APOBEC3G expression correlates with T-cell infiltration and improved clinical outcomes in high-grade serous ovarian carcinoma

Brandon Leonard, Gabriel J. Starrett, Matthew J. Maurer, Ann L Oberg, Mieke Van Bockstal, Jo Van Dorpe, Olivier De Wever, Jozien Helleman, Anieta M. Sieuwerts, Els M J J Berns, John W M Martens, Brett D. Anderson, William L. Brown, Kimberly R. Kalli, Scott H Kaufmann, Reuben S. Harris

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4746-4755
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2016

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Ovarian Neoplasms
Carcinoma
T-Lymphocytes
Neoplasms
Tumor-Infiltrating Lymphocytes
Cytosine Deaminase
Research Design
Biomarkers
Immunohistochemistry
Viruses
Gene Expression
Mutation
DNA
Genes
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

APOBEC3G expression correlates with T-cell infiltration and improved clinical outcomes in high-grade serous ovarian carcinoma. / Leonard, Brandon; Starrett, Gabriel J.; Maurer, Matthew J.; Oberg, Ann L; Van Bockstal, Mieke; Van Dorpe, Jo; De Wever, Olivier; Helleman, Jozien; Sieuwerts, Anieta M.; Berns, Els M J J; Martens, John W M; Anderson, Brett D.; Brown, William L.; Kalli, Kimberly R.; Kaufmann, Scott H; Harris, Reuben S.

In: Clinical Cancer Research, Vol. 22, No. 18, 15.09.2016, p. 4746-4755.

Research output: Contribution to journalArticle

Leonard, B, Starrett, GJ, Maurer, MJ, Oberg, AL, Van Bockstal, M, Van Dorpe, J, De Wever, O, Helleman, J, Sieuwerts, AM, Berns, EMJJ, Martens, JWM, Anderson, BD, Brown, WL, Kalli, KR, Kaufmann, SH & Harris, RS 2016, 'APOBEC3G expression correlates with T-cell infiltration and improved clinical outcomes in high-grade serous ovarian carcinoma', Clinical Cancer Research, vol. 22, no. 18, pp. 4746-4755. https://doi.org/10.1158/1078-0432.CCR-15-2910
Leonard, Brandon ; Starrett, Gabriel J. ; Maurer, Matthew J. ; Oberg, Ann L ; Van Bockstal, Mieke ; Van Dorpe, Jo ; De Wever, Olivier ; Helleman, Jozien ; Sieuwerts, Anieta M. ; Berns, Els M J J ; Martens, John W M ; Anderson, Brett D. ; Brown, William L. ; Kalli, Kimberly R. ; Kaufmann, Scott H ; Harris, Reuben S. / APOBEC3G expression correlates with T-cell infiltration and improved clinical outcomes in high-grade serous ovarian carcinoma. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 18. pp. 4746-4755.
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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.",
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T1 - APOBEC3G expression correlates with T-cell infiltration and improved clinical outcomes in high-grade serous ovarian carcinoma

AU - Leonard, Brandon

AU - Starrett, Gabriel J.

AU - Maurer, Matthew J.

AU - Oberg, Ann L

AU - Van Bockstal, Mieke

AU - Van Dorpe, Jo

AU - De Wever, Olivier

AU - Helleman, Jozien

AU - Sieuwerts, Anieta M.

AU - Berns, Els M J J

AU - Martens, John W M

AU - Anderson, Brett D.

AU - Brown, William L.

AU - Kalli, Kimberly R.

AU - Kaufmann, Scott H

AU - Harris, Reuben S.

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N2 - 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.

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