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. 2017 May;49(5):680-691.
doi: 10.1038/ng.3826. Epub 2017 Mar 27.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Catherine M Phelan  1   2 Karoline B Kuchenbaecker  3   4 Jonathan P Tyrer  5 Siddhartha P Kar  5 Kate Lawrenson  6 Stacey J Winham  7 Joe Dennis  5 Ailith Pirie  5 Marjorie J Riggan  8 Ganna Chornokur  1 Madalene A Earp  9 Paulo C Lyra Jr  1 Janet M Lee  10 Simon Coetzee  10 Jonathan Beesley  11 Lesley McGuffog  12 Penny Soucy  13 Ed Dicks  5 Andrew Lee  12 Daniel Barrowdale  12 Julie Lecarpentier  12 Goska Leslie  12 Cora M Aalfs  14 Katja K H Aben  15   16 Marcia Adams  17 Julian Adlard  18 Irene L Andrulis  19   20 Hoda Anton-Culver  21   22 Natalia Antonenkova  23 AOCS study groupGerasimos Aravantinos  24 Norbert Arnold  25 Banu K Arun  26 Brita Arver  27 Jacopo Azzollini  28 Judith Balmaña  29 Susana N Banerjee  30 Laure Barjhoux  31 Rosa B Barkardottir  32   33 Yukie Bean  34   35 Matthias W Beckmann  36 Alicia Beeghly-Fadiel  37   38   39   40 Javier Benitez  41   42 Marina Bermisheva  43 Marcus Q Bernardini  44 Michael J Birrer  45 Line Bjorge  46   47 Amanda Black  48 Kenneth Blankstein  49 Marinus J Blok  50 Clara Bodelon  48 Natalia Bogdanova  51 Anders Bojesen  52 Bernardo Bonanni  53 Åke Borg  54 Angela R Bradbury  55 James D Brenton  56 Carole Brewer  57 Louise Brinton  48 Per Broberg  58 Angela Brooks-Wilson  59 Fiona Bruinsma  60 Joan Brunet  61 Bruno Buecher  62 Ralf Butzow  63 Saundra S Buys  64 Trinidad Caldes  65 Maria A Caligo  66 Ian Campbell  67   68 Rikki Cannioto  69 Michael E Carney  70 Terence Cescon  49 Salina B Chan  71 Jenny Chang-Claude  72   73 Stephen Chanock  48 Xiao Qing Chen  11 Yoke-Eng Chiew  74   75 Jocelyne Chiquette  76 Wendy K Chung  77 Kathleen B M Claes  78 Thomas Conner  64 Linda S Cook  79 Jackie Cook  80 Daniel W Cramer  81 Julie M Cunningham  82 Aimee A D'Aloisio  83 Mary B Daly  84 Francesca Damiola  31 Sakaeva Dina Damirovna  85 Agnieszka Dansonka-Mieszkowska  86 Fanny Dao  87 Rosemarie Davidson  88 Anna DeFazio  74   75 Capucine Delnatte  89 Kimberly F Doheny  17 Orland Diez  90   91 Yuan Chun Ding  92 Jennifer Anne Doherty  93 Susan M Domchek  55 Cecilia M Dorfling  94 Thilo Dörk  95 Laure Dossus  96 Mercedes Duran  97 Matthias Dürst  98 Bernd Dworniczak  99 Diana Eccles  100 Todd Edwards  37   38   39   40 Ros Eeles  101 Ursula Eilber  72 Bent Ejlertsen  102 Arif B Ekici  103 Steve Ellis  12 Mingajeva Elvira  85 EMBRACE StudyKevin H Eng  104 Christoph Engel  105 D Gareth Evans  106 Peter A Fasching  36   107 Sarah Ferguson  44 Sandra Fert Ferrer  108 James M Flanagan  109 Zachary C Fogarty  7 Renée T Fortner  72 Florentia Fostira  110 William D Foulkes  111 George Fountzilas  112 Brooke L Fridley  113 Tara M Friebel  114 Eitan Friedman  115   116 Debra Frost  12 Patricia A Ganz  117 Judy Garber  118 María J García  41   42 Vanesa Garcia-Barberan  65 Andrea Gehrig  119 GEMO Study CollaboratorsAleksandra Gentry-Maharaj  120 Anne-Marie Gerdes  121 Graham G Giles  60   122   123 Rosalind Glasspool  124 Gord Glendon  125 Andrew K Godwin  126 David E Goldgar  127 Teodora Goranova  56 Martin Gore  128 Mark H Greene  129 Jacek Gronwald  130 Stephen Gruber  131 Eric Hahnen  132 Christopher A Haiman  133 Niclas Håkansson  134 Ute Hamann  135 Thomas V O Hansen  136 Patricia A Harrington  5 Holly R Harris  134 Jan Hauke  132 HEBON StudyAlexander Hein  36 Alex Henderson  137 Michelle A T Hildebrandt  138 Peter Hillemanns  139 Shirley Hodgson  140 Claus K Høgdall  141 Estrid Høgdall  142   143 Frans B L Hogervorst  144 Helene Holland  11 Maartje J Hooning  145 Karen Hosking  5 Ruea-Yea Huang  146 Peter J Hulick  147 Jillian Hung  74   75 David J Hunter  148 David G Huntsman  149   150 Tomasz Huzarski  130 Evgeny N Imyanitov  151 Claudine Isaacs  152 Edwin S Iversen  153 Louise Izatt  154 Angel Izquierdo  61 Anna Jakubowska  130 Paul James  155   156 Ramunas Janavicius  157   158 Mats Jernetz  159 Allan Jensen  142 Uffe Birk Jensen  160 Esther M John  161 Sharon Johnatty  11 Michael E Jones  162 Päivi Kannisto  159 Beth Y Karlan  6 Anthony Karnezis  149   150 Karin Kast  163 KConFab InvestigatorsCatherine J Kennedy  74   75 Elza Khusnutdinova  43 Lambertus A Kiemeney  15 Johanna I Kiiski  164 Sung-Won Kim  165 Susanne K Kjaer  141   142 Martin Köbel  166 Reidun K Kopperud  46   47 Torben A Kruse  167 Jolanta Kupryjanczyk  86 Ava Kwong  168   169   170 Yael Laitman  115   116 Diether Lambrechts  171   172 Nerea Larrañaga  173   174 Melissa C Larson  7 Conxi Lazaro  175 Nhu D Le  176 Loic Le Marchand  177 Jong Won Lee  178 Shashikant B Lele  179 Arto Leminen  164 Dominique Leroux  180 Jenny Lester  6 Fabienne Lesueur  181   182 Douglas A Levine  87 Dong Liang  183 Clemens Liebrich  184 Jenna Lilyquist  185 Loren Lipworth  37   38   40 Jolanta Lissowska  186 Karen H Lu  187 Jan Lubinński  130 Craig Luccarini  5 Lene Lundvall  188 Phuong L Mai  129 Gustavo Mendoza-Fandiño  1 Siranoush Manoukian  28 Leon F A G Massuger  15 Taymaa May  44 Sylvie Mazoyer  189 Jessica N McAlpine  190 Valerie McGuire  191 John R McLaughlin  192 Iain McNeish  193 Hanne Meijers-Heijboer  194 Alfons Meindl  195 Usha Menon  120 Arjen R Mensenkamp  196 Melissa A Merritt  197 Roger L Milne  60   122 Gillian Mitchell  155   156 Francesmary Modugno  198   199   200 Joanna Moes-Sosnowska  86 Melissa Moffitt  35   201 Marco Montagna  202 Kirsten B Moysich  69 Anna Marie Mulligan  20   203 Jacob Musinsky  204 Katherine L Nathanson  55 Lotte Nedergaard  205 Roberta B Ness  206 Susan L Neuhausen  92 Heli Nevanlinna  164 Dieter Niederacher  207 Robert L Nussbaum  208   209 Kunle Odunsi  179 Edith Olah  210 Olufunmilayo I Olopade  211 Håkan Olsson  58   212 Curtis Olswold  185 David M O'Malley  213 Kai-Ren Ong  214 N Charlotte Onland-Moret  215 OPAL study groupNicholas Orr  216 Sandra Orsulic  6 Ana Osorio  41 Domenico Palli  217 Laura Papi  218 Tjoung-Won Park-Simon  139 James Paul  219 Celeste L Pearce  133   220 Inge Søkilde Pedersen  221 Petra H M Peeters  215 Bernard Peissel  28 Ana Peixoto  222 Tanja Pejovic  35   201 Liisa M Pelttari  164 Jennifer B Permuth  1 Paolo Peterlongo  223 Lidia Pezzani  28 Georg Pfeiler  224 Kelly-Anne Phillips  122   156   225 Marion Piedmonte  226 Malcolm C Pike  133   227 Anna M Piskorz  56 Samantha R Poblete  179 Timea Pocza  210 Elizabeth M Poole  228 Bruce Poppe  78 Mary E Porteous  229 Fabienne Prieur  230 Darya Prokofyeva  85 Elizabeth Pugh  17 Miquel Angel Pujana  231 Pascal Pujol  232 Paolo Radice  233 Johanna Rantala  234 Christine Rappaport-Fuerhauser  224 Gad Rennert  235   236 Kerstin Rhiem  132 Patricia Rice  49 Andrea Richardson  237 Mark Robson  238 Gustavo C Rodriguez  239 Cristina Rodríguez-Antona  42   240 Jane Romm  17 Matti A Rookus  241 Mary Anne Rossing  242 Joseph H Rothstein  191 Anja Rudolph  72 Ingo B Runnebaum  98 Helga B Salvesen  46   47 Dale P Sandler  243 Minouk J Schoemaker  162 Leigha Senter  244 V Wendy Setiawan  133 Gianluca Severi  245   246   247   248 Priyanka Sharma  249 Tameka Shelford  17 Nadeem Siddiqui  250 Lucy E Side  251 Weiva Sieh  191 Christian F Singer  224 Hagay Sobol  252 Honglin Song  5 Melissa C Southey  253 Amanda B Spurdle  11 Zsofia Stadler  238 Doris Steinemann  254 Dominique Stoppa-Lyonnet  62 Lara E Sucheston-Campbell  255 Grzegorz Sukiennicki  130 Rebecca Sutphen  256 Christian Sutter  257 Anthony J Swerdlow  162   258 Csilla I Szabo  259 Lukasz Szafron  86 Yen Y Tan  224 Jack A Taylor  243 Muy-Kheng Tea  224 Manuel R Teixeira  222   260 Soo-Hwang Teo  261   262 Kathryn L Terry  81   263 Pamela J Thompson  264 Liv Cecilie Vestrheim Thomsen  46   47 Darcy L Thull  265 Laima Tihomirova  266 Anna V Tinker  267 Marc Tischkowitz  111   268 Silvia Tognazzo  202 Amanda Ewart Toland  269 Alicia Tone  44 Britton Trabert  48 Ruth C Travis  270 Antonia Trichopoulou  271   272 Nadine Tung  273 Shelley S Tworoger  228   263 Anne M van Altena  274 David Van Den Berg  133 Annemarie H van der Hout  275 Rob B van der Luijt  276 Mattias Van Heetvelde  78 Els Van Nieuwenhuysen  277 Elizabeth J van Rensburg  94 Adriaan Vanderstichele  277 Raymonda Varon-Mateeva  278 Ana Vega  279   280 Digna Velez Edwards  38   40   281 Ignace Vergote  277 Robert A Vierkant  7 Joseph Vijai  204 Athanassios Vratimos  110 Lisa Walker  282 Christine Walsh  6 Dorothea Wand  283 Shan Wang-Gohrke  284 Barbara Wappenschmidt  132 Penelope M Webb  285 Clarice R Weinberg  286 Jeffrey N Weitzel  287 Nicolas Wentzensen  48 Alice S Whittemore  191   288 Juul T Wijnen  289 Lynne R Wilkens  177 Alicja Wolk  134 Michelle Woo  149   150 Xifeng Wu  138 Anna H Wu  133 Hannah Yang  48 Drakoulis Yannoukakos  110 Argyrios Ziogas  22 Kristin K Zorn  265 Steven A Narod  290 Douglas F Easton  4   5 Christopher I Amos  291 Joellen M Schildkraut  292 Susan J Ramus  293   294 Laura Ottini  295 Marc T Goodman  264   296 Sue K Park  297   298   299 Linda E Kelemen  300 Harvey A Risch  301 Mads Thomassen  167 Kenneth Offit  204 Jacques Simard  13 Rita Katharina Schmutzler  132 Dennis Hazelett  302 Alvaro N Monteiro  1 Fergus J Couch  82 Andrew Berchuck  8 Georgia Chenevix-Trench  11 Ellen L Goode  9 Thomas A Sellers  1 Simon A Gayther  10 Antonis C Antoniou  4   5 Paul D P Pharoah  4   5
Affiliations

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Catherine M Phelan et al. Nat Genet. 2017 May.

Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

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Conflict of interest statement

Competing interests

The authors declare no competing financial interests related to this manuscript.

Figures

Figure 1
Figure 1. Histotype specific associations (odds ratios) of top SNP in 12 novel EOC susceptibility regions
The forest plot shows the point estimates of odds ratios with 95% confidence intervals around each estimate. Odds ratios and confidence intervals in bold are histotypes significant at nominal P<0.05.
Figure 2
Figure 2. Number of overlaps between causal SNPs and H3K27ac in relevant tissues and cell lines
Height of each bar in the histogram represents the number of candidate causal SNPs at each locus overlapping H3K27ac marks in a particular cell line. Loci are grouped according to their association with different histotypes of ovarian cancer. The number of causal SNPs at 100:1 odds relative to the top regional SNP is indicated by the red circles (scale below, right). In the key cell lines are grouped according to their likely relevance to the different histotypes. Abbreviations: mucinous ovarian cancer (MOC), low grade serous ovarian cancer (LGSOC), high grade serous ovarian cancer (HGSOC), and epithelial ovarian cancer (EOC) precursors.
Figure 3
Figure 3. Functional analysis of the chr10q24.33 locus
(a) Active chromatin, denoted by H3K27ac signaling, in EOC-relevant cell types. (b) Regional association plot for genotyped and imputed SNPs. The dashed box highlights the region shown in panel (a) (c) MotifbreakR analysis, a non-canonical CTCF motif is significantly altered by SNP rs2488000. (d) EQTL analysis, OBFC1 expression is associated with rs11597399 genotype in HGSOCs from TCGA. Box and whisker plot showing median (horizontal line within box), interquartile range (IQR; length of box) and 1.5 times the IQR (whiskers) of OBFC1 expression for each genotype.

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