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APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation.

ABSTRACT: Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3B(del)), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B(del) individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B(del) breast cancers, which seems to be related to hypermutation arising in A3B(del) carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B(del) require additional study, these findings nominate the A3B(del) polymorphism as a potential predictor for cancer immunotherapy.

SUBMITTER: Cescon DW

PROVIDER: S-EPMC4352793 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation.

Cescon David W DW Haibe-Kains Benjamin B Mak Tak W TW

Proceedings of the National Academy of Sciences of the United States of America 20150217 9

Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3B(del)), which has been associated with a paradoxical increase in breast cancer risk. To examine causes an ...[more]

PMID: 25730878

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Project description: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.

Project description:APOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system.In this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour-infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT.The minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one-copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values?<?0.05). Analysis of breast cancers from METABRIC revealed breast cancers from APOBEC3B deletion carriers to have significantly higher abundance of tumour-infiltrating immune cells (P?<?0.001).Taken together, our data suggests that tumour-infiltrating immune cells may be an important feature of breast cancers arising in women with APOBEC3B germline deletion, and that this may be of particular interest in Asian women where the germline deletion is more common.

Project description:Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) mRNA expression is associated with the poor prognosis of estrogen receptor positive (ER+) breast cancer. However, the clinical relevance of APOBEC3B protein expression in patients with breast cancer remains unclear. The present study evaluated the association of APOBEC3B protein expression with clinicopathological features, as well as survival outcomes of patients with breast cancer. Furthermore, the association between APOBEC3B protein expression and tumor infiltrating lymphocytes (TILs) was investigated. APOBEC3B protein expression in 120 patients with breast cancer was evaluated via immunohistochemistry, using a constructed tumor microarray, and TILs were analyzed by hematoxylin and eosin staining. The relevance of APOBEC3B mRNA expression in breast cancer was assessed using a Kaplan-Meier Plotter online tool, as well as the Tumor Immune Estimation Response and The Cancer Genome Atlas databases. The present study assessed APOBEC3B expression in 116 patients with breast cancer and demonstrated that protein expression was significantly associated with ER and progesterone receptor expression, as well as different subtypes of breast cancer. Notably, APOEBC3B protein expression was significantly associated with TILs. Overall, high expression levels of APOBEC3B protein and high levels of TILs were indicative of longer disease-free survival rate. High APOBEC3B mRNA expression was associated with poor relapse-free survival rate, overall survival rate and distant metastasis-free survival rate in patients with breast cancer, particularly for the Luminal A subtype. APOBEC3B mRNA expression was also indicated to be associated with the immune status of patients with breast cancer. Overall, the results of the present study demonstrated that APOBEC3B mRNA and protein expression levels presented different prognostic values in the survival of patients with breast cancer. However, both APOBEC3B mRNA and protein expression levels were associated with TILs in breast cancer. Therefore, APOBEC3B may be a prognostic biomarker for breast cancer.

Project description:Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) is regulated by the mTOR (mammalian target of rapamycin) signaling pathway. Phosphorylated EIF4EBP1 protein leads to pathway activation and correlates with aggressive breast cancer features. However, the clinical relevance of EIF4EBP1 gene expression as a prognostic biomarker in bulk breast tumors is not understood. In this study, EIF4EBP1 expression was analyzed in over 5000 breast cancers from three large independent cohorts, TCGA, METABRIC, and SCAN-B (GSE96058), and expression was dichotomized into low and high groups by the median. We also performed gene set enrichment analysis (GSEA) and cell cybersorting via the xCell algorithm to investigate EIF4EBP1 biology and expression patterns within the tumor microenvironment (TME). We additionally confirmed EIF4EBP1 expression location in the TME via single cell RNA sequencing. EIF4EBP1 expression was highest in both triple negative and high-grade tumors (both P<0.001), and tumor mutational burden scores were highest in the high EIF4EBP1-expression groups (all P<0.001). High EIF4EBP1 expression significantly correlated to worse overall survival in all three cohorts (hazard ratios (HR) 1.4-1.9), and worse distant relapse-free survival in patients treated with neoadjuvant taxane-anthracycline chemotherapy (HR 2.4). GSEA demonstrated enriched mTOR and cell proliferation-related gene sets, including, MYC, G2M checkpoint, and E2F targets across all three bulk tumor and single cell RNA sequencing cohorts. Phenotypically, these pathways were reflected by increased Ki67 gene expression and signaling via pharmacologically-activated mTOR gene sets in EIF4EBP1 high-expressing tumors (all P<0.001). EIF4EBP1 expression was increased in whole breast tumors compared to normal breast tissue (P<0.001), and was expressed predominantly in cancer epithelial cells, particularly in basal epithelial cell subclasses. EIF4EBP1 expression did not correlate to a consistent immune system phenotype across all three cohorts. Overall, these findings support that high EIF4EBP1 gene expression in bulk breast tumors could represent a poor prognostic marker via mTOR signaling pathways activation and upregulation of cell cycling, ultimately leading to increased tumorigenesis.

Dataset Information

APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation.

Publications

APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation.

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