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. 2017 Nov 2;551(7678):92-94.
doi: 10.1038/nature24284. Epub 2017 Oct 23.

Association Analysis Identifies 65 New Breast Cancer Risk Loci

Kyriaki Michailidou  1   2 Sara Lindström  3   4 Joe Dennis  1 Jonathan Beesley  5 Shirley Hui  6 Siddhartha Kar  7 Audrey Lemaçon  8 Penny Soucy  8 Dylan Glubb  5 Asha Rostamianfar  6 Manjeet K Bolla  1 Qin Wang  1 Jonathan Tyrer  7 Ed Dicks  7 Andrew Lee  1 Zhaoming Wang  9   10 Jamie Allen  1 Renske Keeman  11 Ursula Eilber  12 Juliet D French  5 Xiao Qing Chen  5 Laura Fachal  7 Karen McCue  5 Amy E McCart Reed  13 Maya Ghoussaini  7 Jason S Carroll  14 Xia Jiang  4 Hilary Finucane  4   15 Marcia Adams  16 Muriel A Adank  17 Habibul Ahsan  18 Kristiina Aittomäki  19 Hoda Anton-Culver  20 Natalia N Antonenkova  21 Volker Arndt  22 Kristan J Aronson  23 Banu Arun  24 Paul L Auer  25   26 François Bacot  27 Myrto Barrdahl  12 Caroline Baynes  7 Matthias W Beckmann  28 Sabine Behrens  12 Javier Benitez  29   30 Marina Bermisheva  31 Leslie Bernstein  32 Carl Blomqvist  33 Natalia V Bogdanova  21   34   35 Stig E Bojesen  36   37   38 Bernardo Bonanni  39 Anne-Lise Børresen-Dale  40 Judith S Brand  41 Hiltrud Brauch  42   43   44 Paul Brennan  45 Hermann Brenner  22   44   46 Louise Brinton  47 Per Broberg  48 Ian W Brock  49 Annegien Broeks  11 Angela Brooks-Wilson  50   51 Sara Y Brucker  52 Thomas Brüning  53 Barbara Burwinkel  54   55 Katja Butterbach  22 Qiuyin Cai  56 Hui Cai  56 Trinidad Caldés  57 Federico Canzian  58 Angel Carracedo  59   60 Brian D Carter  61 Jose E Castelao  62 Tsun L Chan  63   64 Ting-Yuan David Cheng  65 Kee Seng Chia  66 Ji-Yeob Choi  67   68 Hans Christiansen  34 Christine L Clarke  69 NBCS CollaboratorsMargriet Collée  70 Don M Conroy  7 Emilie Cordina-Duverger  71 Sten Cornelissen  11 David G Cox  72   73 Angela Cox  49 Simon S Cross  74 Julie M Cunningham  75 Kamila Czene  41 Mary B Daly  76 Peter Devilee  77   78 Kimberly F Doheny  16 Thilo Dörk  35 Isabel Dos-Santos-Silva  79 Martine Dumont  8 Lorraine Durcan  80   81 Miriam Dwek  82 Diana M Eccles  81 Arif B Ekici  83 A Heather Eliassen  84   85 Carolina Ellberg  48   86 Mingajeva Elvira  87 Christoph Engel  88   89 Mikael Eriksson  41 Peter A Fasching  28   90 Jonine Figueroa  47   91 Dieter Flesch-Janys  92   93 Olivia Fletcher  94 Henrik Flyger  95 Lin Fritschi  96 Valerie Gaborieau  45 Marike Gabrielson  41 Manuela Gago-Dominguez  59   97 Yu-Tang Gao  98 Susan M Gapstur  61 José A García-Sáenz  57 Mia M Gaudet  61 Vassilios Georgoulias  99 Graham G Giles  100   101 Gord Glendon  102 Mark S Goldberg  103   104 David E Goldgar  105 Anna González-Neira  29 Grethe I Grenaker Alnæs  40 Mervi Grip  106 Jacek Gronwald  107 Anne Grundy  108 Pascal Guénel  71 Lothar Haeberle  28 Eric Hahnen  109   110   111 Christopher A Haiman  112 Niclas Håkansson  113 Ute Hamann  114 Nathalie Hamel  27 Susan Hankinson  115 Patricia Harrington  7 Steven N Hart  116 Jaana M Hartikainen  117   118   119 Mikael Hartman  66   120 Alexander Hein  28 Jane Heyworth  121 Belynda Hicks  10 Peter Hillemanns  35 Dona N Ho  64 Antoinette Hollestelle  122 Maartje J Hooning  122 Robert N Hoover  47 John L Hopper  101 Ming-Feng Hou  123 Chia-Ni Hsiung  124 Guanmengqian Huang  114 Keith Humphreys  41 Junko Ishiguro  125   126 Hidemi Ito  125   126 Motoki Iwasaki  127 Hiroji Iwata  128 Anna Jakubowska  107 Wolfgang Janni  129 Esther M John  130   131   132 Nichola Johnson  94 Kristine Jones  10 Michael Jones  133 Arja Jukkola-Vuorinen  134 Rudolf Kaaks  12 Maria Kabisch  114 Katarzyna Kaczmarek  107 Daehee Kang  67   68   135 Yoshio Kasuga  136 Michael J Kerin  137 Sofia Khan  138 Elza Khusnutdinova  31   87 Johanna I Kiiski  138 Sung-Won Kim  139 Julia A Knight  140   141 Veli-Matti Kosma  117   118   119 Vessela N Kristensen  40   142   143 Ute Krüger  48 Ava Kwong  63   144   145 Diether Lambrechts  146   147 Loic Le Marchand  148 Eunjung Lee  112 Min Hyuk Lee  149 Jong Won Lee  150 Chuen Neng Lee  120   151 Flavio Lejbkowicz  152 Jingmei Li  41 Jenna Lilyquist  116 Annika Lindblom  153 Jolanta Lissowska  154 Wing-Yee Lo  42   43 Sibylle Loibl  155 Jirong Long  56 Artitaya Lophatananon  156   157 Jan Lubinski  107 Craig Luccarini  7 Michael P Lux  28 Edmond S K Ma  63   64 Robert J MacInnis  100   101 Tom Maishman  80   81 Enes Makalic  101 Kathleen E Malone  158 Ivana Maleva Kostovska  159 Arto Mannermaa  117   118   119 Siranoush Manoukian  160 JoAnn E Manson  85   161 Sara Margolin  162 Shivaani Mariapun  163 Maria Elena Martinez  97   164 Keitaro Matsuo  126   165 Dimitrios Mavroudis  99 James McKay  45 Catriona McLean  166 Hanne Meijers-Heijboer  17 Alfons Meindl  167 Primitiva Menéndez  168 Usha Menon  169 Jeffery Meyer  75 Hui Miao  66 Nicola Miller  137 Nur Aishah Mohd Taib  170 Kenneth Muir  156   157 Anna Marie Mulligan  171   172 Claire Mulot  173 Susan L Neuhausen  32 Heli Nevanlinna  138 Patrick Neven  174 Sune F Nielsen  36   37 Dong-Young Noh  175 Børge G Nordestgaard  36   37   38 Aaron Norman  116 Olufunmilayo I Olopade  176 Janet E Olson  116 Håkan Olsson  48 Curtis Olswold  116 Nick Orr  94 V Shane Pankratz  177 Sue K Park  67   68   135 Tjoung-Won Park-Simon  35 Rachel Lloyd  178 Jose I A Perez  179 Paolo Peterlongo  180 Julian Peto  79 Kelly-Anne Phillips  101   181   182   183 Mila Pinchev  152 Dijana Plaseska-Karanfilska  159 Ross Prentice  25 Nadege Presneau  82 Darya Prokofyeva  87 Elizabeth Pugh  16 Katri Pylkäs  184   185 Brigitte Rack  186 Paolo Radice  187 Nazneen Rahman  188 Gadi Rennert  152 Hedy S Rennert  152 Valerie Rhenius  7 Atocha Romero  57   189 Jane Romm  16 Kathryn J Ruddy  190 Thomas Rüdiger  191 Anja Rudolph  12 Matthias Ruebner  28 Emiel J T Rutgers  192 Emmanouil Saloustros  193 Dale P Sandler  194 Suleeporn Sangrajrang  195 Elinor J Sawyer  196 Daniel F Schmidt  101 Rita K Schmutzler  109   110   111 Andreas Schneeweiss  54   197 Minouk J Schoemaker  133 Fredrick Schumacher  198 Peter Schürmann  35 Rodney J Scott  199   200 Christopher Scott  116 Sheila Seal  188 Caroline Seynaeve  122 Mitul Shah  7 Priyanka Sharma  201 Chen-Yang Shen  202   203 Grace Sheng  112 Mark E Sherman  204 Martha J Shrubsole  56 Xiao-Ou Shu  56 Ann Smeets  174 Christof Sohn  197 Melissa C Southey  205 John J Spinelli  206   207 Christa Stegmaier  208 Sarah Stewart-Brown  156 Jennifer Stone  178   209 Daniel O Stram  112 Harald Surowy  54   55 Anthony Swerdlow  133   210 Rulla Tamimi  4   84   85 Jack A Taylor  194   211 Maria Tengström  117   212   213 Soo H Teo  163   170 Mary Beth Terry  214 Daniel C Tessier  27 Somchai Thanasitthichai  215 Kathrin Thöne  93 Rob A E M Tollenaar  216 Ian Tomlinson  217 Ling Tong  18 Diana Torres  114   218 Thérèse Truong  71 Chiu-Chen Tseng  112 Shoichiro Tsugane  219 Hans-Ulrich Ulmer  220 Giske Ursin  221   222 Michael Untch  223 Celine Vachon  116 Christi J van Asperen  224 David Van Den Berg  112 Ans M W van den Ouweland  70 Lizet van der Kolk  225 Rob B van der Luijt  226 Daniel Vincent  27 Jason Vollenweider  75 Quinten Waisfisz  17 Shan Wang-Gohrke  227 Clarice R Weinberg  228 Camilla Wendt  162 Alice S Whittemore  131   132 Hans Wildiers  174 Walter Willett  85   229 Robert Winqvist  184   185 Alicja Wolk  113 Anna H Wu  112 Lucy Xia  112 Taiki Yamaji  127 Xiaohong R Yang  47 Cheng Har Yip  230 Keun-Young Yoo  231   232 Jyh-Cherng Yu  233 Wei Zheng  56 Ying Zheng  234 Bin Zhu  10 Argyrios Ziogas  20 Elad Ziv  235 ABCTB InvestigatorsConFab/AOCS InvestigatorsSunil R Lakhani  13   236 Antonis C Antoniou  1 Arnaud Droit  8 Irene L Andrulis  102   237 Christopher I Amos  238 Fergus J Couch  75 Paul D P Pharoah  1   7 Jenny Chang-Claude  12   239 Per Hall  41   240 David J Hunter  4   85 Roger L Milne  100   101 Montserrat García-Closas  47 Marjanka K Schmidt  11   241 Stephen J Chanock  47 Alison M Dunning  7 Stacey L Edwards  5 Gary D Bader  6 Georgia Chenevix-Trench  5 Jacques Simard  8 Peter Kraft  4   85 Douglas F Easton  1   7
Affiliations
Free PMC article

Association Analysis Identifies 65 New Breast Cancer Risk Loci

Kyriaki Michailidou et al. Nature. .
Free PMC article

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.

Conflict of interest statement

The authors confirm that they have no competing financial interests.

Figures

Extended data Figure 1
Extended data Figure 1. Global mapping of biofeatures across novel loci associated with overall breast cancer risk.
The overlaps between potential genomic predictors in relevant breast cell lines and candidate causal risk variants (CRVs) within each locus. On the x-axis, each column represents a CRV (see Online Methods). The most significant SNPs are identified in each region. On the y-axis, biofeatures are grouped into five functional categories: genomic structure (red), enhancer marks (dark green), histone marks (blue), open chromatin marks (dark blue) and transcription factor binding sites (dark violet). Colored elements indicate SNPs for which the feature is present. For data sources, see Online Methods (“In-Silico Analysis of CRVs”).
Extended data Figure 2
Extended data Figure 2. Pathway enrichment map for susceptibility loci based on summary association statistics.
Each circle (node) represents a pathway (gene set), coloured by enrichment score (ES) where redder nodes indicate lower FDRs. Larger nodes indicate pathways with more genes. Green lines connect pathways with overlapping genes (minimum overlap 0.55). Pathways are grouped by similarity and organized into major themes (large labelled circles).
Extended data Figure 3
Extended data Figure 3. Heatmap showing patterns of cell type-specific enrichments for breast tissue across three histone marks (H3K4me1, H3K4me3 and H3K9ac) for breast cancer overall, ER-positive breast cancer and ER-negative breast cancer as well as 16 other traits.
Extended data Figure 4
Extended data Figure 4. Heatmap showing patterns of cell type-specific enrichments for histone mark H3K27ac in breast cancer overall, ER+ and ER- breast cancer as well as 16 other traits.
Extended data Figure 5
Extended data Figure 5. Heatmap showing patterns of cell type-specific enrichments for histone mark H3K4me1 in breast cancer overall, ER+ and ER- breast cancer as well as 16 other traits.
Extended data Figure 6
Extended data Figure 6. Heatmap showing patterns of cell type-specific enrichments for histone mark H3K4me3 in breast cancer overall, ER+ and ER- breast cancer as well as 16 other traits.
Extended data Figure 7
Extended data Figure 7. Heatmap showing patterns of cell type-specific enrichments for histone mark H3K9ac in breast cancer overall, ER-positive and ER-negative breast cancer as well as 16 other traits.
Extended data Figure 8
Extended data Figure 8. Functional assessment of regulatory variants at 1p36, 11p15 and 1p34 risk loci.
a, The KLHDC7A or b, PIDD1 promoter regions containing the reference (prom-Ref) or risk alleles (prom-Hap), were cloned upstream of the pGL3 luciferase reporter gene. MCF7 or Bre-80 cells were transfected with constructs and assayed for luciferase activity after 24 h. Error bars denote 95% CI (n=3). P-values were determined by two-way ANOVA followed by Dunnett’s multiple comparisons test (*P<0.05, **P<0.01, ***P<0.001). c, 3C assays. A physical map of the region interrogated by 3C is shown first. Grey boxes depict the putative regulatory elements (PREs), blue vertical lines indicate the risk-associated SNPs and black dotted line represents chromatin looping. The graphs represent three independent 3C interaction profiles. 3C libraries were generated with EcoRI, grey vertical boxes indicate the interacting restriction fragment (containing PRE1 and PRE2). Error bars denote SD. d, PRE1 or PRE2 containing the reference (PRE-ref) or risk (PRE-Hap) haplotypes were cloned downstream of a CITED4 promoter-driven luciferase construct (CITED4 prom). MCF7 or Bre-80 cells were transfected with constructs and assayed for luciferase activity after 24 h. Error bars denote 95% CI (n=3). P-values were determined by two-way ANOVA followed by Dunnett’s multiple comparisons test (**P<0.01, ***P<0.001).
Extended data Figure 9
Extended data Figure 9. Functional assessment of regulatory variants at the 7q22 risk locus.
a-e, 3C assays. A physical map of the region interrogated by 3C is shown first. Grey horizontal boxes depict the putative regulatory elements (PREs), blue vertical lines indicate the risk-associated SNPs and black dotted line represents chromatin looping. The graphs represent three independent 3C interaction profiles between the a, CUX1, b, d, PRKRIP1 or c, e, RASA4 promoter regions and PREs. 3C libraries were generated with EcoRI, grey vertical boxes indicate the interacting restriction fragment (containing PRE1 and/or PRE2). Error bars denote SD. f, g, Allele-specific 3C. 3C followed by Sanger sequencing for the f, PRKRIP1-PRE2 or g, RASA4-PRE1 or -PRE2 in heterozygous MDA-MB-231 breast cancer cells.
Figure 1
Figure 1
(a) Manhattan plot showing log10P-values for SNP associations with overall breast cancer (b) Manhattan plot after excluding previously identified associated regions. The red line denotes “genome-wide” significance (P<5x10-8); the blue line denotes P<10-5.

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