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

Authors:
Maria Escala-Garcia Qi Guo Thilo Dörk Sander Canisius Renske Keeman Joe Dennis Jonathan Beesley Julie Lecarpentier Manjeet K Bolla Qin Wang Jean Abraham Irene L Andrulis Hoda Anton-Culver Volker Arndt Paul L Auer Matthias W Beckmann Sabine Behrens Javier Benitez Marina Bermisheva Leslie Bernstein Carl Blomqvist Bram Boeckx Stig E Bojesen Bernardo Bonanni Anne-Lise Børresen-Dale Hiltrud Brauch Hermann Brenner Adam Brentnall Louise Brinton Per Broberg Ian W Brock Sara Y Brucker Barbara Burwinkel Carlos Caldas Trinidad Caldés Daniele Campa Federico Canzian Angel Carracedo Brian D Carter Jose E Castelao Jenny Chang-Claude Stephen J Chanock Georgia Chenevix-Trench Ting-Yuan David Cheng Suet-Feung Chin Christine L Clarke Emilie Cordina-Duverger Fergus J Couch David G Cox Angela Cox Simon S Cross Kamila Czene Mary B Daly Peter Devilee Janet A Dunn Alison M Dunning Lorraine Durcan Miriam Dwek Helena M Earl Arif B Ekici A Heather Eliassen Carolina Ellberg Christoph Engel Mikael Eriksson D Gareth Evans Jonine Figueroa Dieter Flesch-Janys Henrik Flyger Marike Gabrielson Manuela Gago-Dominguez Eva Galle Susan M Gapstur Montserrat García-Closas José A García-Sáenz Mia M Gaudet Angela George Vassilios Georgoulias Graham G Giles Gord Glendon David E Goldgar Anna González-Neira Grethe I Grenaker Alnæs Mervi Grip Pascal Guénel Lothar Haeberle Eric Hahnen Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Susan Hankinson Elaine F Harkness Patricia A Harrington Steven N Hart Jaana M Hartikainen Alexander Hein Peter Hillemanns Louise Hiller Bernd Holleczek Antoinette Hollestelle Maartje J Hooning Robert N Hoover John L Hopper Anthony Howell Guanmengqian Huang Keith Humphreys David J Hunter Wolfgang Janni Esther M John Michael E Jones Arja Jukkola-Vuorinen Audrey Jung Rudolf Kaaks Maria Kabisch Katarzyna Kaczmarek Michael J Kerin Sofia Khan Elza Khusnutdinova Johanna I Kiiski Cari M Kitahara Julia A Knight Yon-Dschun Ko Linetta B Koppert Veli-Matti Kosma Peter Kraft Vessela N Kristensen Ute Krüger Tabea Kühl Diether Lambrechts Loic Le Marchand Eunjung Lee Flavio Lejbkowicz Lian Li Annika Lindblom Sara Lindström Martha Linet Jolanta Lissowska Wing-Yee Lo Sibylle Loibl Jan Lubiński Michael P Lux Robert J MacInnis Melanie Maierthaler Tom Maishman Enes Makalic Arto Mannermaa Mehdi Manoochehri Siranoush Manoukian Sara Margolin Maria Elena Martinez Dimitrios Mavroudis Catriona McLean Alfons Meindl Pooja Middha Nicola Miller Roger L Milne Fernando Moreno Anna Marie Mulligan Claire Mulot Rami Nassir Susan L Neuhausen William T Newman Sune F Nielsen Børge G Nordestgaard Aaron Norman Håkan Olsson Nick Orr V Shane Pankratz Tjoung-Won Park-Simon Jose I A Perez Clara Pérez-Barrios Paolo Peterlongo Christos Petridis Mila Pinchev Karoliona Prajzendanc Ross Prentice Nadege Presneau Darya Prokofieva Katri Pylkäs Brigitte Rack Paolo Radice Dhanya Ramachandran Gadi Rennert Hedy S Rennert Valerie Rhenius Atocha Romero Rebecca Roylance Emmanouil Saloustros Elinor J Sawyer Daniel F Schmidt Rita K Schmutzler Andreas Schneeweiss Minouk J Schoemaker Fredrick Schumacher Lukas Schwentner Rodney J Scott Christopher Scott Caroline Seynaeve Mitul Shah Jacques Simard Ann Smeets Christof Sohn Melissa C Southey Anthony J Swerdlow Aline Talhouk Rulla M Tamimi William J Tapper Manuel R Teixeira Maria Tengström Mary Beth Terry Kathrin Thöne Rob A E M Tollenaar Ian Tomlinson Diana Torres Thérèse Truong Constance Turman Clare Turnbull Hans-Ulrich Ulmer Michael Untch Celine Vachon Christi J van Asperen Ans M W van den Ouweland Elke M van Veen Camilla Wendt Alice S Whittemore Walter Willett Robert Winqvist Alicja Wolk Xiaohong R Yang Yan Zhang Douglas F Easton Peter A Fasching Heli Nevanlinna Diana M Eccles Paul D P Pharoah Marjanka K Schmidt

Br J Cancer 2019 03 21;120(6):647-657. Epub 2019 Feb 21.

The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Division of Molecular Pathology, Amsterdam, The Netherlands.

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. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10, 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, 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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Source
http://www.nature.com/articles/s41416-019-0393-x
Publisher Site
http://dx.doi.org/10.1038/s41416-019-0393-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461853PMC
March 2019
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