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

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.

Low Tumor Mitochondrial DNA Content Is Associated with Better Outcome in Breast Cancer Patients Receiving Anthracycline-Based Chemotherapy

“…DNA extracts from an earlier retrospective study (21) were selected from our bio-bank at the Erasmus MC ( Supplementary Fig. S1).…”

“…22). Followup and tumor response were defined based on the criteria by the International Union Against Cancer (23) and the European Organization for Research and Treatment of Cancer (24) as described previously (21). Estrogen receptor (ER) status, progesterone receptor (PR) status, and ERBB2 (HER2) amplification were determined as described before (25,26,27).…”

“…Of the 121 patients, none (0%) received neoadjuvant therapy and 34 (28%) received prior adjuvant chemotherapy (7 CMF, 17 FAC/FEC, and 9 cyclophosphamide monotherapy). Overall response was defined as described previously (21), and a total of 69 patients responded to chemotherapy (5 with complete remission, 38 with partial remission, 26 with stable disease > 6 courses) and 51 patients showed no response to chemotherapy (36 with progression, 15 with stable disease 6 courses; Supplementary Table S3). For 1 patient, the type of response was ambiguous.…”

Induced mutagenesis by the DNA cytosine deaminase APOBEC3H Haplotype I protects against lung cancer

“…A3H Hap I was identified to induce genomic mutations specifically in lung cancer 13 . Interestingly, the activity of A3H Hap I was found because researchers wanted to investigate how genomic mutations with a cytidine deaminase signature were still occurring in people with an A3B-/-deletion [51][52][53][54] , which occurs in the world population at 22.5%, although it primarily occurs in Oceanic populations 44 . Although A3A is also involved in cancer mutagenesis, it appears to be strongly associated with breast cancer 31,55 .…”

The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population

“…On the other hand, our expression results are generally inline with the results of Starrett et al [ 64 ] who, also using artificial model (CRISPR/Cas9 generated deletion), showed high expression of APOBEC3B and very low but similar expression of APOBEC3A and APOBEC3A/APOBEC3B. The previous studies of the APOBEC3B deletion genotype-expression relationship (i) did not distinguish the canonical APOBEC3A and the hybrid APOBEC3A/APOBEC3B transcripts, and/or (ii) were conducted using artificially created cell line models with transfected reporter constructs, and/or (iii) were performed with the use of single tissue or cell line samples, and/or (iv) were often inconclusive, at least partially due to high homology between APOBEC3A and APOBEC3B , as well as other members of the APOBEC3 gene family [ 32 , 33 , 40 , 63 , 64 , 73 , 78 , 80 , 81 ].…”