Abstract
Human endogenous retroviruses (HERV) encode 8% of the human genome. While HERVs may play a role in autoimmune and neoplastic disease, no mechanistic association has yet been established. We studied the expression and immunogenicity of a HERV-K GAG protein encoded on chromosome 22q11.23 in relation to the clinical course of prostate cancer. In vitro expression of GAG-HERV-K was analyzed in panels of normal and malignant tissues, microarrays, and cell lines, and effects of demethylation and androgen stimulation were evaluated. Patient sera were analyzed for seroreactivity to GAG-HERV-K and other self-antigens by ELISA and seromics (protein array profiling). GAG-HERV-K expression was most frequent in prostate tissues and regulated both by demethylation of the promoter region and by androgen stimulation. Serum screening revealed that antibodies to GAG-HERV-K are found in a subset of patients with prostate cancer (33 of 483, 6.8%) but rarely in male healthy donors (1 of 55, 1.8%). Autoantibodies to GAG-HERV-K occurred more frequently in patients with advanced prostate cancer (29 of 191 in stage III-IV, 21.0%) than in early prostate cancer (4 of 292 in stages I-II, 1.4%). Presence of GAG-HERV-K serum antibody was correlated with worse survival of patients with prostate cancer, with a trend for faster biochemical recurrence in patients with antibodies to GAG-HERV-K. Preferential expression of GAG-HERV-K ch22q11.23 in prostate cancer tissue and increased frequency of autoantibodies observed in patients with advanced prostate cancer make this protein one of the first bona fide retroviral cancer antigens in humans, with potential as a biomarker for progression and biochemical recurrence rate of prostate cancer. Clin Cancer Res; 19(22); 6112-25. ©2013 AACR.
Highlights
Human endogenous retroviruses (HERV) are genome modifiers of exogenous origin that became integrated in the human genome millions of years ago and represent 8% of total DNA sequences
Serum screening revealed that antibodies to GAG-HERV-K are found in a subset of patients with prostate cancer (33 of 483, 6.8%) but rarely in male healthy donors (1 of 55, 1.8%)
Preferential expression of GAG-HERV-K ch22q11.23 in prostate cancer tissue and increased frequency of autoantibodies observed in patients with advanced prostate cancer make this protein one of the first bona fide retroviral cancer antigens in humans, with potential as a biomarker for progression and biochemical recurrence rate of prostate cancer
Summary
Human endogenous retroviruses (HERV) are genome modifiers of exogenous origin that became integrated in the human genome millions of years ago and represent 8% of total DNA sequences. They are classified into 30 to 50. Authors' Affiliations: 1Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center; Departments of 2Surgery, 3Medicine, 4Pathology, 5Biostatistics, and 6Immunology, Memorial Sloan-Kettering Cancer Center; 7NYU Langone Medical Center, New York; 8Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama; 9RIKEN Bioresource Center, Tsukuba, Ibaraki, Japan; and 10Klinik fu€r Onkologie und Ha€matologie, Krankenhaus Nordwest, Frankfurt, Germany. Ritter: Ludwig Institute for Cancer Research Ltd, families, family K being the most recently identified [1]. Most HERV genes have mutations or deletions in their coding and promoter sequence, which compromise their gene and/or protein
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