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Meta-Analysis
. 2019 Mar;120(6):647-657.
doi: 10.1038/s41416-019-0393-x. Epub 2019 Feb 21.

Genome-wide association study of germline variants and breast cancer-specific mortality

Maria Escala-Garcia  1 , Qi Guo  2 , Thilo Dörk  3 , Sander Canisius  1   4 , Renske Keeman  1 , Joe Dennis  5 , Jonathan Beesley  6 , Julie Lecarpentier  5 , Manjeet K Bolla  5 , Qin Wang  5 , Jean Abraham  7   8   9 , Irene L Andrulis  10   11 , Hoda Anton-Culver  12 , Volker Arndt  13 , Paul L Auer  14   15 , Matthias W Beckmann  16 , Sabine Behrens  17 , Javier Benitez  18   19 , Marina Bermisheva  20 , Leslie Bernstein  21 , Carl Blomqvist  22   23 , Bram Boeckx  24   25 , Stig E Bojesen  26   27   28 , Bernardo Bonanni  29 , Anne-Lise Børresen-Dale  30   31   32   33   34   35   36   37   38   39 , Hiltrud Brauch  40   41   42 , Hermann Brenner  13   42   43 , Adam Brentnall  44 , Louise Brinton  45 , Per Broberg  46 , Ian W Brock  47 , Sara Y Brucker  48 , Barbara Burwinkel  49   50 , Carlos Caldas  8   9   51 , Trinidad Caldés  52 , Daniele Campa  17   53 , Federico Canzian  50 , Angel Carracedo  54   55   56 , Brian D Carter  57 , Jose E Castelao  58 , Jenny Chang-Claude  17   59 , Stephen J Chanock  45 , Georgia Chenevix-Trench  6 , Ting-Yuan David Cheng  60 , Suet-Feung Chin  61 , Christine L Clarke  62 ; NBCS Collaborators; Emilie Cordina-Duverger  63 , Fergus J Couch  64 , David G Cox  65   66 , Angela Cox  47 , Simon S Cross  67 , Kamila Czene  68 , Mary B Daly  69 , Peter Devilee  70   71 , Janet A Dunn  72 , Alison M Dunning  7 , Lorraine Durcan  73   74 , Miriam Dwek  75 , Helena M Earl  9   76 , Arif B Ekici  77 , A Heather Eliassen  78   79 , Carolina Ellberg  46 , Christoph Engel  80   81 , Mikael Eriksson  68 , D Gareth Evans  82   83 , Jonine Figueroa  45   84   85 , Dieter Flesch-Janys  86   87 , Henrik Flyger  88 , Marike Gabrielson  68 , Manuela Gago-Dominguez  54   89 , Eva Galle  24   25 , Susan M Gapstur  57 , Montserrat García-Closas  45   90 , José A García-Sáenz  52 , Mia M Gaudet  57 , Angela George  91   92 , Vassilios Georgoulias  93 , Graham G Giles  94   95   96 , Gord Glendon  10 , David E Goldgar  97 , Anna González-Neira  18 , Grethe I Grenaker Alnæs  30 , Mervi Grip  98 , Pascal Guénel  63 , Lothar Haeberle  99 , Eric Hahnen  100   101 , Christopher A Haiman  102 , Niclas Håkansson  103 , Per Hall  68   104 , Ute Hamann  105 , Susan Hankinson  106 , Elaine F Harkness  107   108   109 , Patricia A Harrington  7 , Steven N Hart  110 , Jaana M Hartikainen  111   112   113 , Alexander Hein  16 , Peter Hillemanns  3 , Louise Hiller  72 , Bernd Holleczek  114 , Antoinette Hollestelle  115 , Maartje J Hooning  115 , Robert N Hoover  45 , John L Hopper  95 , Anthony Howell  116 , Guanmengqian Huang  105 , Keith Humphreys  68 , David J Hunter  79   117   118 , Wolfgang Janni  85 , Esther M John  119   120   121 , Michael E Jones  90 , Arja Jukkola-Vuorinen  122 , Audrey Jung  17 , Rudolf Kaaks  17 , Maria Kabisch  105 , Katarzyna Kaczmarek  123 , Michael J Kerin  124 , Sofia Khan  125 , Elza Khusnutdinova  20   126 , Johanna I Kiiski  125 , Cari M Kitahara  127 , Julia A Knight  128   129 , Yon-Dschun Ko  130 , Linetta B Koppert  131 , Veli-Matti Kosma  111   112   113 , Peter Kraft  79   117 , Vessela N Kristensen  30   31   32   33   34   35   36   37   38   39 , Ute Krüger  46 , Tabea Kühl  59 , Diether Lambrechts  24   25 , Loic Le Marchand  132 , Eunjung Lee  102 , Flavio Lejbkowicz  133 , Lian Li  134 , Annika Lindblom  135 , Sara Lindström  136   137 , Martha Linet  127 , Jolanta Lissowska  138 , Wing-Yee Lo  40   41 , Sibylle Loibl  139 , Jan Lubiński  123 , Michael P Lux  99 , Robert J MacInnis  94   95 , Melanie Maierthaler  50 , Tom Maishman  73   74 , Enes Makalic  95 , Arto Mannermaa  111   112   113 , Mehdi Manoochehri  105 , Siranoush Manoukian  140 , Sara Margolin  141 , Maria Elena Martinez  89   142 , Dimitrios Mavroudis  93 , Catriona McLean  143 , Alfons Meindl  144 , Pooja Middha  17   145 , Nicola Miller  124 , Roger L Milne  94   95 , Fernando Moreno  52 , Anna Marie Mulligan  146   147 , Claire Mulot  148 , Rami Nassir  149 , Susan L Neuhausen  21 , William T Newman  82   83 , Sune F Nielsen  26   27 , Børge G Nordestgaard  26   27   28 , Aaron Norman  110 , Håkan Olsson  46 , Nick Orr  150 , V Shane Pankratz  151 , Tjoung-Won Park-Simon  3 , Jose I A Perez  152 , Clara Pérez-Barrios  153 , Paolo Peterlongo  154 , Christos Petridis  155 , Mila Pinchev  133 , Karoliona Prajzendanc  123 , Ross Prentice  14 , Nadege Presneau  75 , Darya Prokofieva  126 , Katri Pylkäs  156   157 , Brigitte Rack  144 , Paolo Radice  158 , Dhanya Ramachandran  3 , Gadi Rennert  133 , Hedy S Rennert  133 , Valerie Rhenius  7 , Atocha Romero  153 , Rebecca Roylance  159 , Emmanouil Saloustros  160 , Elinor J Sawyer  155 , Daniel F Schmidt  95 , Rita K Schmutzler  100   101 , Andreas Schneeweiss  49   161 , Minouk J Schoemaker  91 , Fredrick Schumacher  162 , Lukas Schwentner  85 , Rodney J Scott  163   164   165   166 , Christopher Scott  110 , Caroline Seynaeve  115 , Mitul Shah  7 , Jacques Simard  167 , Ann Smeets  168 , Christof Sohn  161 , Melissa C Southey  169   170 , Anthony J Swerdlow  91   171 , Aline Talhouk  172   173   174 , Rulla M Tamimi  78   79   117 , William J Tapper  175 , Manuel R Teixeira  176   177 , Maria Tengström  111   178   179 , Mary Beth Terry  180 , Kathrin Thöne  59 , Rob A E M Tollenaar  181 , Ian Tomlinson  182   183 , Diana Torres  105   184 , Thérèse Truong  63 , Constance Turman  79 , Clare Turnbull  91 , Hans-Ulrich Ulmer  185 , Michael Untch  186 , Celine Vachon  110 , Christi J van Asperen  187 , Ans M W van den Ouweland  188 , Elke M van Veen  82   83 , Camilla Wendt  189 , Alice S Whittemore  120   121 , Walter Willett  79   190   191 , Robert Winqvist  156   157 , Alicja Wolk  192 , Xiaohong R Yang  45 , Yan Zhang  13   42 , Douglas F Easton  5   7 , Peter A Fasching  16   193 , Heli Nevanlinna  125 , Diana M Eccles  74 , Paul D P Pharoah  5   7 , Marjanka K Schmidt  1   194
Affiliations
Meta-Analysis

Genome-wide association study of germline variants and breast cancer-specific mortality

Maria Escala-Garcia et al. Br J Cancer. 2019 Mar.

Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.

Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).

Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.

Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Association plot for the meta-analysis of the twelve datasets for breast cancer-specific mortality analyses (censored at 15 years) for a all breast tumours (censored at 15 years), b ER-negative tumours and c ER-positive tumours. The y-axis shows the −log10 P values of each variant analysed, and the x-axis shows their chromosome position. The red horizontal line represents P = 5 × 10−8
Fig. 2
Fig. 2
Q–Q plots for the meta-analysis of the twelve datasets for breast cancer-specific mortality analyses (censored at 15 years) for a all breast cancer tumours (censored at 15 years), b ER-negative tumours and c ER-positive tumours. The y-axis represents the observed −log10 P value, and the x-axis represents the expected −log10 P value. The red line represents the expected distribution under the null hypothesis of no association. Analyses were not corrected for LD-structure
Fig. 3
Fig. 3
Forest plot showing the association between the ER-negative variant rs67918676 and breast cancer-specific mortality in ER-negative tumours for the datasets used in the meta-analysis. The size of the square reflects the size of the study (see also Supplementary Table 3)
Fig. 4
Fig. 4
Forest plot showing the association between the ER-positive variant rs4717568 and breast cancer-specific mortality in ER-positive tumours for the datasets used in the meta-analysis. The size of the square reflects the size of the study (see also Supplementary Table 3)
See this image and copyright information in PMC

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