Common germline polymorphisms associated with breast cancer-specific survival
Authors: Pirie Ailith , Guo Qi , Kraft Peter , Canisius Sander , Eccles Diana M , Rahman Nazneen , Nevanlinna Heli , Chen Constance , Khan Sofia , Tyrer Jonathan , Bolla Manjeet K , Wang Qin , Dennis Joe , Michailidou Kyriaki , Lush Michael , Dunning Alison M , Shah Mitul , Czene Kamila , Darabi Hatef , Eriksson Mikael , Lambrechts Dieter , Weltens Caroline , Leunen Karin , van Ongeval Chantal , Nordestgaard Børge G , Nielsen Sune F , Flyger Henrik , Rudolph Anja , Seibold Petra , Flesch-Janys Dieter , Blomqvist Carl , Aittomäki Kristiina , Fagerholm Rainer , Muranen Taru A , Olsen Janet E , Hallberg Emily , Vachon Celine , Knight Julia A , Glendon Gord , Mulligan Anna Marie , Broeks Annegien , Cornelissen Sten , Haiman Christopher A , Henderson Brian E , Schumacher Frederick , Le Marchand Loic , Hopper John L , Tsimiklis Helen , Apicella Carmel , Southey Melissa C , Cross Simon S , Reed Malcolm WR , Giles Graham G , Milne Roger L , McLean Catriona , Winqvist Robert , Pylkäs Katri , Jukkola-Vuorinen Arja , Grip Mervi , Hooning Maartje J , Hollestelle Antoinette , Martens John WM , van den Ouweland Ans MW , Marme Federick , Schneeweiss Andreas , Yang Rongxi , Burwinkel Barbara , Figueroa Jonine , Chanock Stephen J , Lissowska Jolanta , Sawyer Elinor J , Tomlinson Ian , Kerin Michael J , Miller Nicola , Brenner Hermann , Butterbach Katja , Holleczek Bernd , Kataja Vesa , Kosma Veli-Matti , Hartikainen Jaana M , Li Jingmei , Brand Judith S , Humphreys Keith , Devilee Peter , Tollenaar Robert AEM , Seynaeve Caroline , Radice Paolo , Peterlongo Paolo , Manoukian Siranoush , Ficarazzi Filomena , Beckmann Matthias W , Hein Alexander , Ekici Arif B , Balleine Rosemary , Phillips Kelly-Anne ,   kConFab Investigators, Benitez Javier , Zamora M Pilar , Perez Jose Ignacio Arias , Menéndez Primitiva , Jakubowska Anna , Lubinski Jan , Gronwald Jacek , Durda Katarzyna , Hamann Ute , Kabisch Maria , Ulmer Hans Ulrich , Rüdiger Thomas , Margolin Sara , Kristensen Vessela , Nord Siljie ,   NBCS Investigators, Evans D Gareth , Abraham Jean , Earl Helena , Poole Christopher J , Hiller Louise , Dunn Janet A , Bowden Sarah , Yang Rose , Campa Daniele , Diver W Ryan , Gapstur Susan M , Gaudet Mia M , Hankinson Susan , Hoover Robert N , Hüsing Anika , Kaaks Rudolf , Machiela Mitchell J , Willett Walter , Barrdahl Myrto , Canzian Federico , Chin Suet-Feung , Caldas Carlos , Hunter David J , Lindstrom Sara , Garcia-Closas Montserrat , Couch Fergus J , Chenevix-Trench Georgia , Mannermaa Arto , Andrulis Irene L , Hall Per , Chang-Claude Jenny , Easton Douglas F , Bojesen Stig E , Cox Angela , Fasching Peter A , Pharoah Paul DP , Schmidt Marjanka K 
Published: April 2015

Abstract
Introduction
Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.

Methods
A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect.

Results
Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease.

Conclusions
Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.