Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis
Authors: Escala-Garcia Maria , Canisius Sander , Keeman Renske , Beesley Jonathan , Anton-Culver Hoda , Arndt Volker , Augustinsson Annelie , Becher Heiko , Beckmann Matthias W. , Behrens Sabine , Bermisheva Marina , Bojesen Stig E. , Bolla Manjeet K. , Brenner Hermann , Canzian Federico , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Couch Fergus J. , Czene Kamila , Daly Mary B. , Dennis Joe , Devilee Peter , Dörk Thilo , Dunning Alison M. , Easton Douglas F. , Ekici Arif B. , Eliassen A. Heather , Fasching Peter A. , Flyger Henrik , Gago-Dominguez Manuela , García-Closas Montserrat , García-Sáenz José A. , Geisler Jürgen , Giles Graham G. , Grip Mervi , Gündert Melanie , Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Hartikainen Jaana M. , Heemskerk-Gerritsen Bernadette A. M. , Hollestelle Antoinette , Hoppe Reiner , Hopper John L. , Hunter David J. , Jacot William , Jakubowska Anna , John Esther M. , Jung Audrey Y. , Kaaks Rudolf , Khusnutdinova Elza , Koppert Linetta B. , Kraft Peter , Kristensen Vessela N. , Kurian Allison W. , Lambrechts Diether , Le Marchand Loic , Lindblom Annika , Luben Robert N. , Lubiński Jan , Mannermaa Arto , Manoochehri Mehdi , Margolin Sara , Mavroudis Dimitrios , Muranen Taru A. , Nevanlinna Heli , Olshan Andrew F. , Olsson Håkan , Park-Simon Tjoung-Won , Patel Alpa V. , Peterlongo Paolo , Pharoah Paul D. P. , Punie Kevin , Radice Paolo , Rennert Gad , Rennert Hedy S. , Romero Atocha , Roylance Rebecca , Rüdiger Thomas , Ruebner Matthias , Saloustros Emmanouil , Sawyer Elinor J. , Schmutzler Rita K. , Schoemaker Minouk J. , Scott Christopher , Southey Melissa C. , Surowy Harald , Swerdlow Anthony J. , Tamimi Rulla M. , Teras Lauren R. , Thomas Emilie , Tomlinson Ian , Troester Melissa A. , Vachon Celine M. , Wang Qin , Winqvist Robert , Wolk Alicja , Ziogas Argyrios ,   kConFab/AOCS Investigators, Michailidou Kyriaki , Chenevix-Trench Georgia , Bachelot Thomas , Schmidt Marjanka K. 
Published: October 2021

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.