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1. Study on the Efficacy and Safety of the Huangqi Guizhi Wuwu Decoction in the Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy: Meta-Analysis of 32 Randomized Controlled Trials

Author: Yang XR, Zhang XY, Xia YJ, Fu J, Lian XX, Liang XR, He YQ, and Li ZH
Subjects: huangqi guizhi wuwu decoction, chemotherapy-induced peripheral neuropathy, chemotherapy-induced peripheral neurotoxicity, chinese medicine, meta-analysis, Medicine (General), R5-920
Abstract: Xin-Rong Yang,1 Xin-Yi Zhang,1 Yi-Jia Xia,1 Jin Fu,1 Xiao-Xuan Lian,2 Xin-Ru Liang,2 Ying-Qi He,2 Zhuo-Hong Li1 1Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of ChinaCorrespondence: Zhuo-Hong Li, Email lizhuohong@cdutcm.edu.cnPurpose: Chemotherapy-induced peripheral neuropathy (CIPN) still lacks efficient therapeutic drugs. This study aimed to systematically evaluate the effects of Huangqi Guizhi Wuwu Decoction (HGWD) alone or combined with positive drugs on CIPN prevention and treatment.Methods: The PubMed, Embase, Web of Science, Cochrane, China National Knowledge Infrastructure (CNKI), Wan Fang Data, China Science and Technology Journal (VIP) and Chinese Biomedical (CBM) databases were searched for randomized controlled trials (RCTs) of HGWD for CIPN prevention and treatment. The search time ranged from database establishment to October 17, 2023. The Cochrane risk-of-bias assessment tool was used for quality assessment, Review Manager 5.3 and STATA 12.0 were used for meta-analysis, and GRADEprofiler was used for evidence level assessment.Results: A total of 32 RCTs involving 1987 patients were included. The meta-analysis results revealed the following: 1. In terms of the total CIPN incidence, that in the HGWD group was lower than that in the blank control group. The incidence in both the HGWD and HGWD+positive drug groups was lower than that in the monotherapy-positive drug group. 2. In terms of the incidence of severe CIPN, that in the HGWD group was lower than that in the blank control and positive drug groups. There was no statistically significant difference between the HGWD+positive drug and positive drug groups. Sensitivity analysis revealed that the results of severe incidence in the HGWD group was lower than that in the positive drug group were unstable 3. HGWD did not increase the number of chemotherapy-related adverse events.Conclusion: HGWD can safely and effectively prevent CIPN, reduce symptoms, improve quality of life and reduce the impact of chemotherapy drugs on sensory nerve conduction. However, more high-quality RCTs are needed to compare the efficacy of HGWD with that of positive control drugs in preventing severe CIPN.Keywords: huangqi guizhi wuwu decoction, chemotherapy-induced peripheral neuropathy, chemotherapy-induced peripheral neurotoxicity, Chinese medicine, meta-analysis
Published: 2024

2. Progress in Clinical Research on Gonadotropin-Releasing Hormone Receptor Antagonists for the Treatment of Prostate Cancer

Author: Liu YF, Fu SQ, Yan YC, Gong BB, Xie WJ, Yang XR, Sun T, and Ma M
Subjects: gonadotropin-releasing hormone, prostate cancer, degarelix, relugolix., Therapeutics. Pharmacology, RM1-950
Abstract: Yi-Fu Liu, Sheng-Qiang Fu, Yu-Chang Yan, Bin-Bin Gong, Wen-Jie Xie, Xiao-Rong Yang, Ting Sun, Ming Ma Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People’s Republic of ChinaCorrespondence: Ming MaDepartment of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People’s Republic of ChinaEmail mm15070835359@163.comAbstract: Gonadotropin-releasing hormone (GnRH) receptor agonists are still the most commonly used androgen deprivation treatment (ADT) drugs for prostate cancer in clinical practice. Currently, the GnRH receptor antagonists used for endocrine therapy for prostate cancer primarily include degarelix and relugolix (TAK-385). The former is administered by subcutaneous injection, while the latter is an oral drug. Compared to GnRH agonists, GnRH antagonists reduce serum testosterone levels more rapidly without an initial testosterone surge or subsequent microsurges. This review focuses on the mechanism of action of GnRH antagonists and agonists, the developmental history of GnRH antagonists, and emerging data from clinical studies of the two antagonists used as endocrine therapy for prostate cancer.Keywords: gonadotropin-releasing hormone, prostate cancer, degarelix, relugolix
Published: 2021

3. Clinical and biological implications of IDH1/2 in acute myeloid leukemia with DNMT3Amut

Author: Zhang XP, Shi JL, Zhang JL, Yang XR, Zhang GQ, Yang SY, Wang J, Ke XY, and Fu L
Subjects: acute myeloid leukemia, molecular mutations, prognosis, next-generation sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Xinpei Zhang,1 Jinlong Shi,2 Jilei Zhang,1 Xinrui Yang,1 Gaoqi Zhang,1 Siyuan Yang,1 Jing Wang,1 Xiaoyan Ke,1 Lin Fu1 1Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing 100191, China; 2Department of Biomedical Engineering, Chinese PLA General Hospital, Beijing 100853, China Purpose: The incidence of DNMT3A mutations in acute myeloid leukemia (AML) is quite high and often confers a poorer prognosis. Another common gene involved in AML is IDH1/2. However, the influence of IDH1/2 mutations on outcomes in DNMT3A-mutated patients remains unknown. This study aims to determine the effect of IDH1/2mut on the prognosis in patients with DNMT3A-mutated AML. Patients and methods: We screened patients from The Cancer Genome Atlas database and selected 51 patients with AML and the DNMT3A mutation, among which 16 patients (31.4%) had both DNMT3A and IDH1/2mut. Results: Among our sample, 11 cases had the IDH1 mutation (21.7%), and 5 cases had the IDH2 mutation (9.8%). Patients in the DNMT3AmutIDH1/2wild group showed a greater number of NPM1 mutation (P=0.022), and higher event-free survival (EFS) and overall survival (OS) after hematopoietic stem cell transplantation (HSCT) (P=0.010 and P=0.007, respectively). Patients in the DNMT3AmutIDH1/2mut group showed no increase in EFS or OS after HSCT or chemotherapy. Other factors, like white blood cells, bone marrow blasts, peripheral blood blasts, and mutated recurrent gene numbers had no significant influence on EFS and OS. Conclusion: The IDH1/2 gene had little influence on the prognosis of patients with the DNMT3A mutation. For patients in the DNMT3AmutIDH1/2wild group, HSCT had a more favorable therapeutic effect. For patients with DNMT3A and IDH1/2mut, chemotherapy and HSCT appeared to have similar efficacy. Keywords: acute myeloid leukemia, molecular mutations, prognosis, next-generation sequencing
Published: 2018

4. In vivo MRI tracking of iron oxide nanoparticle-labeled human mesenchymal stem cells in limb ischemia

Author: Li XX, Li KA, Qin JB, Ye KC, Yang XR, Li WM, Xie QS, Jiang ME, Zhang GX, and Lu XW.
Subjects: Medicine (General), R5-920
Abstract: Xiang-Xiang Li,1,2,* Kang-An Li,3,* Jin-Bao Qin,1,2 Kai-Chuang Ye,1,2 Xin-Rui Yang,1,2 Wei-Min Li,1,2 Qing-Song Xie,4 Mi-Er Jiang,1,2 Gui-Xiang Zhang,3 Xin-Wu Lu1,21Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, 2Vascular Center, Shanghai JiaoTong University, 3Department of Radiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; 4Department of Neurosurgery, Cixi Municipal People's Hospital, Zhejiang Province, People's Republic of China *These authors contributed equally to this work Background: Stem cell transplantation has been investigated for repairing damaged tissues in various injury models. Monitoring the safety and fate of transplanted cells using noninvasive methods is important to advance this technique into clinical applications. Methods: In this study, lower-limb ischemia models were generated in nude mice by femoral artery ligation. As negative-contrast agents, positively charged magnetic iron oxide nanoparticles (aminopropyltriethoxysilane-coated Fe2O3) were investigated in terms of in vitro labeling efficiency, effects on human mesenchymal stromal cell (hMSC) proliferation, and in vivo magnetic resonance imaging (MRI) visualization. Ultimately, the mice were sacrificed for histological analysis three weeks after transplantation. Results: With efficient labeling, aminopropyltriethoxysilane-modified magnetic iron oxide nanoparticles (APTS-MNPs) did not significantly affect hMSC proliferation. In vivo, APTS-MNP-labeled hMSCs could be monitored by clinical 3 Tesla MRI for at least three weeks. Histological examination detected numerous migrated Prussian blue-positive cells, which was consistent with the magnetic resonance images. Some migrated Prussian blue-positive cells were positive for mature endothelial cell markers of von Willebrand factor and anti-human proliferating cell nuclear antigen. In the test groups, Prussian blue-positive nanoparticles, which could not be found in other organs, were detected in the spleen. Conclusion: APTS-MNPs could efficiently label hMSCs, and clinical 3 Tesla MRI could monitor the labeled stem cells in vivo, which may provide a new approach for the in vivo monitoring of implanted cells. Keywords: hind-limb ischemia, magnetic resonance imaging, iron oxide particles, stem cell implant
Published: 2013

5. Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

Author: Dalmasso, B, Pastorino, L, Nathan, V, Shah, NN, Palmer, JM, Howlie, M, Johansson, PA, Freedman, ND, Carter, BD, Beane-Freeman, L, Hicks, B, Molven, A, Helgadottir, H, Sankar, A, Tsao, H, Stratigos, AJ, Helsing, P, Van Doorn, R, Gruis, NA, Visser, M, Wadt, KAW, Mann, G, Holland, EA, Nagore, E, Potrony, M, Puig, S, Menin, C, Peris, K, Fargnoli, MC, Calista, D, Soufir, N, Harland, M, Bishop, T, Kanetsky, PA, Elder, DE, Andreotti, V, Vanni, I, Bruno, W, Höiom, V, Tucker, MA, Yang, XR, Andresen, PA, Adams, DJ, Landi, MT, Hayward, NK, Goldstein, AM, and Ghiorzo, P
Subjects: Genetics, Human Genome, Cancer, 2.1 Biological and endogenous factors, Aetiology, Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Australia, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Melanoma, GenoMEL, MelaNostrum consortia, Clinical Sciences, Genetics & Heredity
Abstract: PurposeAtaxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.MethodsFrom 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set.ResultsLOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p
Published: 2021

6. Determination of the α -decay half-life of Po 210 based on film and slice bismuth samples at room temperature

Author: Zhao, QZ, Wang, XM, Wang, W, He, M, Dong, KJ, Xiao, CJ, Ruan, XD, Shen, HT, Wu, SY, Yang, XR, Dou, L, Xu, YN, Cai, L, Pang, FF, Zhang, H, Pang, YJ, and Jiang, S
Subjects: Nuclear & Particles Physics, Atomic, Molecular, Nuclear, Particle and Plasma Physics, Atomic, Molecular, Nuclear, Particle and Plasma Physics
Abstract: The α decay rate of Po210 was measured in a film sample (Po210@Bi2O3) and a slice sample (Po210@Bimetal), respectively. The former was used as a reference sample. The half-lives of Po210@Bi2O3 and Po210@Bi metal environments were observed to be (138.40±0.21d) and (138.87±0.87d) at room temperature, respectively. It was found that the half-life of Po210 is consistent with international recommendations within the uncertainty limits, and we did not find any deviation of the α decay rate of Po210 between film sample (Po210@Bi2O3) and slice sample (Po210@Bimetal).
Published: 2015

7. Determination of the α-decay half-life of Po210 based on film and slice bismuth samples at room temperature

Author: Zhao, QZ, Wang, XM, Wang, W, He, M, Dong, KJ, Xiao, CJ, Ruan, XD, Shen, HT, Wu, SY, Yang, XR, Dou, L, Xu, YN, Cai, L, Pang, FF, Zhang, H, Pang, YJ, and Jiang, S
Subjects: Atomic, Molecular, Nuclear, Particle and Plasma Physics, Nuclear & Particles Physics
Abstract: The α decay rate of Po210 was measured in a film sample (Po210@Bi2O3) and a slice sample (Po210@Bimetal), respectively. The former was used as a reference sample. The half-lives of Po210@Bi2O3 and Po210@Bi metal environments were observed to be (138.40±0.21d) and (138.87±0.87d) at room temperature, respectively. It was found that the half-life of Po210 is consistent with international recommendations within the uncertainty limits, and we did not find any deviation of the α decay rate of Po210 between film sample (Po210@Bi2O3) and slice sample (Po210@Bimetal).
Published: 2015

8. Measurement of the half-life of79Se with accelerator mass spectrometry

Author: Dou, L, Jiang, S, Wang, XB, Dong, KJ, Wu, SY, Yang, XR, Wang, XM, Lan, XX, Xia, QL, and He, M
Subjects: Nuclear & Particles Physics, Atomic, Molecular, Nuclear, Particle and Plasma Physics
Abstract: The accelerator mass spectrometry (AMS) is an effective method for the determination of the half-life of long-lived radionuclides. In this paper, we report a method for measurement of the half-life of 79Se. The number of 79Se atoms was determined from measured 79Se/Se absolute ratios with the AMS system at the China Institute of Atomic Energy and the decay rate of 79Se was determined by counting the emitted β-rays with a liquid scintillation spectrometer. The major improvements of our measurements include using the high abundance of an 79Se sample which was cooled for many years to exclude the interference of short-lived nuclides, the extraction of SeO2- molecular ions, that results in a suppression of the 79Br background by as much as about five orders of magnitude. Also, an AMS measurement of the absolute ratio of 79Se/Se was developed to avoid systematic errors. The results show that 79Se/Se is (2.35±0.12)×10-7 in the reference sample and the radioactivity of 79Se is (1.24±0.05) Bq/g, so the half-life of 79Se is (2.78±0.18)×105 a.
Published: 2014

9. Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

Author: Figlioli, G, Billaud, A, Wang, Q, Bolla, MK, Dennis, J, Lush, M, Kvist, A, Adank, MA, Ahearn, TU, Antonenkova, NN, Auvinen, P, Behrens, S, Bermisheva, M, Bogdanova, N, Bojesen, SE, Bonanni, B, Bruening, T, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Czene, K, Devilee, P, Doerk, T, Eriksson, M, Fasching, PA, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Glendon, G, Garcia, EG, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Hahnen, E, Hamann, U, Hillemanns, P, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jakubowska, A, Khusnutdinova, EK, Kristensen, VN, Lindblom, A, Loizidou, MA, Lubinski, J, Mannermaa, A, Maurer, T, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, M, Radice, P, Rashid, MU, Rhenius, V, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shah, MT, Southey, MC, Tomlinson, I, Truong, T, van Veen, EM, Wendt, C, Yang, XR, Michailidou, K, Dunning, AM, Pharoah, PDP, Easton, DF, Andrulis, IL, Evans, DG, Hollestelle, A, Chang-Claude, J, Milne, RL, Peterlongo, P, Figlioli, G, Billaud, A, Wang, Q, Bolla, MK, Dennis, J, Lush, M, Kvist, A, Adank, MA, Ahearn, TU, Antonenkova, NN, Auvinen, P, Behrens, S, Bermisheva, M, Bogdanova, N, Bojesen, SE, Bonanni, B, Bruening, T, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Czene, K, Devilee, P, Doerk, T, Eriksson, M, Fasching, PA, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Glendon, G, Garcia, EG, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Hahnen, E, Hamann, U, Hillemanns, P, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jakubowska, A, Khusnutdinova, EK, Kristensen, VN, Lindblom, A, Loizidou, MA, Lubinski, J, Mannermaa, A, Maurer, T, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, M, Radice, P, Rashid, MU, Rhenius, V, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shah, MT, Southey, MC, Tomlinson, I, Truong, T, van Veen, EM, Wendt, C, Yang, XR, Michailidou, K, Dunning, AM, Pharoah, PDP, Easton, DF, Andrulis, IL, Evans, DG, Hollestelle, A, Chang-Claude, J, Milne, RL, and Peterlongo, P
Abstract: FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.
Published: 2023

10. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author: Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, Elkon, R, Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, and Elkon, R
Abstract: BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Published: 2023

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

Author: Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, Kuchenbaecker, KB, Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, and Kuchenbaecker, KB
Abstract: BACKGROUND: Low-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. METHODS: We 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. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.
Published: 2023

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

Author: Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, Peterlongo, P, Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, and Peterlongo, P
Abstract: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
Published: 2023

13. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, Chatterjee, N, Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, and Chatterjee, N
Abstract: BACKGROUND: Genome-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. METHODS: Among 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. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2022

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

Author: Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, Easton, DF, Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, and Easton, DF
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 < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
Published: 2022

15. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author: Dorling, L, Carvalho, S, Allen, J, Parsons, MT, Fortuno, C, Gonzalez-Neira, A, Heijl, SM, Adank, MA, Ahearn, TU, Andrulis, IL, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bremer, M, Briceno, I, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Collee, JM, Czene, K, Dennis, J, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Glendon, G, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, E, Kim, S-W, Ko, Y-D, Kristensen, VN, Lakeman, IMM, Li, J, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Luccarini, C, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Mohd Taib, NA, Muir, K, Nevanlinna, H, Newman, WG, Oosterwijk, JC, Park, SK, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Surowy, H, Suvanto, M, Tomlinson, I, Torres, D, Truong, T, van Asperen, CJ, Waltes, R, Wang, Q, Yang, XR, Pharoah, PDP, Schmidt, MK, Benitez, J, Vroling, B, Dunning, AM, Teo, SH, Kvist, A, de la Hoya, M, Devilee, P, Spurdle, AB, Vreeswijk, MPG, Easton, DF, Dorling, L, Carvalho, S, Allen, J, Parsons, MT, Fortuno, C, Gonzalez-Neira, A, Heijl, SM, Adank, MA, Ahearn, TU, Andrulis, IL, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bremer, M, Briceno, I, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Collee, JM, Czene, K, Dennis, J, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Glendon, G, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, E, Kim, S-W, Ko, Y-D, Kristensen, VN, Lakeman, IMM, Li, J, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Luccarini, C, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Mohd Taib, NA, Muir, K, Nevanlinna, H, Newman, WG, Oosterwijk, JC, Park, SK, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Surowy, H, Suvanto, M, Tomlinson, I, Torres, D, Truong, T, van Asperen, CJ, Waltes, R, Wang, Q, Yang, XR, Pharoah, PDP, Schmidt, MK, Benitez, J, Vroling, B, Dunning, AM, Teo, SH, Kvist, A, de la Hoya, M, Devilee, P, Spurdle, AB, Vreeswijk, MPG, and Easton, DF
Abstract: BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Published: 2022

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

Author: Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, Chang-Claude, J, Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, and Chang-Claude, J
Abstract: BACKGROUND: Reproductive 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. METHODS: Analyses 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. RESULTS: Compared 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
Published: 2022

17. Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium

Author: Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, Chang-Claude, J, Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, and Chang-Claude, J
Abstract: BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We 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. RESULTS: There 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 <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
Published: 2021

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

Author: Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, Chang-Claude, J, Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, and Chang-Claude, J
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

19. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (vol 12, 1078, 2021)

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
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 < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

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

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
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 < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

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

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
Published: 2021

22. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Brüning, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Collée, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, González-Neira, A, Alnæs, GIG, Grip, M, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, C, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Fox, S, Campbell, I, Bowtell, D, Spurdle, A, Webb, P, de Fazio, A, Tassell, M, Kirk, J, Lindeman, G, Price, M, Southey, M, Milne, R, Deb, S, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Krüger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, AV, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkäs, K, Radice, P, Rennert, G, Romero, A, Rüdiger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schöttker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, García-Closas, M, Chatterjee, N, Ahearn, Thomas U [0000-0003-0771-7752], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, Clinical Genetics, Medical Oncology, and Pathology
Subjects: False discovery rate, Oncology, Common breast cancer susceptibility variants, Receptor, ErbB-2, Estrogen receptor, PROGRESSION, Etiologic heterogeneity, Logistic regression, Basic medicine, Breast cancer, 0302 clinical medicine, PRIMARY THERAPY, HETEROGENEITY, RC254-282, HISTOLOGICAL GRADE, 0303 health sciences, Breast Neoplasms/epidemiology, Receptors, Estrogen/genetics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, INTERNATIONAL EXPERT CONSENSUS, humanities, Receptor, ErbB-2/genetics, 3. Good health, Receptors, Estrogen, Receptors, Progesterone/genetics, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Receptors, Progesterone, Medical Genetics, Research Article, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, Biomarkers, Tumor, medicine, Genetic predisposition, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Genetic association, Medicinsk genetik, 030304 developmental biology, Cancer och onkologi, medicine.disease, Cancer and Oncology, Clinical medicine, Genome-Wide Association Study
Abstract: Background Genome-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. Methods Among 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. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate p Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2020

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

Author: Zhang, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O’Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Ful, ZA, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Brüning, T, Burwinkel, B, Buys, SS, Byers, H, Caldés, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Dörk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Gronwald, J, Guénel, P, Häberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, OI, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Rübner, M, Rüdiger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schöttker, B, Schürmann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, CI, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, and García-Closas, M
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1,2,3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P
Published: 2020

24. Assessment of interactions between 205 breast cancer susceptibility loci and 13 established risk factors in relation to breast cancer risk, in the Breast Cancer Association Consortium

Author: Kapoor, PM, Lindström, S, Behrens, S, Wang, X, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, García-Closas, M, Easton, DF, Milne, RL, Chang-Claude, J, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Freeman, LEB, Beckmann, MW, Benitez, J, Bernstein, L, Berrandou, T, Bojesen, SE, Brauch, H, Brenner, H, Brock, IW, Broeks, A, Brooks-Wilson, A, Butterbach, K, Cai, Q, Campa, D, Canzian, F, Carter, BD, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Dite, GS, Earp, HS, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, Gaudet, MM, Giles, GG, González-Neira, A, Grundy, A, Guénel, P, Haeberle, L, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Hankinson, SE, Harkness, EF, Harstad, T, He, W, Heyworth, J, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Marrón, PI, John, EM, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Krüger, U, Lambrechts, D, Marchand, LL, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, Makalic, E, Martinez, ME, Maurer, T, Muñoz-Garzon, VM, Neuhausen, SL, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pinchev, M, Prentice, R, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Schneider, MO, Schoemaker, MJ, Schöttker, B, Scott, RJ, Scott, C, Sherman, ME, Shrubsole, MJ, Shu, X-O, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Thöne, K, Troester, MA, Truong, T, Vachon, CM, van Ongeval, C, van Veen, EM, Wagner, P, Weinberg, CR, Wildiers, H, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, and Ziogas, A
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Breast Neoplasms, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Risk Factors, single nucleotide polymorphism, Internal medicine, medicine, SNP, Humans, risk factors, Genetic Predisposition to Disease, Breast, Alleles, Cancer och onkologi, Factor XIII, Europeans, business.industry, Gene-environment interaction, epidemiology, Case-control study, Cancer, General Medicine, Odds ratio, medicine.disease, Europe, Genetics and Environment, 030104 developmental biology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer and Oncology, Female, Gene-Environment Interaction, business, Genome-Wide Association Study
Abstract: Background Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions. Methods Analyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions. Results Noteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10–4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10–5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth. Conclusions Overall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.
Published: 2020

25. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author: Escala-Garcia, M, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Ashworth, A, Auer, PL, Auvinen, P, Beckmann, MW, Beesley, J, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, W, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Caldas, C, Canzian, F, Chang-Claude, J, Chanock, SJ, Chin, S-F, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dunn, JA, Dunning, AM, Dwek, M, Earl, HM, Eccles, DM, Eliassen, AH, Ellberg, C, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Giles, GG, Goldgar, DE, Gonzalez-Neira, A, Grip, M, Guenel, P, Guo, Q, Haiman, CA, Hakansson, N, Hamann, U, Harrington, PA, Hiller, L, Hooning, MJ, Hopper, JL, Howell, A, Huang, C-S, Huang, G, Hunter, DJ, Jakubowska, A, John, EM, Kaaks, R, Kapoor, PM, Keeman, R, Kitahara, CM, Koppert, LB, Kraft, P, Kristensen, VN, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Maurer, T, Mavroudis, D, Meindl, A, Milne, RL, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Newman, WG, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Peterlongo, P, Petridis, C, Prentice, RL, Presneau, N, Punie, K, Ramachandran, D, Rennert, G, Romero, A, Sachchithananthan, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schwentner, L, Scott, C, Simard, J, Sohn, C, Southey, MC, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teixeira, MR, Terry, MB, Thorne, H, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Turnbull, C, Vachon, CM, van der Kolk, LE, Wang, Q, Winqvist, R, Wolk, A, Yang, XR, Ziogas, A, Pharoah, PDP, Hall, P, Wessels, LFA, Chenevix-Trench, G, Bader, GD, Doerk, T, Easton, DF, Canisius, S, Schmidt, MK, Escala-Garcia, M, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Ashworth, A, Auer, PL, Auvinen, P, Beckmann, MW, Beesley, J, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, W, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Caldas, C, Canzian, F, Chang-Claude, J, Chanock, SJ, Chin, S-F, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dunn, JA, Dunning, AM, Dwek, M, Earl, HM, Eccles, DM, Eliassen, AH, Ellberg, C, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Giles, GG, Goldgar, DE, Gonzalez-Neira, A, Grip, M, Guenel, P, Guo, Q, Haiman, CA, Hakansson, N, Hamann, U, Harrington, PA, Hiller, L, Hooning, MJ, Hopper, JL, Howell, A, Huang, C-S, Huang, G, Hunter, DJ, Jakubowska, A, John, EM, Kaaks, R, Kapoor, PM, Keeman, R, Kitahara, CM, Koppert, LB, Kraft, P, Kristensen, VN, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Maurer, T, Mavroudis, D, Meindl, A, Milne, RL, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Newman, WG, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Peterlongo, P, Petridis, C, Prentice, RL, Presneau, N, Punie, K, Ramachandran, D, Rennert, G, Romero, A, Sachchithananthan, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schwentner, L, Scott, C, Simard, J, Sohn, C, Southey, MC, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teixeira, MR, Terry, MB, Thorne, H, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Turnbull, C, Vachon, CM, van der Kolk, LE, Wang, Q, Winqvist, R, Wolk, A, Yang, XR, Ziogas, A, Pharoah, PDP, Hall, P, Wessels, LFA, Chenevix-Trench, G, Bader, GD, Doerk, T, Easton, DF, Canisius, S, and Schmidt, MK
Abstract: Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
Published: 2020

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

Author: Zhan, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O'Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Abu Ful, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Doerk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, Garcia-Closas, M, Zhan, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O'Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Abu Ful, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Doerk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, and Garcia-Closas, M
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020

27. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author: Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, Jiang, X, Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, and Jiang, X
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
Published: 2020

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

Author: Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, J, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomaki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Freeman, LEB, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, N, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Guenel, P, Gutierrez-Barrera, AM, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hopper, JL, Hosgood, HD, Howell, A, Hu, C, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Karlan, BY, Khusnutdinova, E, Kitahara, CM, Konstantopoulou, I, Koutros, S, Kraft, P, Lambrechts, D, Lazaro, C, Le Marchand, L, Lester, J, Lesueur, F, Lilyquist, J, Loud, JT, Lu, KH, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Maurer, T, Mavroudis, D, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Montagna, M, Nathanson, KL, Neuhausen, SL, Newman, WG, Nguyen-Dumont, T, Nielsen, FC, Nielsen, S, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Peissel, B, Peixoto, A, Peto, J, Plaseska-Karanfilska, D, Pocza, T, Presneau, N, Angel Pujana, M, Punie, K, Rack, B, Rantala, J, Rashid, MU, Rau-Murthy, R, Rennert, G, Lejbkowicz, F, Rhenius, V, Romero, A, Rookus, MA, Ross, EA, Rossing, M, Rudaitis, V, Ruebner, M, Saloustros, E, Sanden, K, Santamarina, M, Scheuner, MT, Schmutzler, RK, Schneider, M, Scott, C, Senter, L, Shah, M, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Steele, L, Stoppa-Lyonnet, D, Tapper, WJ, Teixeira, MR, Terry, MB, Thomassen, M, Thompson, J, Thull, DL, Tischkowitz, M, Tollenaar, RAEM, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, 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S, Arnold, L, Kefford, R, Kirk, J, Rickard, E, Bastick, P, Beesley, J, Hayward, N, Spurdle, A, Walker, L, Beilby, J, Saunders, C, Bennett, I, Blackburn, A, Bogwitz, M, Gaff, C, Lindeman, G, Pachter, N, Sexton, A, Visvader, J, Taylor, J, Winship, I, Brennan, M, Brown, M, French, J, Edwards, S, Burgess, M, Burke, J, Patterson, B, Butow, P, Culling, B, Caldon, L, Callen, D, Chauhan, D, Eisenbruch, M, Heiniger, L, Chauhan, M, Christian, A, Dixon, J, Kidd, A, Cohen, P, Colley, A, Fenton, G, Crook, A, Dickson, R, Field, M, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dudding, T, Edkins, T, Farshid, G, Flanagan, J, Fong, P, Forrest, L, Gallego-Ortega, D, George, P, Gill, G, Kollias, J, Haan, E, Hart, S, Jenkins, M, Hunt, C, Lakhani, S, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, O'Connell, S, O'Sullivan, S, Pieper, E, Robinson, B, Saunus, J, Scott, E, Shelling, A, Williams, R, Young, MA, Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, J, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomaki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Freeman, LEB, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, N, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, 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Walker, L, Beilby, J, Saunders, C, Bennett, I, Blackburn, A, Bogwitz, M, Gaff, C, Lindeman, G, Pachter, N, Sexton, A, Visvader, J, Taylor, J, Winship, I, Brennan, M, Brown, M, French, J, Edwards, S, Burgess, M, Burke, J, Patterson, B, Butow, P, Culling, B, Caldon, L, Callen, D, Chauhan, D, Eisenbruch, M, Heiniger, L, Chauhan, M, Christian, A, Dixon, J, Kidd, A, Cohen, P, Colley, A, Fenton, G, Crook, A, Dickson, R, Field, M, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dudding, T, Edkins, T, Farshid, G, Flanagan, J, Fong, P, Forrest, L, Gallego-Ortega, D, George, P, Gill, G, Kollias, J, Haan, E, Hart, S, Jenkins, M, Hunt, C, Lakhani, S, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, O'Connell, S, O'Sullivan, S, Pieper, E, Robinson, B, Saunus, J, Scott, E, Shelling, A, Williams, R, and Young, MA
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
Published: 2019

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

Author: Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, and Yip, D
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Published: 2019

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

Author: Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, Schmidt, MK, Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, and Schmidt, MK
Abstract: BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Published: 2019

31. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Author: Mavaddat, N, Michailidou, K, Dennis, J, Lush, M, Fachal, L, Lee, A, Tyrer, JP, Chen, T-H, Wang, Q, Bolla, MK, Yang, X, Adank, MA, Ahearn, T, Aittomaki, K, Allen, J, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Auer, PL, Auvinen, P, Barrdahl, M, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Bremer, M, Brenner, H, Brentnall, A, Brock, IW, Brooks-Wilson, A, Brucker, SY, Bruening, T, Burwinkel, B, Campa, D, Carter, BD, Castelao, JE, Chanock, SJ, Chlebowski, R, Christiansen, H, Clarke, CL, Collee, JM, Cordina-Duverger, E, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Foersti, A, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Gilyazova, IR, Glendon, G, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Gronwald, J, Grundy, A, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hankinson, SE, Harkness, EF, Hart, SN, He, W, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Jakimovska, M, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kaczmarek, K, Kataja, V, Keeman, R, Kerin, MJ, Khusnutdinova, E, Kiiski, J, Knight, JA, Ko, Y-D, Kosma, V-M, Koutros, S, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Lilyquist, J, Lindblom, A, Lindstrom, S, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lubinski, J, Lux, MP, MacInnis, RJ, Maishman, T, Makalic, E, Kostovska, IM, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Menon, U, Middha, P, Miller, N, Moreno, F, Mulligan, AM, Mulot, C, Munoz-Garzon, VM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, Offit, K, Olson, JE, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Peto, J, Pinchev, M, Plaseska-Karanfilska, D, Polley, EC, Prentice, R, Presneau, N, Prokofyeva, D, Purrington, K, Pylkas, K, Rack, B, Radice, P, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Robson, M, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schuermann, P, Schwentner, L, Scott, C, Scott, RJ, Seynaeve, C, Shah, M, Sherman, ME, Shrubsole, MJ, Shu, X-O, Slager, S, Smeets, A, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Stegmaier, C, Stone, J, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tzardi, M, Ulmer, H-U, Untch, M, Vachon, CM, van Veen, EM, Vijai, J, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zhang, Y, Zheng, W, Ziogas, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Sexton, A, Dobrovic, A, Christian, A, Trainer, A, Fellows, A, Shelling, A, De Fazio, A, Blackburn, A, Crook, A, Meiser, B, Patterson, B, Saunders, C, Hunt, C, Amor, D, Ortega, DG, Edkins, E, Salisbury, E, Haan, E, Macrea, F, Farshid, G, Lindeman, G, Trench, G, Mann, G, Giles, G, Gill, G, Thorne, H, Campbell, I, Hickie, I, Caldon, L, Winship, I, Cui, J, Flanagan, J, Kollias, J, Visvader, J, Taylor, J, Burke, J, Saunus, J, Forbs, J, Hopper, J, Beesley, J, Kirk, J, French, J, Tucker, K, Wu, K, Phillips, K, Forrest, L, Lipton, L, Andrews, L, Lobb, L, Walker, L, Kentwell, M, Spurdle, M, Cummings, M, Gleeson, M, Harris, M, Jenkins, M, Young, MA, Delatycki, M, Wallis, M, Burgess, M, Brown, M, Southey, M, Bogwitz, M, Field, M, Friedlander, M, Gattas, M, Saleh, M, Aghmesheh, M, Hayward, N, Pachter, N, Cohen, P, Duijf, P, James, P, Fong, P, Butow, P, Williams, R, Kefford, R, Simard, J, Balleine, R-M, Dawson, S-J, Lok, S, O'connell, S, Greening, S, Nightingale, S, Edwards, S, Fox, S, McLachlan, S-A, Lakhani, S, Dudding, T, Antill, Y, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dunning, AM, Thompson, DJ, Chenevix-Trench, G, Chang-Claude, J, Schmidt, MK, Hall, P, Milne, RL, Pharoah, PDP, Antoniou, AC, Chatterjee, N, Kraft, P, Garcia-Closas, M, Easton, DF, Mavaddat, N, Michailidou, K, Dennis, J, Lush, M, Fachal, L, Lee, A, Tyrer, JP, Chen, T-H, Wang, Q, Bolla, MK, Yang, X, Adank, MA, Ahearn, T, Aittomaki, K, Allen, J, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Auer, PL, Auvinen, P, Barrdahl, M, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Bremer, M, Brenner, H, Brentnall, A, Brock, IW, Brooks-Wilson, A, Brucker, SY, Bruening, T, Burwinkel, B, Campa, D, Carter, BD, Castelao, JE, Chanock, SJ, Chlebowski, R, Christiansen, H, Clarke, CL, Collee, JM, Cordina-Duverger, E, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Foersti, A, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Gilyazova, IR, Glendon, G, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Gronwald, J, Grundy, A, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hankinson, SE, Harkness, EF, Hart, SN, He, W, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Jakimovska, M, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kaczmarek, K, Kataja, V, Keeman, R, Kerin, MJ, Khusnutdinova, E, Kiiski, J, Knight, JA, Ko, Y-D, Kosma, V-M, Koutros, S, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Lilyquist, J, Lindblom, A, Lindstrom, S, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lubinski, J, Lux, MP, MacInnis, RJ, Maishman, T, Makalic, E, Kostovska, IM, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Menon, U, Middha, P, Miller, N, Moreno, F, Mulligan, AM, Mulot, C, Munoz-Garzon, VM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, Offit, K, Olson, JE, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Peto, J, Pinchev, M, Plaseska-Karanfilska, D, Polley, EC, Prentice, R, Presneau, N, Prokofyeva, D, Purrington, K, Pylkas, K, Rack, B, Radice, P, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Robson, M, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schuermann, P, Schwentner, L, Scott, C, Scott, RJ, Seynaeve, C, Shah, M, Sherman, ME, Shrubsole, MJ, Shu, X-O, Slager, S, Smeets, A, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Stegmaier, C, Stone, J, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tzardi, M, Ulmer, H-U, Untch, M, Vachon, CM, van Veen, EM, Vijai, J, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zhang, Y, Zheng, W, Ziogas, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Sexton, A, Dobrovic, A, Christian, A, Trainer, A, Fellows, A, Shelling, A, De Fazio, A, Blackburn, A, Crook, A, Meiser, B, Patterson, B, Saunders, C, Hunt, C, Amor, D, Ortega, DG, Edkins, E, Salisbury, E, Haan, E, Macrea, F, Farshid, G, Lindeman, G, Trench, G, Mann, G, Giles, G, Gill, G, Thorne, H, Campbell, I, Hickie, I, Caldon, L, Winship, I, Cui, J, Flanagan, J, Kollias, J, Visvader, J, Taylor, J, Burke, J, Saunus, J, Forbs, J, Hopper, J, Beesley, J, Kirk, J, French, J, Tucker, K, Wu, K, Phillips, K, Forrest, L, Lipton, L, Andrews, L, Lobb, L, Walker, L, Kentwell, M, Spurdle, M, Cummings, M, Gleeson, M, Harris, M, Jenkins, M, Young, MA, Delatycki, M, Wallis, M, Burgess, M, Brown, M, Southey, M, Bogwitz, M, Field, M, Friedlander, M, Gattas, M, Saleh, M, Aghmesheh, M, Hayward, N, Pachter, N, Cohen, P, Duijf, P, James, P, Fong, P, Butow, P, Williams, R, Kefford, R, Simard, J, Balleine, R-M, Dawson, S-J, Lok, S, O'connell, S, Greening, S, Nightingale, S, Edwards, S, Fox, S, McLachlan, S-A, Lakhani, S, Dudding, T, Antill, Y, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dunning, AM, Thompson, DJ, Chenevix-Trench, G, Chang-Claude, J, Schmidt, MK, Hall, P, Milne, RL, Pharoah, PDP, Antoniou, AC, Chatterjee, N, Kraft, P, Garcia-Closas, M, and Easton, DF
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Published: 2019

32. Prognostic value of fever grade combined with neutrophil percentage in hepatocellular carcinoma patients presenting fever as the initial manifestation

Author: Gong ZJ, Guo W, Sun YF, Zhang X, Qiu SJ, Zhou J, Fan J, and Yang XR
Subjects: Fever, Hepatocellular carcinoma, Neutrophils, Hepatectomy, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282
Abstract: Zi-Jun Gong,1,2 Wei Guo,1–3 Yun-Fan Sun,1,2 Xin Zhang,1,2 Shuang-Jian Qiu,1,2 Jian Zhou,1,2,4Jia Fan,1,2,4 Xin-Rong Yang1,2 1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People’s Republic of China; 3Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China Background: Hepatocellular carcinoma (HCC) patients with fever as the initial presentation are extremely rare. Our aim was to investigate the clinical characteristics and prognosis of patients with this disease.Patients and methods: The clinical features were analyzed in a retrospective study of 63 HCC patients with fever as the first manifestation and 300 HCC patients without fever as the control group.Results: HCC patients with fever had a higher neutrophil percentage, larger tumor size, worse tumor differentiation, advanced Barcelona Clinic Liver Cancer stage, and more hilar lymph node metastasis than HCC patients without fever (all P70%, fever grade ≥38.5°C, tumor size >5cm, and hilar lymph node metastasis were independent factors for OS and TTR. A positive correlation was observed between body temperature and serum neutrophil percentage (r=0.527, P70% presented with more incomplete encapsulation, vascular invasion, and worse tumor differentiation. Patients with a fever grade ≥38.5°C combined with a neutrophil percentage >70% had worse OS and TTR than other groups.Conclusion: HCC patients presenting with fever have poorer prognosis than those without fever; however, their prognosis could be improved by timely surgical intervention. Patients with a neutrophil percentage >70% and a fever grade ≥38.5°C represent a rare HCC subgroup with an extremely dismal outcome and more aggressive clinical course. Keywords: hepatocellular carcinoma, fever, neutrophils, prognosis, hepatectomy
Published: 2016

33. Abstract P1-09-12: TP53 expression in relation to clinical and etiologic factors in breast cancer subtypes

Author: Yang, XR, primary, Abubakar, M, additional, Guo, C, additional, Koka, H, additional, Sung, H, additional, Guida, J, additional, Deng, J, additional, Zhou, B, additional, Hu, N, additional, and Lu, N, additional
Published: 2019
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34. A comprehensive analysis of polymorphic variants in steroid hormone and insulin-like growth factor-1 metabolism and risk of in situ breast cancer: Results from the Breast and Prostate Cancer Cohort Consortium

Author: Barrdahl, M, Canzian, F, Gaudet, MM, Gapstur, SM, Trichopoulou, A, Tsilidis, K, van Gils, CH, Borgquist, S, Weiderpass, E, Khaw, K-T, Giles, GG, Milne, RL, Le Marchand, L, Haiman, C, Lindstrom, S, Kraft, P, Hunter, DJ, Ziegler, R, Chanock, SJ, Yang, XR, Buring, JE, Lee, I-M, Kaaks, R, Campa, D, Barrdahl, M, Canzian, F, Gaudet, MM, Gapstur, SM, Trichopoulou, A, Tsilidis, K, van Gils, CH, Borgquist, S, Weiderpass, E, Khaw, K-T, Giles, GG, Milne, RL, Le Marchand, L, Haiman, C, Lindstrom, S, Kraft, P, Hunter, DJ, Ziegler, R, Chanock, SJ, Yang, XR, Buring, JE, Lee, I-M, Kaaks, R, and Campa, D
Abstract: We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and insulin-like growth factor 1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was carried out using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (ORhom = 3.05, 95%CI = 1.72-5.44, Phom = 1.47 × 10-4 ), MAST2-rs12124649 (ORhom = 1.73, 95% CI =1.18-2.54, Phom = 5.24 × 10-3 ), and INSR-rs10500204 (ORhom = 1.96, 95% CI = 1.44-2.67, Phom =1.68 × 10-5 ) were associated with increased risk of BCIS; however, only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with the risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (ORhom = 1.78, 95% CI = 1.30-2.44, Phom = 3.23 × 10-4 ). The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further.
Published: 2018

35. Optical Extinction Combined with Phase Measurements for Probing DNA−Small-Molecule Interactions Using an Evanescent Waveguide Biosensor

Author: Yang Xr, Swann Mj, Coffey Pd, Fan Yang, and Wang Ja
Subjects: Antimetabolites, Antineoplastic, Chemistry, Intercalation (chemistry), Analytical chemistry, Biosensing Techniques, DNA, Small molecule, Intercalating Agents, Dissociation (chemistry), Analytical Chemistry, Methylene Blue, Kinetics, chemistry.chemical_compound, Methotrexate, Nucleic Acid Conformation, Molecule, sense organs, Surface plasmon resonance, DNA Probes, Spectroscopy, Biosensor
Abstract: We demonstrate the use of both optical extinction and phase measurements for probing the interactions between DNA and small molecules by dual polarization interferometry. On binding to DNA at the interface, mitoxantrone (MTX) and methylene blue (MB) induced reversible concentration-dependent optical extinction due to light absorption, which clearly revealed the association and dissociation of small molecules with DNA in real time. The binding constants of MTX-DNA and MB-DNA determined from the masses derived from optical extinction are 1.8 x 10(5) and 4.2 x 10(4) M(-1), respectively, and shown to be buffer salt concentration-dependent. Apart from optical extinction, phase measurements reflected the overall change of the interaction; namely, a combined result of the binding of small molecules and any changes in DNA structure. The masses derived from phase could be very different from those derived from optical extinction. The structural changes detected by phase measurements showed a contraction and densification of DNA upon intercalation by MTX or MB. The combination of optical extinction and phase measurements allows a detailed understanding of the interaction process.
Published: 2010

36. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomaeki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Foersti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkaes, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teule, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, van Deurzen, CHM, van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, Garcia-Closas, M, Easton, DF, Antoniou, AC, Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomaeki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Foersti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkaes, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teule, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, van Deurzen, CHM, van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, Garcia-Closas, M, Easton, DF, and Antoniou, AC
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Published: 2016

37. Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers

Author: Sung, H, Garcia-Closas, M, Chang-Claude, J, Blows, FM, Ali, HR, Figueroa, J, Nevanlinna, H, Fagerholm, R, Heikkila, P, Blomqvist, C, Giles, GG, Milne, RL, Southey, MC, McLean, C, Mannermaa, A, Kosma, V-M, Kataja, V, Sironen, R, Couch, FJ, Olson, JE, Hallberg, E, Olswold, C, Cox, A, Cross, SS, Kraft, P, Tamimi, RM, Eliassen, AH, Schmidt, MK, Bolla, MK, Wang, Q, Easton, D, Howat, WJ, Coulson, P, Pharoah, PDP, Sherman, ME, Yang, XR, Sung, H, Garcia-Closas, M, Chang-Claude, J, Blows, FM, Ali, HR, Figueroa, J, Nevanlinna, H, Fagerholm, R, Heikkila, P, Blomqvist, C, Giles, GG, Milne, RL, Southey, MC, McLean, C, Mannermaa, A, Kosma, V-M, Kataja, V, Sironen, R, Couch, FJ, Olson, JE, Hallberg, E, Olswold, C, Cox, A, Cross, SS, Kraft, P, Tamimi, RM, Eliassen, AH, Schmidt, MK, Bolla, MK, Wang, Q, Easton, D, Howat, WJ, Coulson, P, Pharoah, PDP, Sherman, ME, and Yang, XR
Abstract: BACKGROUND: Luminal A breast cancer defined as hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative is known to be heterogeneous. Previous study showed that luminal A tumours with the expression of basal markers ((cytokeratin (CK) 5 or CK5/6) or epidermal growth factor receptor (EGFR)) were associated with poorer prognosis compared with those that stained negative for basal markers. Prompted by this study, we assessed whether tumour characteristics and risk factors differed by basal marker status within luminal A tumours. METHODS: We pooled 5040 luminal A cases defined by immunohistochemistry (4490 basal-negative ((CK5 (or CK5/6))- and EGFR-) and 550 basal-positive ((CK5 (or CK5/6+)) or EGFR+)) from eight studies participating in the Breast Cancer Association Consortium. Case-case comparison was performed using unconditional logistic regression. RESULTS: Tumour characteristics and risk factors did not vary significantly by the expression of basal markers, although results suggested that basal-positive luminal tumours tended to be smaller and node negative, and were more common in women with a positive family history and lower body mass index. CONCLUSIONS: Most established breast cancer risk factors were similar in basal-positive and basal-negative luminal A tumours. The non-significant but suggestive differences in tumour features and family history warrant further investigations.
Published: 2016

38. Abstract P6-10-10: Association between mammographic density and breast cancer subtypes among Chinese women

Author: Yang, XR, primary, Li, J, additional, Li, E-N, additional, Guida, JL, additional, Li, M, additional, Sung, H, additional, Lu, N, additional, Hu, N, additional, and Gierach, GL, additional
Published: 2016
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39. Duplication of CXC chemokine genes on chromosome 4q13 in a melanoma-prone family

Author: Yang, Xr, Brown, K, Landi, Mt, Ghiorzo, Paola, Badenas, C, Xu, M, Hayward, Nk, Calista, D, Landi, G, Bruno, William, Bianchi, Giovanna, Aguilera, P, Puig, S, Goldstein, Am, and Tucker, Ma
Published: 2012

40. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Author: Shi, J, Yang, Xr, Ballew, B, Rotunno, M, Calista, D, Fargnoli, Mc, Ghiorzo, P, Bressac De Paillerets, B, Nagore, E, Avril, Mf, Caporaso, Ne, Mcmaster, Ml, Cullen, M, Wang, Z, Zhang, X, Bruno, W, Pastorino, L, Queirolo, P, Banuls Roca, J, Garcia Casado, Z, Vaysse, A, Mohamdi, H, Riazalhosseini, Y, Foglio, M, Jouenne, F, Hua, X, Hyland, Pl, Yin, J, Vallabhaneni, H, Chai, W, Minghetti, P, Pellegrini, C, Ravichandran, S, Eggermont, A, Lathrop, M, Peris, Ketty, Scarra, Gb, Landi, G, Savage, Sa, Sampson, Jn, He, J, Yeager, M, Goldin, Lr, Demenais, F, Chanock, Sj, Tucker, Ma, Goldstein, Am, Liu, Y, Landi, Mt, Peris, Ketty (ORCID:0000-0002-5237-0463), Shi, J, Yang, Xr, Ballew, B, Rotunno, M, Calista, D, Fargnoli, Mc, Ghiorzo, P, Bressac De Paillerets, B, Nagore, E, Avril, Mf, Caporaso, Ne, Mcmaster, Ml, Cullen, M, Wang, Z, Zhang, X, Bruno, W, Pastorino, L, Queirolo, P, Banuls Roca, J, Garcia Casado, Z, Vaysse, A, Mohamdi, H, Riazalhosseini, Y, Foglio, M, Jouenne, F, Hua, X, Hyland, Pl, Yin, J, Vallabhaneni, H, Chai, W, Minghetti, P, Pellegrini, C, Ravichandran, S, Eggermont, A, Lathrop, M, Peris, Ketty, Scarra, Gb, Landi, G, Savage, Sa, Sampson, Jn, He, J, Yeager, M, Goldin, Lr, Demenais, F, Chanock, Sj, Tucker, Ma, Goldstein, Am, Liu, Y, Landi, Mt, and Peris, Ketty (ORCID:0000-0002-5237-0463)
Abstract: Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.
Published: 2014

41. Association of genetic variants in CDK6 and XRCC1 with the risk of dysplastic nevi in melanoma-prone families

Author: Liang, X, Pfeiffer, Rm, Li, W, Brossard, M, Burke, L, Wheeler, W, Calista, D, Fargnoli, Mc, Ghiorzo, P, Peris, Ketty, Bianchi Scarra, G, Chaudru, V, Zelenika, D, Maeder, D, Burdette, L, Yeager, M, Chanock, S, Landi, Mt, Demenais, F, Tucker, Ma, Goldstein, Am, Yang, Xr, Peris, Ketty (ORCID:0000-0002-5237-0463), Liang, X, Pfeiffer, Rm, Li, W, Brossard, M, Burke, L, Wheeler, W, Calista, D, Fargnoli, Mc, Ghiorzo, P, Peris, Ketty, Bianchi Scarra, G, Chaudru, V, Zelenika, D, Maeder, D, Burdette, L, Yeager, M, Chanock, S, Landi, Mt, Demenais, F, Tucker, Ma, Goldstein, Am, Yang, Xr, and Peris, Ketty (ORCID:0000-0002-5237-0463)
Abstract: Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation-positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.
Published: 2014

42. On the interplay of telomeres, nevi and the risk of melanoma

Author: Bodelon, C, Pfeiffer, Rm, Bollati, V, Debbache, J, Calista, D, Ghiorzo, P, Fargnoli, Mc, Bianchi Scarra, G, Peris, Ketty, Hoxha, M, Hutchinson, A, Burdette, L, Burke, L, Fang, S, Tucker, Ma, Goldstein, Am, Lee, Je, Wei, Q, Savage, Sa, Yang, Xr, Amos, C, Landi, Mt, Peris, Ketty (ORCID:0000-0002-5237-0463), Bodelon, C, Pfeiffer, Rm, Bollati, V, Debbache, J, Calista, D, Ghiorzo, P, Fargnoli, Mc, Bianchi Scarra, G, Peris, Ketty, Hoxha, M, Hutchinson, A, Burdette, L, Burke, L, Fang, S, Tucker, Ma, Goldstein, Am, Lee, Je, Wei, Q, Savage, Sa, Yang, Xr, Amos, C, Landi, Mt, and Peris, Ketty (ORCID:0000-0002-5237-0463)
Abstract: The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
Published: 2012

43. Abstract P3-08-02: Common variants at 10p14 and 1p11.2 display heterogeneity in breast cancer associations by E-cadherin tumor tissue expression in two independent datasets

Author: Horne, HN, primary, Sherman, ME, additional, Garcia-Closas, M, additional, Pharoah, PD, additional, Blows, FM, additional, Yang, XR, additional, Lissowska, J, additional, Brinton, LA, additional, Chanock, SJ, additional, and Figueroa, JD, additional
Published: 2012
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44. Association analysis identifies 65 new breast cancer risk loci

Author: Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Brinton, L, Broberg, P, Brock, IW, Broeks, A, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Butterbach, K, Cai, Q, Cai, H, Caldés, T, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chan, TL, David Cheng, T-Y, Seng Chia, K, Choi, J-Y, Christiansen, H, Clarke, CL, NBCS Collaborators, Collée, M, Conroy, DM, Cordina-Duverger, E, Cornelissen, S, Cox, DG, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Elvira, M, Engel, C, Eriksson, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gaborieau, V, Gabrielson, M, Gago-Dominguez, M, Gao, Y-T, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hamel, N, Hankinson, S, Harrington, P, Hart, SN, Hartikainen, JM, Hartman, M, Hein, A, Heyworth, J, Hicks, B, Hillemanns, P, Ho, DN, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Hou, M-F, Hsiung, C-N, Huang, G, Humphreys, K, Ishiguro, J, Ito, H, Iwasaki, M, Iwata, H, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, M, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kang, D, Kasuga, Y, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kim, S-W, Knight, JA, Kosma, V-M, Kristensen, VN, Krüger, U, Kwong, A, Lambrechts, D, Le Marchand, L, Lee, E, Lee, MH, Lee, JW, Neng Lee, C, Lejbkowicz, F, Li, J, Lilyquist, J, Lindblom, A, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lophatananon, A, Lubinski, J, Luccarini, C, Lux, MP, Ma, ESK, MacInnis, RJ, Maishman, T, Makalic, E, Malone, KE, Kostovska, IM, Mannermaa, A, Manoukian, S, Manson, JE, Margolin, S, Mariapun, S, Martinez, ME, Matsuo, K, Mavroudis, D, McKay, J, McLean, C, Meijers-Heijboer, H, Meindl, A, Menéndez, P, Menon, U, Meyer, J, Miao, H, Miller, N, Taib, NAM, Muir, K, Mulligan, AM, Mulot, C, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Noh, D-Y, Nordestgaard, BG, Norman, A, Olopade, OI, Olson, JE, Olsson, H, Olswold, C, Orr, N, Pankratz, VS, Park, SK, Park-Simon, T-W, Lloyd, R, Perez, JIA, Peterlongo, P, Peto, J, Phillips, K-A, Pinchev, M, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Prokofyeva, D, Pugh, E, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Ruddy, KJ, Rüdiger, T, Rudolph, A, Ruebner, M, Rutgers, EJT, Saloustros, E, Sandler, DP, Sangrajrang, S, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Scott, RJ, Scott, C, Seal, S, Seynaeve, C, Shah, M, Sharma, P, Shen, C-Y, Sheng, G, Sherman, ME, Shrubsole, MJ, Shu, X-O, Smeets, A, Sohn, C, Southey, MC, Spinelli, JJ, Stegmaier, C, Stewart-Brown, S, Stone, J, Stram, DO, Surowy, H, Swerdlow, A, Tamimi, R, Taylor, JA, Tengström, M, Teo, SH, Beth Terry, M, Tessier, DC, Thanasitthichai, S, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Tong, L, Torres, D, Truong, T, Tseng, C-C, Tsugane, S, Ulmer, H-U, Ursin, G, Untch, M, Vachon, C, Van Asperen, CJ, Van Den Berg, D, Van Den Ouweland, AMW, Van Der Kolk, L, Van Der Luijt, RB, Vincent, D, Vollenweider, J, Waisfisz, Q, Wang-Gohrke, S, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Wu, AH, Xia, L, Yamaji, T, Yang, XR, Har Yip, C, Yoo, K-Y, Yu, J-C, Zheng, W, Zheng, Y, Zhu, B, Ziogas, A, Ziv, E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani, Antoniou, AC, Droit, A, Andrulis, IL, Amos, CI, Couch, FJ, Pharoah, PDP, Chang-Claude, J, Hall, P, Hunter, DJ, Milne, RL, García-Closas, M, Schmidt, MK, Chanock, SJ, Dunning, AM, Edwards, SL, Bader, GD, Chenevix-Trench, G, Simard, J, Kraft, P, and Easton, DF
Subjects: ConFab/AOCS Investigators, ABCTB Investigators, skin and connective tissue diseases, 3. Good health, NBCS Collaborators
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

45. Chronic hypoxia upregulates transient receptor potential channels in rat pulmonary arterial myocytes

Author: Lin, Mj, Leung, Gph, Zhang, Wm, Shimoda, La, Yang, Xr, Kay-Pong Yip, Tse, Cm, and Sham, Jsk

46. Chronic hypoxia up-regulates store-and receptor-operated Ca2+ channels in rat pulmonary arterial smooth muscle cells

Author: Lin, Mj, Leung, Gp, Zhang, Wm, Shimoda, La, Yang, Xr, Kay-Pong Yip, Tse, Cm, and Sham, Js

47. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomäki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, De La Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Försti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Gronwald, J, Guénel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkäs, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teulé, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, Van Deurzen, CHM, Van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, García-Closas, M, Easton, DF, and Antoniou, AC
Subjects: Heterozygote, tRNA Methyltransferases, Genotype, BRCA1 Protein, Breast Neoplasms, Polymorphism, Single Nucleotide, 3. Good health, Cyclophilins, Receptors, Estrogen, Risk Factors, Chromosomes, Human, Pair 2, Mutation, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms11375, Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P

48. Peripheral CD4 + T cell phenotype and brain microglial activation associated with cognitive heterogeneity in aged rats.

Author: Yu L, Liu MM, Guan MQ, Wang R, Yang XR, Zhang XM, Wei JJ, Wu SF, Gu H, Fu Q, Guo JH, and Li YL
Abstract: Cognitive decline is a critical hallmark of brain aging. Although aging is a natural process, there is significant heterogeneity in cognition levels among individuals; however, the underlying mechanisms remain uncertain. In our study, we classified aged male Sprague‒Dawley rats into aged cognition-unimpaired (AU) group and aged cognition-impaired (AI) group by using an attentional set-shifting task. The transcriptome sequencing results of medial prefrontal cortex (mPFC) demonstrated significant differences in microglial activation and inflammatory response pathways between the two groups. Specifically, compared to AU rats, AI rats exhibited a greater presence of CD86-positive microglia and major histocompatibility complex class II (MHC-II)-positive microglia, along with elevated inflammatory molecules, in mPFC. Conversely, AI rats exhibited a reduction in the percentage of microglia expressing CD200R and the anti-inflammatory molecules Arg-1 and TGF-β. Additionally, peripheral blood analysis of AI rats demonstrated elevated levels of Th17 and Th1 cells, along with proinflammatory molecules; however, decreased levels of Treg cells, along with anti-inflammatory molecules, were observed in AI rats. Our research suggested that peripheral Th17/Treg cells and central microglial activation were associated with cognitive heterogeneity in aged rats. These findings may provide a new target for healthy aging., Competing Interests: Declarations Ethical approval The study was approved by Ethics Committee of First Hospital of Shanxi Medical University (DWLL-2023-006). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)
Published: 2024
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49. Mammographic density in relation to breast cancer risk factors among Chinese women.

Author: Koka H, Tian Y, Deng L, Yu K, Li EN, Guo C, Guida JL, Sung H, Chan A, Hu N, Lu N, Gierach GL, Li J, and Yang XR
Abstract: Background Increased mammographic density (MD) is a known breast cancer (BC) risk factor, but its influencing factors are unclear in Asian populations. This study examined the links between known BC risk factors and quantitatively measured MD in 7,351 Chinese women with non-malignant mammographic findings. Methods VolparaDensity software quantified volumetric MD measures: total breast (TBV), absolute dense (ADV), percent dense (PDV= ADV/TBV), and non-dense volumes (NDV= TBV-ADV). Multivariable linear regression models assessed associations between these MD metrics and BC risk factors. Results The mean age of the population was 50.1 (SD=8.3) years. The mean ADV, NDV, and PDV were 58.4 (SD=32.1), 382.8 (SD=202.0) cm³ and 14.8 (SD=7.1) %, respectively. PDV was inversely associated with age, weight, body mass index (BMI), parity, breastfeeding duration, and postmenopausal status, but positively linked to height and age at menopause. NDV showed opposite associations. ADV had similar associations to PDV, except for height, weight, and BMI, which differed for women with the lowest NDV. PDV associations with age at menarche, age at first birth, and breastfeeding duration varied by BMI and menopausal status. Conclusions MD may influence the relationship between reproductive factors and BC risk, depending on MD measure, menopausal status, and BMI. Impact This study examines how quantitative MD measures relate to known BC risk factors in an East Asian population, factoring in menopausal status and BMI. The results underscore the complex role of MD and confounding factors in BC risk, highlighting the need for tailored insights for future research and screening.
Published: 2024
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50. Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

Author: Liu SJ, Yan LJ, Wang HC, Ding ZN, Liu H, Zhang X, Pan GQ, Han CL, Tian BW, Yang XR, Tan SY, Dong ZR, Wang DX, Yan YC, and Li T
Subjects: Humans, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors adverse effects, Neoplasms drug therapy, Neoplasms mortality
Abstract: Backgrounds: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer., Methods: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest., Results: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05)., Conclusion: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings., (© The Author(s) 2024. Published by Oxford University Press.)
Published: 2024
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