Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Morra A, Escala-Garcia M, Beesley J, Keeman R, Canisius S, Ahearn TU, Andrulis IL, Anton-Culver H, Arndt V, Auer PL, Augustinsson A, Freeman LEB, Becher H, Beckmann M, Behrens S, Bojesen SE, Bolla MK, Brenner H, Bruening T, Buys SS, Caan B, Campa D, Canzian F, Castelao JE, Chang-Claude J, Chanock SJ, Cheng TYD, Clarke CL, Colonna S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Dennis J, Dork T, Dossus L, Dunning AM, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Eriksson M, Evans DG, Fasching P, Flyger H, Fritschi L, Gago-Dominguez M, Garcia-Saenz JA, Giles GG, Grip M, Guenel P, Guendert M, Hahnen E, Haiman CA, Hakansson N, Hall P, Hamann U, Hart SN, Hartikainen JM, Hartmann A, He W, Hooning MJ, Hoppe R, Hopper JL, Howell A, Hunter DJ, Jager A, Jakubowska A, Janni W, John EM, Jung AY, Kaaks R, Keupers M, Kitahara CM, Koutros S, Kraft P, Kristensen VN, Kurian AW, Lacey J, Lambrechts D, Le Marchand L, Lindblom A, Linet M, Luben RN, Lush M, Mannermaa A, Manoochehri M, Margolin S, Martens JWM, Martinez ME, Mavroudis D, Michailidou K, Milne RL, Mulligan AM, Muranen TA, Nevanlinna H, Newman WG, Nielsen SF, Nordestgaard BG, Olshan AF, Olsson H, Orr N, Park-Simon TW, Patel A, Peissel B, Peterlongo P, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Rack B, Rennert G, Rennert HS, Rhenius V, Romero A, Roylance R, Lubinski J, Rübner M, Saloustros E, Sawyer EJ, Schmutzler RK, Schneeweiss A, Scott C, Shah M, Smichkoska S, Southey MC, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper WJ, Teras LR, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Truong T, Vachon CM, Wang Q, Hurson AN, Winqvist R, Wolk A, Ziogas A, Brauch H, Garcia-Closas M, Pharoah PDP, Easton DF, Chenevix-Trench G, Schmidt MK (2021)

Publication Type: Journal article

Publication year: 2021


Book Volume: 23

Journal Issue: 1

DOI: 10.1186/s13058-021-01450-7


Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

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Involved external institutions

Antoni van Leeuwenhoek NL Netherlands (NL) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) National Cancer Institute (NCI) US United States (USA) (US) Mount Sinai Hospital (MSH) CA Canada (CA) University of California Irvine US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Fred Hutchinson Cancer Research Center US United States (USA) (US) Lund University / Lunds universitet SE Sweden (SE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Copenhagen University Hospital DK Denmark (DK) University of Cambridge GB United Kingdom (GB) Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung (IPA) DE Germany (DE) University of Utah US United States (USA) (US) Kaiser Permanente US United States (USA) (US) Servizo Galego de Saúde ES Spain (ES) Roswell Park Cancer Institute US United States (USA) (US) University of Sydney (USYD) AU Australia (AU) Mayo Clinic US United States (USA) (US) University of Sheffield GB United Kingdom (GB) Karolinska Institute SE Sweden (SE) Fox Chase Cancer Center US United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) World Health Organization CH Switzerland (CH) University of Westminster GB United Kingdom (GB) University of Southampton GB United Kingdom (GB) Brigham and Women's Hospital (BWH) US United States (USA) (US) University of Manchester GB United Kingdom (GB) Curtin University AU Australia (AU) Fundación Pública Galega de Medicina Xenómica ES Spain (ES) Hospital Clínico San Carlos ES Spain (ES) Cancer Council Victoria AU Australia (AU) Oulun Yliopisto / University of Oulo FI Finland (FI) École Polytechnique - Université Paris-Saclay FR France (FR) Universität zu Köln DE Germany (DE) University of Southern California (USC) US United States (USA) (US) Erasmus University Medical Center (MC) NL Netherlands (NL) Harvard University US United States (USA) (US) Universitätsklinikum Ulm DE Germany (DE) Stanford University US United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) BE Belgium (BE) University of Hawaii (U.H.) US United States (USA) (US) University of Eastern Finland FI Finland (FI) Södersjukhuset SE Sweden (SE) University of California, San Diego US United States (USA) (US) University General Hospital of Heraklion GR Greece (GR) University of Toronto CA Canada (CA) Helsingin yliopisto / University of Helsinki FI Finland (FI) University of North Carolina at Chapel Hill US United States (USA) (US) Queen's University GB United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Saints Cyril and Methodius University of Skopje / Универзитет „Св. Кирил и Методиј“ во Скопје MK Republic of North Macedonia (MK) The University of Melbourne AU Australia (AU) The Institute of Cancer Research (ICR) GB United Kingdom (GB) American Cancer Society US United States (USA) (US) Columbia University US United States (USA) (US) Leiden University Medical Center NL Netherlands (NL) University of Birmingham GB United Kingdom (GB) Robert-Bosch-Krankenhaus DE Germany (DE) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) University of Oslo NO Norway (NO) City of Hope Medical Center US United States (USA) (US) Fondazione IRCCS: Istituto Nazionale dei Tumori IT Italy (IT) IFOM - FIRC Institute of Molecular Oncology IT Italy (IT) Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov" (RCGEB) MK Republic of North Macedonia (MK) Carmel Medical Center IL Israel (IL) Hospital Universitario Puerta de Hierro - Majadahonda ES Spain (ES) University College London Hospitals (UCLH) GB United Kingdom (GB) General University Hospital of Larissa GR Greece (GR) King’s College London GB United Kingdom (GB)

How to cite


Morra, A., Escala-Garcia, M., Beesley, J., Keeman, R., Canisius, S., Ahearn, T.U.,... Schmidt, M.K. (2021). Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. BREAST CANCER RES , 23(1).


Morra, Anna, et al. "Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment." BREAST CANCER RES 23.1 (2021).

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