The 29.5 kb APOBEC3B Deletion Polymorphism Is Not Associated with Clinical Outcome of Breast Cancer.

Jingjing Liu,Maxime P Look,Marion E Meijer-Van Gelder,Anieta M Sieuwerts,John A Foekens,Antoinette Hollestelle,John W M Martens,Michelle Van Der Vlugt-Daane

doi:10.1371/journal.pone.0161731

Jingjing Liu, Maxime P Look + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0161731

Copy DOI

Abstract

Increased APOBEC3B mRNA levels are associated with a hypermutator phenotype and poor prognosis in ER-positive breast cancer patients. In addition, a 29.5 kb deletion polymorphism of APOBEC3B, resulting in an APOBEC3A-B hybrid transcript, has been associated with an increased breast cancer risk and the hypermutator phenotype. Here we evaluated whether the APOBEC3B deletion polymorphism also associates with clinical outcome of breast cancer. Copy number analysis was performed by quantitative PCR (qPCR) in primary tumors of 1,756 Dutch breast cancer patients. The APOBEC3B deletion was found in 187 patients of whom 16 carried a two-copy deletion and 171 carried a one-copy deletion. The prognostic value of the APOBEC3B deletion for the natural course of the disease was evaluated among 1,076 lymph-node negative (LNN) patients who did not receive adjuvant systemic treatment. No association was found between APOBEC3B copy number values and the length of metastasis-free survival (MFS; hazard ratio (HR) = 1.00, 95% confidence interval (CI) = 0.90–1.11, P = 0.96). Subgroup analysis by ER status also did not reveal an association between APOBEC3B copy number values and the length of MFS. The predictive value of the APOBEC3B deletion was assessed among 329 ER-positive breast cancer patients who received tamoxifen as the first-line therapy for recurrent disease and 226 breast cancer patients who received first-line chemotherapy for recurrent disease. No association between APOBEC3B copy number values and the overall response rate (ORR) to either tamoxifen (odds ratio (OR) = 0.88, 95% CI = 0.69–1.13, P = 0.31) or chemotherapy (OR = 0.97, 95% CI = 0.71–1.33, P = 0.87) was found. Thus, in contrast to APOBEC3B mRNA levels, the APOBEC3B deletion polymorphism has neither a prognostic nor a predictive value for breast cancer patients. Although a correlation exists between APOBEC3B copy number and mRNA expression, it is relatively weak. This suggests that other mechanisms exist that may affect and therefore determine the prognostic value of APOBEC3B mRNA levels.

Highlights

IntroductionThe heterogeneous nature of breast cancer, provides challenges for identifying appropriate markers for disease susceptibility and progression, as well as treatment selection
Breast cancer, like most cancer types, is a heterogeneous disease
APOBEC3B mRNA expression is upregulated in multiple tumor types and this has been shown to correlate with an increased mutational load, an increase in C>T transversions [13,14]

Summary

Introduction

The heterogeneous nature of breast cancer, provides challenges for identifying appropriate markers for disease susceptibility and progression, as well as treatment selection. The catalogues of mutations across human cancers have provided us insight into the mutational processes that drive tumorigenesis [6,7]. One of the most pronounced mutational processes impacting breast tumorigenesis is driven by the AID/ APOBEC family of cytidine deaminases and gives rise to C>T and C>G substitutions at TpCpN nucleotides. This mutational process associates with regional somatic hypermutation or kataegis [6,7,8]

Methods

Results

Conclusion