Showing papers in "IARC scientific publications in 1985"

Translocations among antibody genes in human cancer.

Abstract: The characteristic chromosomal translocations that occur in certain human malignancies offer opportunities to understand how two gene systems can affect one another when they are accidentally juxtaposed. In the case of Burkitt's lymphoma, such a translocation joins the cellular oncogene, c-myc, to a region encoding one of the immunoglobulin genes. In at least one example, the coding sequence of the rearranged c-myc gene is identical to that of the normal gene, implying that the gene must be quantitatively, rather than qualitatively, altered in its expression if it is to play a role in transformation. One might expect to find the rearranged c-myc gene in a configuration that would allow it to take advantage of one of the known immunoglobulin promoters or enhancer elements. However, the rearranged c-myc gene is often placed so that it can utilize neither of these structures. Since the level of c-myc messenger RNA is often elevated in Burkitt cells, the translocation may lead to a deregulation of the c-myc gene. Further, since the normal allele in a Burkitt cell is often transcriptionally silent in the presence of a rearranged allele, a model for c-myc regulation is suggested that involves a trans-acting negative control element that might use as its target a highly conserved portion of the c-myc gene encoding two discrete transcriptional promoters.

The use of lymphomatous and lymphoblastoid cell lines in the study of Burkitt's lymphoma.

Abstract: To better characterize the virological and cytogenetic features of Burkitt's lymphoma (BL) occurring in so-called low-incidence areas, biopsy specimens were collected from BL patients diagnosed and treated in France, and attempts were made to cultivate malignant cells in vitro in order to provide large amounts of tumour material for further laboratory investigations. Sixty new BL-derived lymphomatous cell lines have been established from 43 individuals: 24 Caucasians, 14 North Africans and five Africans. Of these, 27 lines (from 18 individuals) were established from non-Epstein-Barr virus (EBV)-associated BL tumours, indicating that the relative ease in cultivating BL malignant cells in vitro is not limited to EBV genome-containing BL tumours. Cytogenetic investigations showed that all the BL cell lines had one of the three 'BL translocations' - t(8;14), t(8;22) or t(2;8). An estimate of the frequency of each translocation, based on the analysis of 51 independent IARC BL cell lines gave the following results: t(8;14), 76%; t(8;22), 16%; t(2;8), 8%. This large panel of cell lines is now a valuable tool for analysing the various phenotypic characteristics of BL cells. Comparisons can be made between multiple lines of BL from high-, intermediate- and low-incidence areas; significant numbers of EBV genome-negative and -positive lines and of tumour cells taken at diagnosis and at various stages of the disease can also be compared. For molecular and immunological investigations, EBV-immortalized lymphoblastoid cell lines (LCL) were also established from non-malignant lymphocytes of BL patients. The 24 paired BL and LCL cell lines obtained so far will allow precise, controlled studies of the molecular consequences of chromosomal translocations and of the comparative susceptibility of BL and LCL to immune effectors.

There is no such thing as ageing, and cancer is not related to it.

Abstract: Several separate cellular processes have to accumulate in a normal cell to alter it into the seed of a growing carcinoma. Even though cancer is much commoner in the old than in the young, there is no good evidence whatever that these separate processes have any systematic tendency to take place more readily among old than among young adults. (Indeed, there are some instances in which carcinogenic treatments actually elicit cancer less rapidly among the old!) There are obvious evolutionary reasons why substantial cancer risks should be delayed until the end of the usual lifespan, and it appears that this is achieved chiefly not by having the component processes of neoplastic transformation themselves particularly dependent on age, but simply by requiring not one, but several, of them en route from full normality to full malignancy, and by giving at least some of them an extraordinarily low daily probability. The daily probabilities of these separate events are, of course, under evolutionary influence, and some of them appear to have changed by orders of magnitude over the tens of millions of years of evolution that separate humanity from various short-lived animals.

Epidemiological evidence for the role of falciparum malaria in the pathogenesis of Burkitt's lymphoma.

Abstract: Nearly all epidemiological characteristics of Burkitt's lymphoma (BL) can be explained on the basis of relationships of BL to the intensity of the host response to Plasmodium falciparum. The major epidemiological associations are: the high degree of geographic correlation between the incidence rate of BL and the intensity of P. falciparum transmission, both at a global level and within individual countries; the close correlation between the age incidence of BL and the age of acquiring maximum levels of antimalarial immunoglobulin; the relative protection from BL by residence in urban areas, where levels of malaria transmission are lower, compared with rural areas; the decline in BL incidence in areas where death rates due to malaria have declined and, within such areas, a differential decline in BL incidence in people making better use of health facilities; the older age of onset in patients who have migrated from low-intensity to high-intensity malaria areas as compared with patients born in the high-intensity areas - the higher absolute age-specific incidence rate in those above age ten in this immigrant group being consistent with the hypothesis that intense malaria infection and consequent host defence response serve as the major triggering event in the pathogenesis of the lymphoma; the inverse geographic correlation between the average age of onset of BL and the intensity of falciparum malaria infection. An inverse association of BL with sickle-cell trait (AS haemoglobin) would provide strong evidence for the role of intense falciparum malaria, but most studies to date have not achieved statistical significance. Time-space clustering and reports of seasonal variation in BL incidence would indicate that a precipitating factor operates over a relatively short time-span, at least in some areas. Combining the evidence concerning cytogenetics, Epstein-Barr virus (EBV) and falciparum malaria, the following three-phase model for the oncogenesis of BL could account for virtually all the currently known facts and be tested by further laboratory and field studies: Primary infection with EBV, perhaps early and intense, leads to the immortalization of large numbers of B lymphocytes. Severe falciparum malaria then leads to an intense host response with particular proliferation of the EBV-infected B lymphocytes. Finally, the great increase in the B lymphocytes provides a much higher statistical opportunity for the emergence of the cytogenetically abnormal BL cell.

Epstein-Barr virus and Burkitt's lymphoma worldwide: the causal relationship revisited.

Abstract: Burkitt's lymphoma (BL) in tropical Africa represents by far the most common tumour in children between 0 and 14 years of age, 97% of the tumours being associated with Epstein-Barr virus (EBV). In North Africa, the tumour is about ten times less frequent than in equatorial Africa, but, according to reports from Algeria, 85% of the cases appear to be associated with EBV. In Western countries, BL represents about 3% of childhood tumours, 10 to 15% of them EBV-associated. Thus, from the northern industrialized countries to the equatorial developing countries, increasing incidences of lymphomas of the BL type are paralleled by an increasing proportion of EBV-associated cases. The Ugandan BL prospective study showed that high antibody titres to viral capsid antigen (VCA) preceded BL development by many years, with a quantifiable relationship between the level of VCA antibodies and tumour risk. If an early and/or massive EBV primary infection seems to represent the critical event for BL development in equatorial Africa, the favourable conditions for EBV-associated tumours in North Africa and in Europe remain to be investigated. Malaria appears to favour BL development through an EBV-specific T-cell immune deficiency. Chromosomal translocations and oncogene activation, considered as the final step in lymphoma development, do not appear to be related to EBV. Intervention against the virus may represent the ultimate proof of a causal relationship between EBV and the majority of BL cases around the world.

Cytogenetics of Burkitt's lymphoma-leukaemia: a review.

Abstract: Two types of chromosomal abnormality have been found in Burkitt's lymphoma-leukaemia. Three specific translocations, t(8;14), t(8;22) and t(2;8), having in common 8q24 band involvement, are thought to be present in the overwhelming majority of cases. These stereotyped translocations have been shown in many cases to be related to DNA molecular rearrangements of the immunoglobulin genes and the c-myc oncogene. Secondary chromosomal abnormalities, some of them nonrandom, have also been described. Their possible relation to other oncogene involvement and to the Epstein-Barr virus genome is discussed.

Burkitt's lymphoma in Europe.

Abstract: Burkitt's lymphoma (BL) is the most frequent childhood non-Hodgkin's malignant lymphoma (NHML) in Europe and accounts for 5 to 10% of adult NHML. Age distribution is similar to that of endemic BL, with a male:female ratio of 3.7:1. Epstein-Barr virus (EBV) association is found in 15% of cases. A better definition of this monoclonal B-cell malignant proliferation is cytogenetic (i.e., 8;14 or variant translocation). Abdominal masses are initially present in 70% of cases, whereas the jaw is involved in only 4%. The disease is characterized by its overwhelming evolution in the absence of therapy. However, complete remission is usually obtained after the first chemotherapy regimen. In the past, death has been related to cerebrospinal fluid involvement, local recurrence or secondary marrow involvement. Today, it is expected that more than 80% of BL cases will be cured, i.e., 100% of stages I and II abdominal, 70% of stage II non-abdominal and stage III, and 50% of stage IV. Ninety percent of patients alive with no evidence of disease eight months after complete remission can be considered as definitively cured.

Cell-mediated immunosurveillance mechanisms and the pathogenesis of Burkitt's lymphoma.

Abstract: Paired Epstein-Barr virus (EBV)-carrying cell lines have been established from Burkitt's lymphoma (BL) patients, one of each pair being the BL cell line derived from the malignant cells of the tumour, the other, the lymphoblastoid cell line (LCL) derived from the patient's normal B cells by experimental infection with the virus. Comparative studies have shown the following: (1) All the lines were to some extent sensitive to in-vitro activated natural-killer cells, individual pairs differing as to whether BL or LCL cells were more susceptible. (2) For six of the seven pairs tested, the BL cell line was clearly sensitive to allo-specific (anti-class 1 HLA) effector T cells, although levels of lysis were slightly below those observed for the corresponding LCL; only one BL cell line showed evidence of a dramatic reduction of HLA antigen expression, and this line was insensitive to allo-specific cytolysis. (3) For two of the three pairs tested to date, EBV-specific cytotoxic T-cell preparations from HLA antigen-matched donors lysed the LCL but not the BL cell line, despite the latter's apparent expression of the relevant restricting antigens. In both of these cases, it was known that the tumour arose in vivo in the face of prevailing EBV-specific T-cell surveillance. An escape of the malignant cells from such surveillance may therefore be important in the overall pathogenesis of EBV genome-positive BL.

Cell culture models of multistep carcinogenesis.

Abstract: The cellular and molecular basis for the multistep process of carcinogenesis can be studied in part by the use of cell culture models. A model system for the study of carcinogen-induced neoplastic transformation of cells in culture is described. Different stages in the neoplastic development of Syrian hamster embryo (SHE) fibroblasts can be identified and quantitated. At least two steps are required for the neoplastic progression of these cells. Morphological alterations are observed early after carcinogen treatment; such cells are preneoplastic and, after further growth in culture, acquire the ability to grow in agar and to form tumours in animals. The induction of morphological transformation of SHE cells occurs within one week after carcinogen treatment in a dose-dependent manner consistent with a one-hit mechanism. Furthermore, this change is induced at frequencies (greater than 1% of the surviving cells) that are higher than those of specific locus mutations. Carcinogens that fail to induce measurable gene mutations induce cell transformation (e.g., diethylstilboestrol, asbestos and arsenic). All three of these carcinogens induce chromosomal changes--either numerical and/or structural aberrations--suggesting a role for such changes in the action of these carcinogens. Different preneoplastic cells vary in the rate of their progression to anchorage-independent growth and tumorigenicity. Cells with the ability to grow in agar arise at rates of 10(-4) to 10(-7) variants/cell per generation, depending on the preneoplastic cell line. Different preneoplastic cell lines also vary in their sensitivity to induction of neoplastic transformation by mutagens and by transfection with viral oncogenes. This heterogenicity of response suggests different intermediate states of neoplastic progression.

Neoplastic transformation in cell cultures: in-vitro/in-vivo correlations.

Abstract: The behaviour of the C3H 10T1/2 C18 (10T1/2) cell line is reviewed in the context of its ability to reflect accurately events known to occur during carcinogenesis in vivo. It is concluded that, despite their embryonic fibroblastic origin and their infinite life-span in culture, 10T1/2 cells are capable of a wide range of responses to carcinogens and modulators of carcinogenesis that correspond closely to those observed in vivo, for the most part in epithelial tissues. For this and other reasons the 10T1/2 cell line has been widely employed in cancer research.

Burkitt's lymphoma in the USA: cases reported to the American Burkitt Lymphoma Registry compared with population-based incidence and mortality data.

Abstract: Since 1971, the American Burkitt Lymphoma Registry (ABLR) has been collecting clinical, epidemiological and laboratory data on patients with Burkitt's lymphoma (BL) diagnosed in the USA. Although the 256 confirmed ABLR cases have the advantage of uniform pathological review, the ABLR is a relatively 'passive' registry, with the majority of cases being submitted by interested physicians. To determine the pattern of BL in the USA on a population basis, we analysed incidence and survival data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI) and mortality data from the National Center for Health Statistics (NCHS). Both SEER and NCHS data demonstrated a more marked predominance of BL in young males than had been found in the ABLR. All three sources of data revealed a broad age spectrum and a relative paucity of cases in the non-white US population. SEER data indicate that the overall incidence of BL in the USA was 1.4 per million for white males and 0.4 per million for white females during 1973-1981. The incidence rate for white males increased over time, perhaps owing to improvements in diagnosis and reporting.

Survival rate as an index in evaluating cancer control.

Abstract: A WHO/IARC Expert Committee on Cancer Statistics (1979) reported that it is of increasing importance to make comparisons of survival experience between countries. Unfortunately, there may be insufficient uniformity between different regions with regard to the criteria or classifications used and to registry policy and methods. The study of time trends in survival is complicated by changes in the degree of case reporting to registries, by the increasing number of cancer patients found by screening programmes, and by changes over time in definitions or coding rules of cancer site, stage, histology and even diagnosis. Such problems are inevitable in the medical field, which is evolving continually. Analysis of such data has, however, made important contributions in the field. Survival rates present problems and limitations; however, the overall results from population-based cancer registries are more representative of the general pattern of survival from cancer than those from hospitals (WHO/IARC Expert Committee on Cancer Statistics, 1979). Interesting though a hospital patient series may be, it should be kept in mind that the real efficacy of a cancer control programme can be judged only from population figures.

Burkitt's lymphoma in the Middle East.

Abstract: The clinical features of 30 retrospectively diagnosed cases of Burkitt's lymphoma (BL) at the American University Medical Center (AUMC) in Beirut differed from those of African Burkitt's in that the majority of the AUMC patients presented with abdominal disease, and from the American form, in that the AUMC patients were younger, with a median age similar to that of African BL patients.

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

Abstract: 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.

The latent period of Burkitt's lymphoma: the evidence from epidemiological clustering.

Abstract: The evidence that the latent period of Burkitt's lymphoma may be short, that is, months rather than years, stems from the observation of seasonal variation in disease onset and time-space clustering. The evidence for both of these effects is equivocal, but both are quite strong in the West Nile district of Uganda, where the disease has been most intensively studied epidemiologically. We have assumed that the interval between some final triggering event and onset of disease follows a log-normal distribution, and we have examined the range of values of the mean and variance of that distribution which are consistent with the observed seasonal variation in incidence. These analyses would suggest that to explain the seasonal variation in the West Nile the latent period must be less than one year on average, and rarely exceed two years.

Saccharin/cyclamates: epidemiological evidence.

Abstract: Adequate data on the carcinogenicity of saccharin and cyclamate to humans are available only for the urinary bladder. In the studies available, exposure to saccharin and to cyclamate cannot be distinguished readily. Descriptive studies have shown no evidence of time trends in bladder cancer that can be related to use of saccharin or cyclamate. Likewise, studies of diabetics, who have used more saccharin and cyclamate than other people, have shown no evidence of an increased risk of bladder cancer. This association, however, is probably confounded negatively by cigarette smoking. Thirteen case-control studies have addressed the relationship of saccharin and cyclamate intake to bladder cancer in individuals. While statistically significant positive associations have been observed, a similar number of significant negative associations has also been observed. Studies of the dose-response relationships have also shown no consistent pattern. Studies of saccharin and cyclamate use with smoking habits have shown no consistent interaction with heavy smoking, as might be expected from a promotional effect. In some studies, however, an increased risk with saccharin and cyclamate use has been observed in female non-smokers--a group otherwise at low risk for bladder cancer.

Advanced stage (III-IV) Burkitt's lymphoma and B-cell acute lymphoblastic leukaemia in children: kinetic and pharmacologic rationale for treatment and recent results (1979-1983).

Abstract: Since 1979, we have treated a total of 29 children with advanced-stage B-cell tumours (diffuse undifferentiated, small non-cleaved cells): 18 stage III and three stage IV, according to a clinical staging classification (Murphy, 1980), and eight with B-cell acute lymphoblastic leukaemia (B-ALL). Treatment has been based upon appreciation of rapid tumour growth kinetics and has consisted of high-dose fractionated cyclophosphamide courses, vincristine, adriamycin and infusions of cytosine arabinoside (Ara-C) with intrathecal chemotherapy. The first 12 patients (1979-1981) received, in addition, superfractionated radiotherapy (twice a day) to the involved field (22.5 Gy) and the craniospinal axis (18 Gy). Since January 1981, radiation therapy has been omitted, and subsequent patients have received the same agents as above plus high doses of methotrexate coordinated with the escalating doses of Ara-C infusions. Toxicity has consisted mainly of universal, severe but reversible haematopoietic suppression with attendant febrile episodes. Complete-remission rate for all 29 patients has been 86%, with three early failures due to progressive disease and one death from infection. Overall disease-free survival for children with stage III disease has been excellent (78%). Initial involvement of central nervous system (CNS) and/or marrow is grave: none of three patients with stage IV lymphoma and only one of eight with B-ALL is surviving off therapy without evidence of disease, suggesting a need for alternative therapies for these cases. Results are significantly better than our historical institutional experience.