title: 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.
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Dr. Molewaterplein 50, 3015 GE, Rotterdam, Netherlands.
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: Scooter
authors.initials: S
authors.lastname: Willis
authors.forename: Michael B
authors.initials: MB
authors.lastname: Burns
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: Marion E
authors.initials: ME
authors.lastname: Meijer-Van Gelder
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.forename: Marinus R
authors.initials: MR
authors.lastname: Heideman
authors.forename: Heinz
authors.initials: H
authors.lastname: Jacobs
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Gray
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D015331:Cohort Studies; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase