Chromosomal alterations in lymphocytes of patients with Balkan endemic nephropathy and of healthy individuals after incubation in vitro with ochratoxin A.

The possible involvement of mycotoxins in chromosomal alterations in patients with Balkan endemic nephropathy (BEN) was investigated cytogenetically. Lymphocyte cultures from patients with BEN and from individuals from a nonendemic region were examined and compared with cultures from healthy people which had been incubated in vitro with noncytotoxic doses of ochratoxin A. Significantly increased numbers of various numerical and structural anomalies were found in patients with BEN. Chromosome X in female patients occurred in both monosomic and polysomic forms. A 'prosomization' effect was seen along the entire length of supernumerary X chromosomes, manifested by retarded contraction resembling early mitotic stages, with a comparably detailed band pattern. No other specific numerical or structural change was found consistently in BEN patients. Incubation of the lymphocytes of healthy people with ochratoxin A induced similar aberrations and prosomization. These findings may support the hypothesis that ochratoxin A is involved in the pathogenesis of BEN.

Induction of characteristic chromosomal aberrations, particularly X-trisomy, in cultured human lymphocytes treated by ochratoxin A, a mycotoxin implicated in Balkan endemic nephropathy.

Ochratoxin A (OA), a mycotoxin which induces nephropathy and kidney tumours in rats and mice, is a contaminant of food consumed by a population with a high incidence of endemic nephropathy (EN). It was therefore tested in vitro for its ability to induce chromosomal aberrations in human peripheral lymphocytes in a small number of subjects, in the presence or absence of a kidney microsomal metabolic activation system. OA was found to induce aberrations on X chromosomes of similar types to those previously detected in lymphocytes from patients suffering from endemic nephropathy.

Complex translocation t(8;12;14) in a cell line derived from a child with nonendemic Burkitt-type acute lymphoblastic leukemia.

A cell line is described with a typical Burkitt lymphoma (BL) marker 14q+ due to the classical reciprocal translocation between chromosome #8 and #14 with breakpoints at 8q24.1 and 14q32.3. In addition, an interstitial piece from the long arm of 12(q24.1-q24.3) is inserted at the site of the exchange on chromosome #8, proximal to 14q32.3.

High resolution chromosome analysis of constitutional and acquired t(15;17) maps c-erbA to subband 17q11.2.

High resolution chromosome analysis was performed on bone marrow cells from four patients with acute promyelocytic leukemia and t(15;17), and in lymphocytes from two unrelated, phenotypically normal persons with an apparently identical constitutional translocation. Scrutiny of prophase-prometaphase chromosomes localized the breakpoints in all six cases to subbands 15q22.3 and 17q11.2. Molecular genetic studies have localized the oncogene c-erbA to chromosome #17 between the breakpoints of the constitutional and the acquired anomaly. The present results, therefore, map c-erbA to subband 17q11.2.

Satellite DNA in the three C-bands of an unusual mouse marker chromosome. A model of chromosomal evolution.

A marker chromosome in the stemline of a new murine cell line is described on the basis of different stainings and in situ hybridization. The marker was characterized originally by three C-bands, one from each centromeric region of the three chromosomes constituting the marker. In the course of stemline evolution, two of the C-bands have been lost and the marker has developed into a monocentric chromosome, phenotypically and functionally normal.

Alternative involvement of two cytogenetically distinguishable breakpoints on chromosome 8 in Burkitt's lymphoma associated translocations.

The chromosomes of 16 Burkitt's lymphoma (BL) derived cell lines were submitted to high-resolution G-band analysis. They included seven lines with t(8;14), three with t(2;8), and four with t(8;22). The translocation breakpoint in chromosome #14 was located in 14q32.3, in chromosome #2 in 2p11.1, and in chromosome #22 in 22q12.12. In chromosome #8, the translocation breakpoint was located in two cytogenetically distinct subbands: 8q24.1 in cell lines with t(8;14) and t(2;8) and 8q24.22 in cell lines with t(8;22). In the light of recent molecular findings, these results indicate that the distance between the c-myc gene, located in 8q24, and the Ig sequences might be much larger in BL lines with t(8;22) than in those with t(2;8).

Chromosome aberrations in peripheral lymphocytes of male homosexuals.

Karyotypes of peripheral lymphocytes of 19 male homosexuals showed increased hypodiploidy. Chromosomes #19 and #20 were most frequently lost. Also, structural chromosome aberrations frequently occurred consisting chiefly of translocations and simple chromosome breaks. Terminal deletions, inversions, and isochromosomes occurred less commonly. In three of the cases, 100% of the cells were involved in a pericentric inversion of a chromosome #9. Chromosomes #3 in p21.1 and 1 in p32.3 were repeatedly affected. Structural aberrations were seen less frequently in men with acquired immunodeficiency syndrome(AIDS) and AIDS-related complex than in asymptomatic homosexuals. The hypodiploidy with preferential loss of chromosomes was constantly present. The marker chromosomes and simple breaks at repeated sites are another manifestation of damage to the immune system in these male homosexuals from Greenwich Village in New York City. The chromosomal damage was potentially the result of exposure to amyl and butyl nitrites, viral infections, or immunologic reactions to sperm, which crossreact with lymphocytes.

Small noncleaved B cell Burkitt-like lymphoma with chromosome t(8;14) translocation and Epstein-Barr virus nuclear-associated antigen in a homosexual man with acquired immune deficiency syndrome.

This case report describes new manifestations of the acquired immune deficiency syndrome (AIDS) in a promiscuous homosexual man. Investigation of upper gastrointestinal bleeding in the patient lead to discovery of a high-grade, small, noncleaved cell (Burkitt-like) gastroduodenal lymphoma with visceral and extralymphatic extension. Specific phenotyping of the lymphoma revealed that it was a monoclonal B cell lymphoma of mu kappa isotype. An in vitro cell line was established that was Epstein-Barr virus nuclear-associated antigen-positive. The lymphoma cells displayed a t(8;14) translocation similar to endemic African Burkitt lymphoma. Epstein-Barr virus genomes were identified in the lymphoma and an axillary lymph node biopsy specimen by molecular hybridization. These data strongly suggest that Epstein-Barr virus actively infected this patient. However, he showed normal Epstein-Barr virus-specific serologic responses, indicating an immune defect against the virus.

Role of Epstein-Barr virus in the etiology of Burkitt's lymphoma.

Although Epstein-Barr virus (EBV) was discovered in cultured Burkitt's lymphoma (BL) cells, its exact role remains unclear. Viral genome is found in 95-98% of endemic BL and 15-20% of non-endemic BL. Children destined to develop BL in Africa show elevated titres of viral capsid antibodies one to two years preceding emergence of BL. A multistep process follows early EBV infection during early childhood. Immune deficiency probably permits continuation of the infections, with smouldering polyclonal B-cell proliferation proceeding. Final steps in the pathogenesis consist of cytogenetic and molecular conversion to monoclonal BL. Reciprocal chromosomal translocations involve breakpoints containing c-myc, heavy- and light-chain Ig loci. Activation of oncogenes, c-myc and B-lym, may be essential in the molecular pathogenesis of BL. A spectrum of EBV-induced pathological entities is found in individuals with X-linked lymphoproliferative and acquired immune deficiency syndromes. Lymphoma identical to endemic BL occurs in these immune-deficient patients. Non-endemic BL is possibly due to immune defects, initiators and promoters of B-cell proliferation, which may not be identical to factors in endemic BL; however, cytogenetic events and activation of oncogenes may be pathways of both endemic and non-endemic BL.

Squamous-cell carcinoma, Kaposi's sarcoma and Burkitt's lymphoma are consequences of impaired immune surveillance of ubiquitous viruses in acquired immune deficiency syndrome, allograft recipients and tropical African patients.

The immune system has evolved under Darwinian pressures as a defence against ubiquitous viruses. Immune surveillance against viral antigens protects the normal host. Individuals with inherited or acquired immune-deficiency disorders can become vulnerable to ubiquitous viruses and neoplasms can ensue, such as B-cell lymphoma, hepatocellular carcinoma, squamous-cell carcinoma, Kaposi's sarcoma, and carcinoma of the penis and uterine cervix. Immunodeficiency permits Epstein-Barr virus, hepatitis B virus, papillomavirus, herpes simplex virus, and cytomegalovirus to induce sustained target-cell proliferation. Each virus selects specific cellular targets bearing viral receptors and the infection leads to proliferation of the target cells rather than lysis. Various co-factors, including nutrition, exposure to tumour-promoting agents, parasitic infection, and ultraviolet light, may promote carcinogenesis. Depending on the type and severity of the immune deficiency, gradual proliferation may lead to evolution of a malignant clone. Conversion of polyclonal virally infected proliferating cells to give monoclonal malignancy is probably due to specific cytogenetic rearrangements which allow oncogene activation and endow an altered tumour cell with selective growth advantages over normal diploid cells. Prevention of viral oncogenesis may be possible by treatment of immune-deficient individuals with premalignant disorders. Immunotherapy and antiviral therapy may prevent progression of viral-induced proliferation to malignancy. The purpose of this paper is to discuss and evaluate the role of immune deficiency and viruses in the induction of malignancies commonly occurring in Africans residing in sub-Saharan Africa (Purtilo, 1976). The types of malignancies commonly occurring in this region are believed to be due to ubiquitous viruses. A failure of immune surveillance mechanisms to recognize viral antigens and abrogate proliferation of infected target cells predisposes to malignancy by increasing the chance of a proliferating cell undergoing a cytogenetic or molecular alteration which endows it with malignant characteristics. The immunological surveillance hypothesis has been elaborated during this century by Ehrlich, Thomas, Burnet, and Schwartz (reviewed by Purtilo & Linder, 1983). This hypothesis rests on several assumptions: that neoplastic cells possess unique tumour antigens: tumour antigens provoke an immune response in the host; and the immune response is protective and eliminates the tumour.(ABSTRACT TRUNCATED AT 400 WORDS)