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

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.

Metadata

Authors/Creators:	Morra, A Escala-Garcia, M Beesley, J Keeman, R Canisius, S Ahearn, TU Andrulis, IL Anton-Culver, H Arndt, V Auer, PL Augustinsson, A Beane Freeman, LE Becher, H Beckmann, MW Behrens, S Bojesen, SE Bolla, MK Brenner, H Brüning, T Buys, SS Caan, B Campa, D Canzian, F Castelao, JE Chang-Claude, J Chanock, SJ Cheng, T-YD Clarke, CL Børresen-Dale, A-L Sahlberg, KK Ottestad, L Kåresen, R Schlichting, E Holmen, MM Sauer, T Haakensen, V Engebråten, O Naume, B Fosså, A Kiserud, CE Reinertsen, KV Helland, Å Riis, M Geisler, J Grenaker Alnæs, GI Colonna, SV Couch, FJ Cox, A https://orcid.org/0000-0002-5138-1099 Cross, SS Czene, K Daly, MB Dennis, J Dörk, T Dossus, L Dunning, AM Dwek, M Eccles, DM Ekici, AB Eliassen, AH Eriksson, M Evans, DG Fasching, PA Flyger, H Fritschi, L Gago-Dominguez, M García-Sáenz, JA Giles, GG Grip, M Guénel, P Gündert, M Hahnen, E Haiman, CA Håkansson, N Hall, P Hamann, U Hart, SN Hartikainen, JM Hartmann, A He, W Hooning, MJ Hoppe, R Hopper, JL Howell, A Hunter, DJ Clarke, C Marsh, D Scott, R Baxter, R Yip, D Carpenter, J Davis, A Pathmanathan, N Simpson, P Graham, JD Sachchithananthan, M 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, JV Lambrechts, D Le Marchand, L Lindblom, A Linet, M Luben, RN Lubiński, J 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, T-W Patel, AV 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 Ruebner, 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 García-Closas, M Pharoah, PDP Easton, DF Chenevix-Trench, G Schmidt, MK
Copyright, Publisher and Additional Information:	© 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords:	Common germline genetic variants; Breast cancer-specific survival; Patient subgroups; Tumor biology; Systemic treatment
Dates:	Accepted: 28 June 2021 Published (online): 18 August 2021 Published: 18 August 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	23 Aug 2021 12:51
Last Modified:	23 Aug 2021 12:51
Status:	Published
Publisher:	BioMed Central
Refereed:	Yes
Identification Number:	https://doi.org/10.1186/s13058-021-01450-7

Download

Published Version

Filename: s13058-021-01450-7.pdf

Licence: CC-BY 4.0

CLICK TO DOWNLOAD

CORE (COnnecting REpositories)

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

Abstract

Metadata

Download

Published Version

Export

Statistics