| Authors: |
Zhang, H.; Ahearn, T. U.; Lecarpentier, J.; Barnes, D.; Beesley, J.; Qi, G.; Jiang, X.; O’Mara, T. A.; Zhao, N.; Bolla, M. K.; Dunning, A. M.; Dennis, J.; Wang, Q.; Ful, Z. A.; Aittomäki, K.; Andrulis, I. L.; Anton-Culver, H.; Arndt, V.; Aronson, K. J.; Arun, B. K.; Auer, P. L.; Azzollini, J.; Barrowdale, D.; Becher, H.; Beckmann, M. W.; Behrens, S.; Benitez, J.; Bermisheva, M.; Bialkowska, K.; Blanco, A.; Blomqvist, C.; Bogdanova, N. V.; Bojesen, S. E.; Bonanni, B.; Bondavalli, D.; Borg, A.; Brauch, H.; Brenner, H.; Briceno, I.; Broeks, A.; Brucker, S. Y.; Brüning, T.; Burwinkel, B.; Buys, S. S.; Byers, H.; Caldés, T.; Caligo, M. A.; Calvello, M.; Campa, D.; Castelao, J. E.; Chang-Claude, J.; Chanock, S. J.; Christiaens, M.; Christiansen, H.; Chung, W. K.; Claes, K. B. M.; Clarke, C. L.; Cornelissen, S.; Couch, F. J.; Cox, A.; Cross, S. S.; Czene, K.; Daly, M. B.; Devilee, P.; Diez, O.; Domchek, S. M.; Dörk, T.; Dwek, M.; Eccles, D. M.; Ekici, A. B.; Evans, D. G.; Fasching, P. A.; Figueroa, J.; Foretova, L.; Fostira, F.; Friedman, E.; Frost, D.; Gago-Dominguez, M.; Gapstur, S. M.; Garber, J.; García-Sáenz, J. A.; Gaudet, M. M.; Gayther, S. A.; Giles, G. G.; Godwin, A. K.; Goldberg, M. S.; Goldgar, D. E.; González-Neira, A.; Greene, M. H.; Gronwald, J.; Guénel, P.; Häberle, L.; Hahnen, E.; Haiman, C. A.; Hake, C. R.; Hall, P.; Hamann, U.; Harkness, E. F.; Heemskerk-Gerritsen, B. A. M.; Hillemanns, P.; Hogervorst, F. B. L.; Holleczek, B.; Hollestelle, A.; Hooning, M. J.; Hoover, R. N.; Hopper, J. L.; Howell, A.; Huebner, H.; Hulick, P. J.; Imyanitov, E. N.; kConFab Investigators; ABCTB Investigators; Isaacs, C.; Izatt, L.; Jager, A.; Jakimovska, M.; Jakubowska, A.; James, P.; Janavicius, R.; Janni, W.; John, E. M.; Jones, M. E.; Jung, A.; Kaaks, R.; Kapoor, P. M.; Karlan, B. Y.; Keeman, R.; Khan, S.; Khusnutdinova, E.; Kitahara, C. M.; Ko, Y. D.; Konstantopoulou, I.; Koppert, L. B.; Koutros, S.; Kristensen, V. N.; Laenkholm, A. V.; Lambrechts, D.; Larsson, S. C.; Laurent-Puig, P.; Lazaro, C.; Lazarova, E.; Lejbkowicz, F.; Leslie, G.; Lesueur, F.; Lindblom, A.; Lissowska, J.; Lo, W. Y.; Loud, J. T.; Lubinski, J.; Lukomska, A.; MacInnis, R. J.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Martinez, M. E.; Matricardi, L.; McGuffog, L.; McLean, C.; Mebirouk, N.; Meindl, A.; Menon, U.; Miller, A.; Mingazheva, E.; Montagna, M.; Mulligan, A. M.; Mulot, C.; Muranen, T. A.; Nathanson, K. L.; Neuhausen, S. L.; Nevanlinna, H.; Neven, P.; Newman, W. G.; Nielsen, F. C.; Nikitina-Zake, L.; Nodora, J.; Offit, K.; Olah, E.; Olopade, O. I.; Olsson, H.; Orr, N.; Papi, L.; Papp, J.; Park-Simon, T. W.; Parsons, M. T.; 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, S. J.; Rantala, J.; Rashid, M. U.; Rennert, G.; Rennert, H. S.; Risch, H. A.; Romero, A.; Rookus, M. A.; Rübner, M.; Rüdiger, T.; Saloustros, E.; Sampson, S.; Sandler, D. P.; Sawyer, E. J.; Scheuner, M. T.; Schmutzler, R. K.; Schneeweiss, A.; Schoemaker, M. J.; Schöttker, B.; Schürmann, P.; Senter, L.; Sharma, P.; Sherman, M. E.; Shu, X. O.; Singer, C. F.; Smichkoska, S.; Soucy, P.; Southey, M. C.; Spinelli, J. J.; Stone, J.; Stoppa-Lyonnet, D.; EMBRACE Study; GEMO Study Collaborators; Swerdlow, A. J.; Szabo, C. I.; Tamimi, R. M.; Tapper, W. J.; Taylor, J. A.; Teixeira, M. R.; Terry, M. B.; Thomassen, M.; Thull, D. L.; Tischkowitz, M.; Toland, A. E.; Tollenaar, R. A. E. M.; Tomlinson, I.; Torres, D.; Troester, M. A.; Truong, T.; Tung, N.; Untch, M.; Vachon, C. M.; van den Ouweland, A. M. W.; van der Kolk, L. E.; van Veen, E. M.; vanRensburg, E. J.; Vega, A.; Wappenschmidt, B.; Weinberg, C. R.; Weitzel, J. N.; Wildiers, H.; Winqvist, R.; Wolk, A.; Yang, X. R.; Yannoukakos, D.; Zheng, W.; Zorn, K. K.; Milne, R. L.; Kraft, P.; Simard, J.; Pharoah, P. D. P.; Michailidou, K.; Antoniou, A. C.; Schmidt, M. K.; Chenevix-Trench, G.; Easton, D. F.; Chatterjee, N.; García-Closas, M. |
| Title: |
Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses |
| 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. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: |
adult; controlled study; gene mutation; major clinical study; case control study; cancer susceptibility; breast cancer; epidermal growth factor receptor 2; gene locus; genetic variability; genotype; genome-wide association study; brca1 protein; heterozygote; tumor marker; risk assessment; genetic susceptibility; histone h3; carcinoma in situ; estrogen receptor; progesterone receptor; computer model; genetic predisposition; tumor classification; genetic heterogeneity; genetic correlation; enhancer region; triple negative breast cancer; histone modification; gene linkage disequilibrium; european; estrogen receptor positive breast cancer; human; female; priority journal; article; estrogen receptor negative breast cancer; luminal b breast cancer; genetic risk score; chromatin immunoprecipitation sequencing
|
| Journal Title: |
Nature Genetics
|
| Volume: |
52 |
| Issue: |
6 |
| ISSN: |
1061-4036 |
| Publisher: |
Nature Publishing Group
|
| Date Published: |
2020-06-01 |
| Start Page: |
572 |
| End Page: |
581 |
| Language: |
English |
| DOI: |
10.1038/s41588-020-0609-2
|
| PUBMED: |
32424353
|
| PROVIDER: |
scopus
|
| PMCID: |
PMC7808397
|
| DOI/URL: |
|
| Notes: |
Article -- Export Date: 1 July 2020 -- Source: Scopus |
