Elevated APOBEC3B correlates with poor outcomes for estrogen-receptor-positive breast cancers

Abstract

Recent observations connected DNA cytosine deaminase APOBEC3B to the genetic evolution of breast cancer. We addressed whether APOBEC3B is associated with breast cancer clinical outcomes. APOBEC3B messenger RNA (mRNA) levels were related in 1,491 primary breast cancers to disease-free (DFS), metastasis-free (MFS), and overall survival (OS). For independent validation, APOBEC3B mRNA expression was associated with patient outcome data in five additional cohorts (over 3,500 breast cancer cases). In univariate Cox regression analysis, increasing APOBEC3B expression as a continuous variable was associated with worse DFS, MFS, and OS (hazard ratio [HR] = 1.20, 1.21, and 1.24, respectively; all P < .001). Also, in untreated ER-positive (ER+), but not in ER-, lymph-node-negative patients, high APOBEC3B levels were associated with a poor DFS (continuous variable: HR = 1.29, P = .001; dichotomized at the median level, HR = 1.66, P = .0002). This implies that APOBEC3B is a marker of pure prognosis in ER + disease. These findings were confirmed in the analyses of five independent patient sets. In these analyses, APOBEC3B expression dichotomized at the median level was associated with adverse outcomes (METABRIC discovery and validation, 788 and 706 ER + cases, disease-specific survival (DSS), HR = 1.77 and HR = 1.77, respectively, both P < .001; Affymetrix dataset, 754 ER + cases, DFS, HR = 1.57, P = 2.46E-04; NKI295, 181 ER + cases, DFS, HR = 1.72, P = .054; and BIG 1-98, 1,219 ER + cases, breast-cancer-free interval (BCFI), HR = 1.42, P = 0.0079). APOBEC3B is a marker of pure prognosis and poor outcomes for ER + breast cancer, which strongly suggests that genetic aberrations induced by APOBEC3B contribute to breast cancer progression.

Fig. 1

Kaplan-Meier survival analysis for the Rotterdam cohort. Kaplan-Meier curves for disease-free survival (a), metastasis-free survival (b), and overall survival analysis (c) for all 633 lymph-node-negative patients with estrogen-receptor-positive disease who did not receive any adjuvant systemic therapy divided at the median APOBEC3B mRNA expression level. Red and blue graphs represent APOBEC3B mRNA expression below and above the median respectively. Y-axis expresses cumulative survival rate (Color figure online)

Fig. 2

Kaplan-Meier survival analysis of validation cohorts including only cases with estrogen-receptor-positive disease. Kaplan-Meier curves for DSS in the METABRIC discovery (a) and METABRIC validation cohort (b), for DFS in the NKI cohort (c) and for DFS in a combined cohort including publically available Affymetrix datasets (d), and for BCFI in the prospective collected BIG 1-98 cohort (e). All cohorts were divided using the median APOBEC3B mRNA expression level. Red and blue graphs represent APOBEC3B mRNA expression below and above the median respectively. Y-axis expresses cumulative survival rate (Color figure online)