Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Michailidou, Kyriaki; Beesley, Jonathan; Lindström, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael; Maranian, Mel; Bolla, Manjeet K.; Wang, Qin; Shah, Mitul; Perkins, Barbara; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S.; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Nielsen, Sune F.; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos‐Santos‐Silva, Isabel; Chang‐Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G.; Whittemore, Alice S.; John, Esther M.; Malone, Kathleen E.; Gammon, Marilie D.; Santella, Regina M.; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F.; Casey, Graham; Hunter, David J.; Gapstur, Susan M.; Gaudet, Mia M.; Diver, W. Ryan; Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Marchand, Loı̈c Le; Berg, Christine D.; Chanock, Stephen J.; Figueroa, Jonine D.; Hoover, Robert N.; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; Limbergen, Erik; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine M.; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A.; Luijt, Rob B. van der; Li, Jingmei; Liu, Jing; Humphreys, Keith; Kang, Daehee; Choi, Ji‐Yeob; Park, Sue Kyung; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guénel, Pascal; Truong, Thérèse; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marmé, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H.; Tseng, Chiu-Chen; Berg, David Van Den; Stram, Daniel O.; González‐Neira, Anna; Benı́tez, Javier; Zamora, M. Pilar; Peŕez, José Ignacio Arias; Shu, Xiao‐Ou; Lü, Wei; Gao, Yu‐Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; Tan, Gie-Hooi; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W.M.; Collée, J. Margriet; Blot, William J.; Signorello, Lisa B.; Cai, Qiuyin; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen‐Yang; Hsiung, Chia‐Ni; Wu, Pei-Ei; Hou, Ming‐Feng; Kristensen, Vessela N.; Nord, Silje; Alnæs, Grethe I.G.; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Canzian, Federico; Trichopoulos, Dimitrios; Peeters, Petra H.M.; Lund, Eiliv; Sund, Malin; Khaw, Kay‐Tee; Gunter, Marc J.; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K.; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart‐Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Swerdlow, Anthony J.; Brinton, Louise A.; García-Closas, Montserrat; Wang, Zheng; Halverson, Sandra L.; Shrubsole, Martha J.; Long, Jirong; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli‐Matti; Hartikainen, Jaana M.; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Asperen, Christi J. van; Jakubowska, Anna; Lubiński, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valérie; Brennan, Paul; McKay, James; Slager, Susan L.; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L.; Anton‐Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Tessier, Daniel C.; Denis, Vincent; Bertucci, François; Pita, Guillermo; Alonso, María R.; Álvarez, Núria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul; Kraft, Peter; Dunning, Alison M.; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F.

doi:10.1038/ng.3242

Cited by 547 publications

(566 citation statements)

References 38 publications

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“…Rather, at the germline level, several intronic KCNN4 single nucleotide polymorphisms (SNPs) have been shown to alter women's breast cancer risk in general and particularly of ER‐positive breast cancer. The observed effect size is small, but is of genome‐wide significance ( P < 10 −6 ) (Lo et al ., 2016; Michailidou et al ., 2015). How the genetic variants affect SK4 expression in normal breast tissue and breast tumour is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.

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Section: Discussionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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“…1,2 Because the majority of identified SNPs fall outside of protein-coding regions, 3 a major challenge is determining how genetic variation in these regions contributes to disease. Several studies have shown that GWAS SNPs are enriched in regulatory regions and can influence the expression of nearby protein-coding genes.…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Betts

Marjaneh

Al-Ejeh

et al. 2017

The American Journal of Human Genetics

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Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

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“…7 Other high-risk susceptibility genes such as TP53, PTEN, CDH1, STK11 and PALB2 have been identified, as well as a number of intermediate-risk genes such as ATM, CHEK2, NBN and NF1, and close to 100 low-risk alleles. 8,9 Despite this, all in all, only about 50% of the excess risk is explained today. Evidence is starting to emerge that some breast cancer genes may harbour different types of variants with inversely correlated cancer risks and allele frequencies: for example, BRCA2 and TP53, on top of a myriad of high-risk rare variants, also harbour more frequent variants associated with lower breast cancer risk, p.K3326X 10 and p.R337H, 11 respectively.…”

Section: Introductionmentioning

confidence: 99%

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

et al. 2016

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Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

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Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Cited by 547 publications

References 38 publications

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

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Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Cited by 547 publications

References 38 publications

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

Contact Info

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SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer