title: APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brandon
authors.initials: B
authors.lastname: Leonard
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Starrett
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Van Bockstal
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Van Dorpe
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Jozien
authors.initials: J
authors.lastname: Helleman
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Anderson
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: William L
authors.initials: WL
authors.lastname: Brown
authors.affiliation: Women's Cancer Program, Mayo Clinic Cancer Center, Rochester, Minnesota.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota. rsh@umn.edu.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D000071480:APOBEC-3G Deaminase / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism*; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human