Citations 2
APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma
Leonard, Brandon , Starrett, Gabriel J. , Oberg, Ann L. , Bockstal, Mieke Van , Helleman, Jozien , Sieuwerts, Anieta M. , Berns, Els M.J.J., Anderson, Brett D. , Brown, William L. , Kalli, Kimberly R., Kaufmann, Scott H. , Maurer, Matthew J. , Van Dorpe, Jo , Wever, Olivier De , Martens, John W.M. , Harris, Reuben S. , Kaufmann, Scott H
Clinical Cancer Research | March 25, 2016 | Volume: 22 | Issue: 18 | Pages: 4746-4755
Abstract Purpose: APOBEC3 DNA cytosine deaminase family members normally defend against viruses and transposons. However, deregulated APOBEC3 activity causes mutations in cancer. Because of broad expression profiles and varying mixtures of normal and cancer cells in tumors, including immune cell infiltration, it is difficult to determine where different APOBEC3s are expressed. Here, we ask whether correlations exist between APOBEC3 expression and T-cell infiltration in high-grade serous ovarian cancer (HGSOC), and assess whether these correlations have prognostic value. Experimental Design: Transcripts for APOBEC3G, APOBEC3B, and the T-cell markers, CD3D, CD4, CD8A, GZMB, PRF1, and RNF128 were quantified by RT-qPCR for a cohort of 354 HGSOC patients. Expression values were correlated with each other and clinical parameters. Two additional cohorts were used to extend HGSOC clinical results. Immunoimaging was used to colocalize APOBEC3G and the T-cell marker CD3. TCGA data extended expression analyses to additional cancer types. Results: A surprising positive correlation was found for expression of APOBEC3G and several T cell genes in HGSOC. Immunohistochemistry and immunofluorescent imaging showed protein colocalization in tumor-infiltrating T lymphocytes. High APOBEC3G expression correlated with improved outcomes in multiple HGSOC cohorts. TCGA data analyses revealed that expression of APOBEC3D and APOBEC3H also correlates with CD3D across multiple cancer types. Conclusions: Our results identify APOBEC3G as a new candidate biomarker for tumor-infiltrating T lymphocytes and favorable prognoses for HGSOC. Our data also highlight the complexity of the tumor environment with respect to differential APOBEC family gene expression in both tumor and surrounding normal cell types. Clin Cancer Res; 22(18); 4746–55. ©2016 AACR.
APOBEC3B Upregulation and Genomic Mutation Patterns in Serous Ovarian Carcinoma
Leonard, Brandon , Hart, Steven N. , Burns, Michael B. , Carpenter, Michael A. , Temiz, Nuri A. , Vogel, Rachel I. , Nikas, Jason B. , Brown, William L. , Zhang, Yuji , Maurer, Matthew J. , Oberg, Ann L. , Cunningham, Julie M. , Shridhar, Viji , Bell, Debra A., April, Craig, Bentley, David, Bibikova, Marina, Cheetham, R. Keira, Fan, Jian‐Bing , Grocock, Russell, Humphray, Sean, Kingsbury, Zoya, Peden, John F., Chien, Jeremy , Swisher, Elizabeth M. , Hartmann, Lynn C. , Kalli, Kimberly R., Goode, Ellen L. , Sicotte, Hugues , Rathore, Anurag Singh , Law, Emily K. , Li, Ying , Kaufmann, Scott H. , Harris, Reuben S. , Maurer, Matthew , Chien, Jeremey , Swisher, Elizabeth M , Vogel, Rachel I , Hart, Steven N , Temiz, Nuri A
Cancer Research | October 24, 2013 | Volume: 73 | Issue: 24 | Pages: 7222-7231
Abstract Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. Cancer Res; 73(24); 7222–31. ©2013 AACR.