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

Journal

Book Volume: 23

Journal Issue: 1

DOI: 10.1186/s13058-021-01450-7

Abstract

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.

Authors with CRIS profile

Involved external institutions

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

How to cite

APA:

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). https://doi.org/10.1186/s13058-021-01450-7

MLA:

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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