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.


Type
Article
Change log
Authors
Morra, Anna 
Escala-Garcia, Maria 
Beesley, Jonathan 
Keeman, Renske 
Canisius, Sander 
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.

Description
Keywords
Breast cancer-specific survival, Common germline genetic variants, Patient subgroups, Systemic treatment, Tumor biology, Breast Neoplasms, Female, Genome-Wide Association Study, Germ-Line Mutation, Humans, Polymorphism, Single Nucleotide, Prognosis, Survival Analysis
Journal Title
Breast Cancer Res
Conference Name
Journal ISSN
1465-5411
1465-542X
Volume Title
23
Publisher
Springer Science and Business Media LLC
Rights
All rights reserved
Sponsorship
Cancer Research UK (A16563)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
European Commission Horizon 2020 (H2020) Societal Challenges (634935)
European Commission Horizon 2020 (H2020) Societal Challenges (633784)
Cancer Research UK (A10710)
Cancer Research UK (A12014)
Cancer Research UK (A10118)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (16565)
National Cancer Institute (U19CA148537)
European Commission (223175)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
Medical Research Council (MR/N003284/1)
National Cancer Institute (P30CA023100)