Relevance of the Viral RAK Alpha Gene in Diagnosis of Malignant Versus Nonmalignant Tumors of the Ovary and Uterus

Abstract

Human immunodeficiency virus type 1 (HIV-1)-like antigens RAK (named after the inventor E. M. Rakowicz) p120, p42, and p25, as well as HIV-1-like segments of cancer DNA (RAK gene alpha), have been found before in breast and prostate cancers. The present study focused on determining the value of markers RAK in the diagnosis and prognosis of gynecological cancer. Expression of RAK antigens in ovarian, uterine, cervical, and vulvar cancer, in benign tumors, in tissues adjacent to cancer, and in normal tissues was tested by Western blot hybridization of the electrophoretically separated proteins with monoclonal antibody RAK BrI. The RAK alpha gene was PCR amplified with HIV-1-derived primers SK68 and SK69. RAK antigens p120, p42, and p25 were found in 95% of ovarian, uterine, and cervical cancer cases and in 75% of vulvar cancer cases. The RAK alpha gene was expressed in 100% of cancer cases, in approximately 25% of benign ovarian tumors, and in 40% of benign tumors of the uterus. DNA sequences amplified in all cancer cases exhibited more than 90% homology to HIV-1 gp41 and were encoded for the functional peptide. DNA sequences found in benign tumors contained frameshift mutations and encoded truncated or nonfunctional peptides. Such sequences have not been amplified in normal tissues. RAK antigens and the RAK alpha gene seem to belong to a lentivirus type that is highly related to HIV-1. Beyond the diagnostic value of RAK markers, future cloning of the full viral genome would lead to a better understanding of the etiology of malignant and nonmalignant tumors of reproductive organs and to the development of novel therapeutic approaches.Cancers of the reproductive organs are the most common malignancies in women (7,13,19). Prognostic factors for those patients are directly dependent on the stage of the cancer at diagnosis. Earlier detection of breast, ovarian, cervical, or endometrial cancer would significantly increase survival rates of female patients (9,20,30). Only 10% of breast and 5% of ovarian cancer cases have a documented inherited pattern, associated mainly with the mutated genes BRCA (15,18,34) or the oncogene Her-2/Neu (31).Except for cervical cancer, which is predominantly associated with human papillomavirus (HPV) (2,8,14,17), a viral etiology of other types of female reproductive tract cancers remains unverified. However, the fact that the majority of papillomavirus-infected women do not develop cervical cancer strongly implies that HPV may be an important cofactor, but not the direct cause, of that cancer. Recent studies of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma (3) strongly suggest that the role of retroviruses in human cancer was somehow underestimated for a long time.Viral particles (4, 5, 6, 10, 11, 16) and DNA sequences (1, 32, 33) with homology to the mouse mammary tumor virus (MMTV) have been observed in breast cancer for some time. Since MMTV-like sequences are present in cancer patients, as well as in healthy patients, an involvement of this virus in the etiology o...