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Meta-Analysis
. 2015 Feb;47(2):164-71.
doi: 10.1038/ng.3185. Epub 2015 Jan 12.

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Karoline B Kuchenbaecker  1 , Susan J Ramus  2 , Jonathan Tyrer  3 , Andrew Lee  1 , Howard C Shen  2 , Jonathan Beesley  4 , Kate Lawrenson  2 , Lesley McGuffog  1 , Sue Healey  4 , Janet M Lee  2 , Tassja J Spindler  2 , Yvonne G Lin  5 , Tanja Pejovic  6 , Yukie Bean  6 , Qiyuan Li  7 , Simon Coetzee  8 , Dennis Hazelett  9 , Alexander Miron  10 , Melissa Southey  11 , Mary Beth Terry  12 , David E Goldgar  13 , Saundra S Buys  14 , Ramunas Janavicius  15 , Cecilia M Dorfling  16 , Elizabeth J van Rensburg  16 , Susan L Neuhausen  17 , Yuan Chun Ding  17 , Thomas V O Hansen  18 , Lars Jønson  18 , Anne-Marie Gerdes  19 , Bent Ejlertsen  20 , Daniel Barrowdale  1 , Joe Dennis  21 , Javier Benitez  22 , Ana Osorio  23 , Maria Jose Garcia  23 , Ian Komenaka  24 , Jeffrey N Weitzel  25 , Pamela Ganschow  26 , Paolo Peterlongo  27 , Loris Bernard  28 , Alessandra Viel  29 , Bernardo Bonanni  30 , Bernard Peissel  31 , Siranoush Manoukian  31 , Paolo Radice  32 , Laura Papi  33 , Laura Ottini  34 , Florentia Fostira  35 , Irene Konstantopoulou  35 , Judy Garber  36 , Debra Frost  1 , Jo Perkins  1 , Radka Platte  1 , Steve Ellis  1 ; EMBRACE; Andrew K Godwin  37 , Rita Katharina Schmutzler  38 , Alfons Meindl  39 , Christoph Engel  40 , Christian Sutter  41 , Olga M Sinilnikova  42 ; GEMO Study Collaborators; Francesca Damiola  43 , Sylvie Mazoyer  43 , Dominique Stoppa-Lyonnet  44 , Kathleen Claes  45 , Kim De Leeneer  45 , Judy Kirk  46 , Gustavo C Rodriguez  47 , Marion Piedmonte  48 , David M O'Malley  49 , Miguel de la Hoya  50 , Trinidad Caldes  50 , Kristiina Aittomäki  51 , Heli Nevanlinna  52 , J Margriet Collée  53 , Matti A Rookus  54 , Jan C Oosterwijk  55 ; Breast Cancer Family Registry; Laima Tihomirova  56 , Nadine Tung  57 , Ute Hamann  58 , Claudine Isaccs  59 , Marc Tischkowitz  60 , Evgeny N Imyanitov  61 , Maria A Caligo  62 , Ian G Campbell  63 , Frans B L Hogervorst  64 ; HEBON; Edith Olah  65 , Orland Diez  66 , Ignacio Blanco  67 , Joan Brunet  68 , Conxi Lazaro  69 , Miquel Angel Pujana  69 , Anna Jakubowska  70 , Jacek Gronwald  70 , Jan Lubinski  70 , Grzegorz Sukiennicki  70 , Rosa B Barkardottir  71 , Marie Plante  72 , Jacques Simard  73 , Penny Soucy  73 , Marco Montagna  74 , Silvia Tognazzo  74 , Manuel R Teixeira  75 ; KConFab Investigators; Vernon S Pankratz  76 , Xianshu Wang  77 , Noralane Lindor  76 , Csilla I Szabo  78 , Noah Kauff  79 , Joseph Vijai  79 , Carol A Aghajanian  79 , Georg Pfeiler  80 , Andreas Berger  80 , Christian F Singer  80 , Muy-Kheng Tea  80 , Catherine M Phelan  81 , Mark H Greene  82 , Phuong L Mai  82 , Gad Rennert  83 , Anna Marie Mulligan  84 , Sandrine Tchatchou  85 , Irene L Andrulis  86 , Gord Glendon  85 , Amanda Ewart Toland  87 , Uffe Birk Jensen  88 , Torben A Kruse  89 , Mads Thomassen  89 , Anders Bojesen  90 , Jamal Zidan  91 , Eitan Friedman  92 , Yael Laitman  92 , Maria Soller  93 , Annelie Liljegren  94 , Brita Arver  94 , Zakaria Einbeigi  95 , Marie Stenmark-Askmalm  96 , Olufunmilayo I Olopade  97 , Robert L Nussbaum  98 , Timothy R Rebbeck  99 , Katherine L Nathanson  99 , Susan M Domchek  99 , Karen H Lu  100 , Beth Y Karlan  101 , Christine Walsh  101 , Jenny Lester  101 ; Australian Cancer Study (Ovarian Cancer Investigators); Australian Ovarian Cancer Study Group; Alexander Hein  102 , Arif B Ekici  103 , Matthias W Beckmann  102 , Peter A Fasching  104 , Diether Lambrechts  105 , Els Van Nieuwenhuysen  106 , Ignace Vergote  106 , Sandrina Lambrechts  106 , Ed Dicks  3 , Jennifer A Doherty  107 , Kristine G Wicklund  108 , Mary Anne Rossing  109 , Anja Rudolph  110 , Jenny Chang-Claude  110 , Shan Wang-Gohrke  111 , Ursula Eilber  110 , Kirsten B Moysich  112 , Kunle Odunsi  113 , Lara Sucheston  112 , Shashi Lele  112 , Lynne R Wilkens  114 , Marc T Goodman  115 , Pamela J Thompson  115 , Yurii B Shvetsov  114 , Ingo B Runnebaum  116 , Matthias Dürst  116 , Peter Hillemanns  117 , Thilo Dörk  118 , Natalia Antonenkova  119 , Natalia Bogdanova  118 , Arto Leminen  52 , Liisa M Pelttari  52 , Ralf Butzow  120 , Francesmary Modugno  121 , Joseph L Kelley  122 , Robert P Edwards  123 , Roberta B Ness  124 , Andreas du Bois  125 , Florian Heitz  125 , Ira Schwaab  126 , Philipp Harter  125 , Keitaro Matsuo  127 , Satoyo Hosono  128 , Sandra Orsulic  101 , Allan Jensen  129 , Susanne Kruger Kjaer  130 , Estrid Hogdall  131 , Hanis Nazihah Hasmad  132 , Mat Adenan Noor Azmi  133 , Soo-Hwang Teo  134 , Yin-Ling Woo  135 , Brooke L Fridley  136 , Ellen L Goode  76 , Julie M Cunningham  77 , Robert A Vierkant  137 , Fiona Bruinsma  138 , Graham G Giles  138 , Dong Liang  139 , Michelle A T Hildebrandt  140 , Xifeng Wu  140 , Douglas A Levine  141 , Maria Bisogna  141 , Andrew Berchuck  142 , Edwin S Iversen  143 , Joellen M Schildkraut  144 , Patrick Concannon  145 , Rachel Palmieri Weber  146 , Daniel W Cramer  147 , Kathryn L Terry  147 , Elizabeth M Poole  148 , Shelley S Tworoger  148 , Elisa V Bandera  149 , Irene Orlow  150 , Sara H Olson  150 , Camilla Krakstad  151 , Helga B Salvesen  151 , Ingvild L Tangen  151 , Line Bjorge  151 , Anne M van Altena  152 , Katja K H Aben  153 , Lambertus A Kiemeney  154 , Leon F A G Massuger  152 , Melissa Kellar  6 , Angela Brooks-Wilson  155 , Linda E Kelemen  156 , Linda S Cook  157 , Nhu D Le  158 , Cezary Cybulski  159 , Hannah Yang  160 , Jolanta Lissowska  161 , Louise A Brinton  160 , Nicolas Wentzensen  160 , Claus Hogdall  162 , Lene Lundvall  162 , Lotte Nedergaard  163 , Helen Baker  3 , Honglin Song  3 , Diana Eccles  164 , Ian McNeish  165 , James Paul  166 , Karen Carty  166 , Nadeem Siddiqui  167 , Rosalind Glasspool  166 , Alice S Whittemore  168 , Joseph H Rothstein  168 , Valerie McGuire  168 , Weiva Sieh  168 , Bu-Tian Ji  160 , Wei Zheng  169 , Xiao-Ou Shu  169 , Yu-Tang Gao  170 , Barry Rosen  171 , Harvey A Risch  172 , John R McLaughlin  173 , Steven A Narod  174 , Alvaro N Monteiro  81 , Ann Chen  175 , Hui-Yi Lin  175 , Jenny Permuth-Wey  81 , Thomas A Sellers  81 , Ya-Yu Tsai  81 , Zhihua Chen  175 , Argyrios Ziogas  176 , Hoda Anton-Culver  176 , Aleksandra Gentry-Maharaj  177 , Usha Menon  177 , Patricia Harrington  3 , Alice W Lee  2 , Anna H Wu  2 , Celeste L Pearce  2 , Gerry Coetzee  9 , Malcolm C Pike  178 , Agnieszka Dansonka-Mieszkowska  179 , Agnieszka Timorek  180 , Iwona K Rzepecka  179 , Jolanta Kupryjanczyk  179 , Matt Freedman  7 , Houtan Noushmehr  181 , Douglas F Easton  1 , Kenneth Offit  79 , Fergus J Couch  182 , Simon Gayther  2 , Paul P Pharoah  3 , Antonis C Antoniou  1 , Georgia Chenevix-Trench  4 ; Consortium of Investigators of Modifiers of BRCA1 and BRCA2
Collaborators, Affiliations
Meta-Analysis

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Karoline B Kuchenbaecker et al. Nat Genet. 2015 Feb.

Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

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Figures

Figure 1
Figure 1
Hazard ratios for the association with EOC of 12 previously reported epithelial ovarian cancer susceptibility variants and the six novel susceptibility variants for OCAC, BRCA1 mutation carriers and BRCA2 mutation carriers
Figure 2
Figure 2
The 1p36 epithelial ovarian cancer susceptibility locus A) The Manhattan plot depicts the strength of association between all imputed and genotyped SNPs across the region bound by hg19 co-ordinates chr1:21922893-22991643. The dotted line represents the genome-wide significance level 5×10−8. Additional tracks show genes and enhancers in ovary as described in Hnisz et al. Positions of SNPs for which imputation r2<0.3 and/or minor allele frequency <0.005 are shown in the bottom track as ‘untyped’ SNPs. B) The shaded iCHAV from (A) is shown depicting the genes and the location of the WNT4 promoter construct as a red box. Red ticks show the positions of the putative causal variants following likelihood ratio testing. Signals from FAIRE-seq data derived from ovarian cells are represented by black marks, and the locations of predicted CDC42 enhancers as blue boxes. The positions of genotyped SNPs, and those that were neither genotyped nor well imputed (‘untyped’), are shown. C) Normalised luciferase reporter activity following triplicate transfections of wildtype and risk haplotype WNT4 promoter constructs in iOSE4 cells. Error bars represent standard error from three independent experiments.
See this image and copyright information in PMC

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