A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
Authors: Escala-Garcia Maria , Abraham Jean , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Ashworth Alan , Auer Paul L. , Auvinen Päivi , Beckmann Matthias W. , Beesley Jonathan , Behrens Sabine , Benitez Javier , Bermisheva Marina , Blomqvist Carl , Blot William , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Børresen-Dale Anne-Lise , Brauch Hiltrud , Brenner Hermann , Brucker Sara Y. , Burwinkel Barbara , Caldas Carlos , Canzian Federico , Chang-Claude Jenny , Chanock Stephen J. , Chin Suet-Feung , Clarke Christine L. , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Dennis Joe , Devilee Peter , Dunn Janet A. , Dunning Alison M. , Dwek Miriam , Earl Helena M. , Eccles Diana M. , Eliassen A. Heather , Ellberg Carolina , Evans D. Gareth , Fasching Peter A. , Figueroa Jonine , Flyger Henrik , Gago-Dominguez Manuela , Gapstur Susan M. , García-Closas Montserrat , García-Sáenz José A. , Gaudet Mia M. , George Angela , Giles Graham G. , Goldgar David E. , González-Neira Anna , Grip Mervi , Guénel Pascal , Guo Qi , Haiman Christopher A. , Håkansson Niclas , Hamann Ute , Harrington Patricia A. , Hiller Louise , Hooning Maartje J. , Hopper John L. , Howell Anthony , Huang Chiun-Sheng , Huang Guanmengqian , Hunter David J. , Jakubowska Anna , John Esther M. , Kaaks Rudolf , Kapoor Pooja Middha , Keeman Renske , Kitahara Cari M. , Koppert Linetta B. , Kraft Peter , Kristensen Vessela N. , Lambrechts Diether , Le Marchand Loic , Lejbkowicz Flavio , Lindblom Annika , Lubiński Jan , Mannermaa Arto , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Martinez Maria Elena , Maurer Tabea , Mavroudis Dimitrios , Meindl Alfons , Milne Roger L. , Mulligan Anna Marie , Neuhausen Susan L. , Nevanlinna Heli , Newman William G. , Olshan Andrew F. , Olson Janet E. , Olsson Håkan , Orr Nick , Peterlongo Paolo , Petridis Christos , Prentice Ross L. , Presneau Nadege , Punie Kevin , Ramachandran Dhanya , Rennert Gad , Romero Atocha , Sachchithananthan Mythily , Saloustros Emmanouil , Sawyer Elinor J. , Schmutzler Rita K. , Schwentner Lukas , Scott Christopher , Simard Jacques , Sohn Christof , Southey Melissa C. , Swerdlow Anthony J. , Tamimi Rulla M. , Tapper William J. , Teixeira Manuel R. , Terry Mary Beth , Thorne Heather , Tollenaar Rob A. E. M. , Tomlinson Ian , Troester Melissa A. , Truong Thérèse , Turnbull Clare , Vachon Celine M. , van der Kolk Lizet E. , Wang Qin , Winqvist Robert , Wolk Alicja , Yang Xiaohong R. , Ziogas Argyrios , Pharoah Paul D. P. , Hall Per , Wessels Lodewyk F. A. , Chenevix-Trench Georgia , Bader Gary D. , Dörk Thilo , Easton Douglas F. , Canisius Sander , Schmidt Marjanka K. 
Published: January 2020

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.