder, Elke, Scott, Rodney, Haupt, Saskia, Möslein, Gabriela, Winship, Ingrid, Broeke, Sanne W. Bajwa-ten, Kohut, Kelly E., Ryan, Neil, Bauerfeind, Peter, Thomas, Laura E., Evans, D. Gareth, Aretz, Stefan, Sijmons, Rolf H., Half, Elizabeth, Heinimann, Karl, Horisberger, Karoline, Monahan, Kevin, Engel, Christoph, Cavestro, Giulia Martina, Fruscio, Robert, Abu-Freha, Naim, Zohar, Levi, Laghi, Luigi, Bertario, Lucio, Bonanni, Bernardo, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Vaccaro, Carlos, Valle, Adriana Della, Rossi, Benedito Mauro, da Silva, Leandro Apolinário, de Oliveira Nascimento, Ivana Lucia, Rossi, Norma Teresa, Dębniak, Tadeusz, Mecklin, Jukka-Pekka, Bernstein, Inge, Lindblom, Annika, Sunde, Lone, Nakken, Sigve, Heuveline, Vincent, Burn, John, Hovig, Eivind, Kloor, Matthias, Sampson, Julian R., and Dominguez-Valentin, Mev

Published
2023
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23. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author

Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph

Published
2023
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25. PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants

Author

Muranen, Taru A., Morra, Anna, Khan, Sofia, Barnes, Daniel R., Bolla, Manjeet K., Dennis, Joe, Keeman, Renske, Leslie, Goska, Parsons, Michael T., Wang, Qin, Ahearn, Thomas U., Aittomäki, Kristiina, Andrulis, Irene L., Arun, Banu K., Behrens, Sabine, Bialkowska, Katarzyna, Bojesen, Stig E., Camp, Nicola J., Chang-Claude, Jenny, Czene, Kamila, Devilee, Peter, Domchek, Susan M., Dunning, Alison M., Engel, Christoph, Evans, D. Gareth, Gago-Dominguez, Manuela, García-Closas, Montserrat, Gerdes, Anne-Marie, Glendon, Gord, Guénel, Pascal, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hooning, Maartje J., Hoppe, Reiner, Izatt, Louise, Jakubowska, Anna, James, Paul A., Kristensen, Vessela N., Lalloo, Fiona, Lindeman, Geoffrey J., Mannermaa, Arto, Margolin, Sara, Neuhausen, Susan L., Newman, William G., Peterlongo, Paolo, Phillips, Kelly-Anne, Pujana, Miquel Angel, Rantala, Johanna, Rønlund, Karina, Saloustros, Emmanouil, Schmutzler, Rita K., Schneeweiss, Andreas, Singer, Christian F., Suvanto, Maija, Tan, Yen Yen, Teixeira, Manuel R., Thomassen, Mads, Tischkowitz, Marc, Tripathi, Vishakha, Wappenschmidt, Barbara, Zhao, Emily, Easton, Douglas F., Antoniou, Antonis C., Chenevix-Trench, Georgia, Pharoah, Paul D. P., Schmidt, Marjanka K., Blomqvist, Carl, and Nevanlinna, Heli

Published
2023
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26. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author

Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Yie, Joanne Ngeow Yuen, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Women's Health, Digestive Diseases, Breast Cancer, Ovarian Cancer, Pancreatic Cancer, Prevention, Cancer, Urologic Diseases, Rare Diseases, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Breast Neoplasms, Male, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Ovarian Neoplasms, Pancreatic Neoplasms, Risk, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Published
2022

27. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated 'Big Bang' pathway to CRC in three of the four Lynch syndromes

Author

Maller, Pål, Haupt, Saskia, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., Sunde, Lone, Seppälä, Toni, Burn, John, Bernstein, Inge, Capella, Gabriel, Evans, D. Gareth, Lindblom, Annika, Winship, Ingrid, Macrae, Finlay, Katz, Lior, Laish, Ido, Vainer, Elez, Monahan, Kevin, Half, Elizabeth, Horisberger, Karoline, da Silva, Leandro Apolinário, Heuveline, Vincent, Therkildsen, Christina, Lautrup, Charlotte, Klarskov, Louise L, Cavestro, Giulia Martina, Möslein, Gabriela, Hovig, Eivind, and Dominguez-Valentin, Mev

Subjects
EPUB (Standard), Colonoscopy -- Analysis, Health
Abstract

Background Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. Materials and methods We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. Results Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. Conclusions Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports. Keywords: MSI, MLH1, MSH2, MSH6, PMS2, dMMR, Lynch syndromes, Colorectal, cancer, Adenoma, Colonoscopy, Sojourn time, Author(s): Pål Maller[sup.1], Saskia Haupt[sup.2,3], Aysel Ahadova[sup.4,5], Matthias Kloor[sup.4,5], Julian R. Sampson[sup.6], Lone Sunde[sup.7,8,9], Toni Seppälä[sup.10,11,12], John Burn[sup.13], Inge Bernstein[sup.14,15], Gabriel Capella[sup.16], D. Gareth Evans[sup.17], Annika Lindblom[sup.18,19], Ingrid Winship[sup.20,21], Finlay [...]

Published
2024
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29. The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2

Author

Hinić, Snežana, Cybulski, Cezary, Van der Post, Rachel S., Vos, Janet R., Schuurs-Hoeijmakers, Janneke, Brugnoletti, Fulvia, Koene, Saskia, Vreede, Lilian, van Zelst-Stams, Wendy A.G., Kets, C. Marleen, Haadsma, Maaike, Spruijt, Liesbeth, Wevers, Marijke R., Evans, D. Gareth, Wimmer, Katharina, Schnaiter, Simon, Volk, Alexander E., Möllring, Anna, de Putter, Robin, Soikkonen, Leila, Kahre, Tiina, Tooming, Mikk, de Jong, Mirjam M., Vaz, Fátima, Mensenkamp, Arjen R., Genuardi, Maurizio, Lubinski, Jan, Ligtenberg, Marjolijn, Hoogerbrugge, Nicoline, and de Voer, Richarda M.

Published
2024
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30. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author

Ahearn, Thomas U, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Lush, Michael, Wang, Qin, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N, Krüger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W, Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G, Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, and McLean, Catriona

Subjects
Human Genome, Cancer, Genetics, Clinical Research, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Tumor, Breast Neoplasms, Female, Genome-Wide Association Study, Humans, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Risk, Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants, NBCS Collaborators, ABCTB Investigators, kConFab/AOCS Investigators, Receptor, erbB-2, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Published
2022

31. Rare germline copy number variants (CNVs) and breast cancer risk

Author

Dennis, Joe, Tyrer, Jonathan P, Walker, Logan C, Michailidou, Kyriaki, Dorling, Leila, Bolla, Manjeet K, Wang, Qin, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Clarke, Christine L, Collée, J Margriet, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Jager, Agnes, Jakubowska, Anna, John, Esther M, Johnson, Nichola, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Linet, Martha, Ogrodniczak, Alicja, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Perou, Charles M, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shibli, Rana, Smeets, Ann, and Soucy, Penny

Subjects
Human Genome, Breast Cancer, Genetics, Clinical Research, Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Case-Control Studies, DNA Copy Number Variations, Female, Genome, Human, Genome-Wide Association Study, Germ Cells, Humans, Risk Factors, NBCS Collaborators, CTS Consortium, ABCTB Investigators, kConFab/AOCS Investigators
Abstract

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value

Published
2022

32. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author

Morra, Anna, Escala-Garcia, Maria, Beesley, Jonathan, Keeman, Renske, Canisius, Sander, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Brüning, Thomas, Buys, Saundra S, Caan, Bette, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Cheng, Ting-Yuan David, Clarke, Christine L, Colonna, Sarah V, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Dörk, Thilo, Dossus, Laure, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, Gago-Dominguez, Manuela, García-Sáenz, José A, Giles, Graham G, Grip, Mervi, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hart, Steven N, Hartikainen, Jaana M, Hartmann, Arndt, He, Wei, Hooning, Maartje J, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Hunter, David J, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Keupers, Machteld, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Linet, Martha, Luben, Robert N, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martens, John WM, Martinez, Maria Elena, Mavroudis, Dimitrios, Michailidou, Kyriaki, Milne, Roger L, Mulligan, Anna Marie, Muranen, Taru A, Nevanlinna, Heli, Newman, William G, and Nielsen, Sune F

Subjects
Clinical Research, Cancer, Breast Cancer, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Female, Genome-Wide Association Study, Germ-Line Mutation, Humans, Polymorphism, Single Nucleotide, Prognosis, Survival Analysis, Common germline genetic variants, Breast cancer-specific survival, Patient subgroups, Tumor biology, Systemic treatment, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundGiven the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.MethodsWe performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP

Published
2021

33. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author

Park, Hanla A, Neumeyer, Sonja, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baten, Adinda, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny, Harkness, Elaine F, Hart, Steven N, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hopper, John L, Hunter, David J, Jager, Agnes, Jakubowska, Anna, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lo, Wing-Yee, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Meindl, Alfons, Menon, Usha, Milne, Roger L, Muranen, Taru A, and Nevanlinna, Heli

Subjects
Genetics, Cancer, Substance Misuse, Clinical Research, Human Genome, Prevention, Drug Abuse (NIDA only), Breast Cancer, Tobacco, Tobacco Smoke and Health, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundDespite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.MethodsWe applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.ResultsGenetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.ConclusionOur MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

Published
2021

34. 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

36. Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing, and definition of groups who may not require testing

Author

Evans, D. Gareth, Woodward, Emma R., Burghel, George J., Allen, Sophie, Torr, Beth, Hamill, Monica, Kavanaugh, Grace, Hubank, Mike, Bremner, Stephen, Jones, Christopher I., Schlecht, Helene, Astley, Susan, Bowers, Sarah, Gibbons, Sarah, Ruane, Helen, Fosbury, Caroline, Howell, Sacha J., Forde, Claire, Lalloo, Fiona, Newman, William G., Smith, Miriam J., Howell, Anthony, Turnbull, Clare, and Gandhi, Ashu

Published
2024
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37. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author

Figlioli, Gisella, Billaud, Amandine, Ahearn, Thomas U., Antonenkova, Natalia N., Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J., Bogdanova, Natalia V., Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Cessna, Melissa H., Chanock, Stephen J., Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine D., Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A., He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K., Ko, Yon-Dschun, Kristensen, Vessela N., Lindblom, Annika, Lissowska, Jolanta, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Newman, William G., Obi, Nadia, Panayiotidis, Mihalis I., Rashid, Muhammad U., Rhenius, Valerie, Rookus, Matti A., Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sironen, Reijo, Southey, Melissa C., Suvanto, Maija, Tollenaar, Rob A. E. M., Tomlinson, Ian, Truong, Thérèse, van der Kolk, Lizet E., van Veen, Elke M., Wappenschmidt, Barbara, Yang, Xiaohong R., Bolla, Manjeet K., Dennis, Joe, Dunning, Alison M., Easton, Douglas F., Lush, Michael, Michailidou, Kyriaki, Pharoah, Paul D. P., Wang, Qin, Adank, Muriel A., Schmidt, Marjanka K., Andrulis, Irene L., Chang-Claude, Jenny, Nevanlinna, Heli, Chenevix-Trench, Georgia, Evans, D. Gareth, Milne, Roger L., Radice, Paolo, and Peterlongo, Paolo

Published
2023
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40. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Author

Legius, Eric, Messiaen, Ludwine, Wolkenstein, Pierre, Pancza, Patrice, Avery, Robert A, Berman, Yemima, Blakeley, Jaishri, Babovic-Vuksanovic, Dusica, Cunha, Karin Soares, Ferner, Rosalie, Fisher, Michael J, Friedman, Jan M, Gutmann, David H, Kehrer-Sawatzki, Hildegard, Korf, Bruce R, Mautner, Victor-Felix, Peltonen, Sirkku, Rauen, Katherine A, Riccardi, Vincent, Schorry, Elizabeth, Stemmer-Rachamimov, Anat, Stevenson, David A, Tadini, Gianluca, Ullrich, Nicole J, Viskochil, David, Wimmer, Katharina, Yohay, Kaleb, Huson, Susan M, Evans, D Gareth, and Plotkin, Scott R

Subjects
Biological Sciences, Genetics, Neurosciences, Rare Diseases, Clinical Research, Neurofibromatosis, Cafe-au-Lait Spots, Consensus, Genetic Testing, Humans, Neurofibromatosis 1, International Consensus Group on Neurofibromatosis Diagnostic Criteria, Clinical Sciences, Genetics & Heredity
Abstract

PurposeBy incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS).MethodsWe used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.ResultsWe reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended.ConclusionThe revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

Published
2021

41. Cognitive and Electrophysiological Correlates of Working Memory Impairments in Neurofibromatosis Type 1

Author

Pobric, Gorana, Taylor, Jason R., Ramalingam, Hemavathy M., Pye, Emily, Robinson, Louise, Vassallo, Grace, Jung, JeYoung, Bhandary, Misty, Szumanska-Ryt, Karolina, Theodosiou, Louise, Evans, D. Gareth, Eelloo, Judith, Burkitt-Wright, Emma, Hulleman, Johan, Green, Jonathan, and Garg, Shruti

Abstract

Neurofibromatosis 1 (NF1) is a single gene disorder associated with working Memory (WM) impairments. The aim of this study was to investigate P300 event-related potential (ERP) associated with WM in NF1. Sixteen adolescents with NF1 were compared with controls on measures of WM and EEG was recorded during a WM nback task. The NF1 group showed poorer performance on measures of WM as compared to the control group. No group differences were observed in P300 amplitude at Pz, but P300 latency was shorter in the NF1 group. Topographic analyses of P300 amplitude showed group differences indicating neural processing differences in the NF1 group relative to controls, which possibly contribute to the cognitive deficits seen in this population.

Published
2022
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42. 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

43. Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association ConsortiumBreast Cancer Risk Factors and Survival By Tumor Subtype

Author

Morra, Anna, Jung, Audrey Y, Behrens, Sabine, Keeman, Renske, Ahearn, Thomas U, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Auvinen, Päivi K, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Briceno, Ignacio, Brucker, Sara Y, Camp, Nicola J, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Choi, Ji-Yeob, Clarke, Christine L, Investigators, for the ABCTB, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Egan, Kathleen M, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny N, Hart, Steven N, Hartman, Mikael, Heyworth, Jane S, Hoppe, Reiner, Hopper, John L, Hunter, David J, Ito, Hidemi, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Collaborators, for the NBCS, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mariapun, Shivaani, Matsuo, Keitaro, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Newman, William G, Noh, Dong-Young, Nordestgaard, Børge G, Obi, Nadia, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Petridis, Christos, Pharoah, Paul DP, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, and Rhenius, Valerie

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Aging, Estrogen, Cancer, Prevention, Breast Cancer, Good Health and Well Being, Adult, Aged, Breast Neoplasms, Cause of Death, Female, Humans, Life Style, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Prospective Studies, Risk Factors, Survival Analysis, ABCTB Investigators, NBCS Collaborators, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundIt is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.MethodsWe analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.ResultsThere was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus 0-

Published
2021

44. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

Author

Fortuno, Cristina, Lee, Kristy, Olivier, Magali, Pesaran, Tina, Mai, Phuong L, Andrade, Kelvin C, Attardi, Laura D, Crowley, Stephanie, Evans, D Gareth, Feng, Bing‐Jian, Foreman, Ann KM, Frone, Megan N, Huether, Robert, James, Paul A, McGoldrick, Kelly, Mester, Jessica, Seifert, Bryce A, Slavin, Thomas P, Witkowski, Leora, Zhang, Liying, Plon, Sharon E, Spurdle, Amanda B, Savage, Sharon A, and Panel, the ClinGen TP53 Variant Curation Expert

Subjects
Human Genome, Prevention, Genetics, Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Genetic Testing, Genetic Variation, Germ Cells, Humans, Li-Fraumeni Syndrome, Tumor Suppressor Protein p53, United States, cancer, pathogenic variant, TP53, variant curation, ClinGen TP53 Variant Curation Expert Panel, Clinical Sciences, Genetics & Heredity
Abstract

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.

Published
2021

45. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

Author

Kapoor, Pooja Middha, Mavaddat, Nasim, Choudhury, Parichoy Pal, Wilcox, Amber N, Lindström, Sara, Behrens, Sabine, Michailidou, Kyriaki, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Jung, Audrey, Abu-Ful, Zomoroda, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chatterjee, Nilanjan, Chenevix-Trench, Georgia, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dai, James Y, Earp, H Shelton, Ekici, Arif B, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hatse, Sigrid, Heyworth, Jane, Holleczek, Bernd, Hoover, Robert N, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, kConFab/AOCS Investigators, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, MacInnis, Robert J, Martinez, Maria Elena, Maurer, Tabea, McLean, Catriona, Neuhausen, Susan L, Newman, William G, Norman, Aaron, O'Brien, Katie M, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, and Orr, Nick

Subjects
ABCTB Investigators, kConFab/AOCS Investigators, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Published
2021

48. 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

49. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E, Schoemaker, Minouk J, Gilham, Clare, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Hunter, David J, Jager, Agnes, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Nielsen, Sune F, Nordestgaard, Børge G, Obi, Nadia, Olshan, Andrew F, and Olson, Janet E

Subjects
Estrogen, Human Genome, Clinical Research, Cancer, Aging, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Cytochrome P-450 CYP3A, Estrone, Female, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Pregnanediol, Premenopause, Progesterone, Receptors, Estrogen, Receptors, Progesterone, NBCS Collaborators, AOCS Group, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundEpidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.MethodsWe carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.ResultsFor pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8).ConclusionsThe CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Published
2021

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