The frequency of the hybrid Vγ/Jβ trans-rearrangement in peripheral blood lymphocytes (PBLs) was analysed in a transversal study of paediatric patients (n = 210) with acute lymphoblastic leukaemia (ALL) and solid tumours (ST). Different amounts of DNA were used as the template for a nested polymerase chain reaction to evaluate the frequency of hybrid Vγ/Jβ genes, using silver-stained gels. The frequency of the rearrangement was evaluated in groups before, during and after therapy. A greatly increased frequency of Vγ/Jβ trans-rearrangement was found in PBLs of both groups of patients during exposure to chemotherapeutic agents compared with patients before chemotherapy. In patients who had finished treatment, the frequency of the rearrangement fell promptly to the baseline levels in ST but showed a slow decrease in ALL in those in whom increased levels could be found until 4 years after the end of treatment, We hypothesize that the chemotherapeutic agents are able to induce the Vγ/Jβ trans-rearrangement, but this is transient in most cases. The exact relationship between the persistence of the rearrangement and the occurrence of secondary leukaemia remains to be determined.113410011008Abdallah, J.M., Lombardi, D.P., Kirsch, I.R., Genetic instability in patients with Hodgkin's disease undergoing chemotherapy (1995) Journal of Clinical Investigations, 96, pp. 2744-2747Begley, C.G., Aplan, P.D., Davey, M.P., Nakahara, K., Tchorz, K., Kurtzberg, J., Hershfield, M., Kirsch, I.R., Chromosomal translocation in a human leukemic stem-cell line disrupts the T cell antigen receptor delta-chain diversity region and results in a previously unreported fusion transcript (1989) Proceedings of the National Academy of Sciences of the United States of America, 86, pp. 2031-2035Berger, N.A., Chatterjee, S., Schmotzer, J.A., Helms, S.R., Etoposide (VP-16-213)-induced gene alterations: Potential contribution to cell death (1991) Proceedings of the National Academy of Sciences of the United States of America, 33, pp. 8740-8743Blin, N., Stafford, D.W., A general method for isolation of high molecular weght DNA from eukaryotes (1976) Nucleic Acids Research, 3, pp. 2303-2308Boder, E., Ataxia-telangiectasia: An overview (1985) Genetics, Neuropathology & Immunology of a Degenerative Disease of Childhood, pp. 1-63. , (ed, by R.A. Gatti & M. Swift), Alan Liss, New YorkBoyum, A., Isolation of molecular cells and granulocytes from human blood. Isolation of molecular cells by one centrifugation and of granulocytes by combining centrifugation and sedimentation at 1g (1968) Scandinavian Journal of Clinical Laboratory and Investigations Supplement, 97, pp. 77-89Brandallse, S., Odone, V., Pereira, W., Andrea, M., Zanichelli, M., Aranega, V., Treatment results of three consecutive Brazilian cooperative childhood ALL protocolos, GBTLI-80, GBTLI-82 and -85 (1993) Leukemia, 7, pp. S142-S145Canellos, G.P., Anderson, J.R., Propert, K.J., Nissen, N., Cooper, M.R., Henderson, E.S., Green, M.R., Peterson, B.A., Chemotherapy of advanced Hodgkin's disease with MOPP. ABVD, or MOPP alternating with ABVD (1992) New England Journal of Medicine, 327, pp. 1478-1484Chambers, S.K., Chopyk, R.L., Chambers, J.T., Schwartz, P.E., Duffy, T.P., Development of leukemia after doxorubicin and cisplatin treatment of ovarian cancer (1989) Cancer, 64, pp. 2459-2461Chen, C.L., Fuscoe, J.C., Liu, Q., Relling, M.V., Etoposide causes illegitimate V (D) J recombination in human lymphoid leukemic cells (1996) Blood, 88, pp. 2210-2218Davodeau, F., Peyrat, M.A., Gaschet, J., Hallet, M.M., Triebel, F., Vie, H., Kabelitz, K., Bonneville, M., Surface expression of functional T-cell receptor chains formed by interlocus recombinations on human T-lymphocytes (1994) Journal of Experimental Medicine, 180, pp. 1685-1691De Benedetti, V., Bennett, W.P., Greenblatt, M.S., Harris, C.C., p53 Tumor suppressor gene: Implications for iatrogenic cancer and cancer therapy (1996) Medicine Pediatrics Oncology, 27, pp. 2-11Fuscoe, J.C., Setzer, R.W., Collard, D.D., Moore, M.M., Quantification of T (14: 18) in the lymphocytes of healthy adult humans as a possible biomarker for enviromental exposures to carcinogens (1996) Carcinogenesis, 17, pp. 1013-1020Fuscoe, J.C., Vira, L.K., Collard, D.D., Moore, M.M., Quantification of hprt gene deletions mediated by ilegitimate V (D) J recombination in peripheral blood cells of humans (1997) Environmental Molecular Mutagen, 29, pp. 28-35Fuscoe, J.C., Knapp, G.W., Hanley, N.M., Setzer, R.W., Sandlund, J.T., Pui, C.H., Relling, M.V., The frequency of illegitimate V (D) J recombinase-mediated mutations in children treated with etoposide-containing antileukemic therapy (1998) Mutation Research, 419, pp. 107-121Griesser, H., Tkachuk, D., Reis, M.D., Mak, T.W., Gene rearrangements and translocations in lymphoprollferative diseases (1989) Blood, 73, pp. 1402-1415Han, Y.H., Austin, M.J., Pommier, Y., Povirk, L.F., Small deletion and insertion mutations induced by the topoisomerase II innhibitor teniposide in CHO cells and comparison with sites of frug-stimulated DNA cleavage in vitro (1993) Journal of Molecular Biology, 220, pp. 52-66Hudson, M.M., Donaldson, S.S., Treatment of pediatric Hodgldn's Lymphoma (1999) Seminars in Hematology, 36, pp. 313-323Jeha, S., Jaffe, N., Robertson, R., Secondary acute non-Lymphoblastic Leukemia in two children following treatment with a Cis-Diamminedichloroplatinum-II-based regimen for osteossarcoma (1992) Medicine Pediatrics Oncology, 20, pp. 71-74Karnaoukhova, L., Moffat, J., Martins, H., Glickman, B., Mutation frequency and spectrum in lymphocytes of samll cell lung cancer patients receiving etoposide chemotherapy (1997) Cancer Research, 57, pp. 4393-4407Kirsch, I.R., Lipkowitz, S.A., A mesure of genomic instability and its relevance to lymphomageneis (1992) Cancer Research, 52, pp. 5545s-5546sLevine, E.G., Bloomfield, C.D., Leukemias and myelodysplastic syndromes secondary to drug, radiation and environmental exposure (1992) Seminars in Oncology, 19, pp. 47-84Lipkowitz, S., Stern, M.H., Kirsch, I.R., Hybrid T-cell receptor genes formed by interlocus recombination in normal and ataxia-teleangiectasia lymphocytes (1990) Journal of Experimental Medicine, 172, pp. 409-418Lipkowitz, S., Garry, V.F., Kirsch, I.R., Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies (1992) Proceedings of the National Academy of Sciences of the United States of America, 89, pp. 5301-5305Meydan, D., Nilsson, T., Törnblom, M., Hagmar, L., Hellgren, D., Fuscoe, J.C., Lambert, B., The frequency of illegitimate TCRβ/γ gene recombination in human lymphocytes: Influence of age, enviromental exposure and cytostatic treatment, and correlation with frequencies of T (1418) and hprt mutation (1999) Mutation Research, 444, pp. 393-403Nichols, C.R., Breeden, E.S., Loeherer, Pj., Willians, S.D., Einhorn, L.H., Secondary leukemia associated with a conventional dose of etoposide. Review of serial germ cell tumor protocols (1993) Journal of the National Cancer Institute, 85, pp. 36-40Pedersen-Bjergaard, J., Daugaard, G., Hansen, S.W., Philip, P., Larsen, S.O., Rorth, M., Increased risk of myelodysplasia and leukemia after etoposide, cisplatin and bleomycin for germ-cell tumors (1991) Lancet, 338, pp. 359-363Pui, C.H., Ribeiro, R., Hancock, M.L., Rivera, G.K., Evans, W.E., Raimondi, S., Head, D.R., Crist, W., Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphocytic leukemia (1991) New England Journal of Medicine, 325, pp. 1682-1687Rabbits, T.H., Chromosomal translocations in human cancer (1994) Nature, 372, pp. 143-149Ratain, M.J., Kaminer, L.S., Bitran, J.D., Larson, R.A., LeBeau, M.M., Skosey, C., Purl, S., Golomb, H.M., Acute nonlymphocytic leukemia following Etoposide and cisplatin combination chemotherapy for advanced non small cell carcinoma of the lung (1987) Blood, 70, pp. 1412-1417Reed, E., Yuspa, S.H., Zwelling, L.A., Ozols, R.F., Poirier, M.C., Quantification of cis-Diamminedichloroplatinum II (cisplatin)-DNA-intrastand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy (1996) Journal of Clinical Investigations, 77, pp. 545-550Reiter, A., Schrappe, M., Ludwig, W., Hiddemann, W., Sauter, S., Henze, G., Zimmermann, M., Riehm, H., Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM'86 (1994) Blood, 84, pp. 3122-3133Sanguinetti, C.J., Dias Neto, E., Simpson, A.J.G., Rapid silver staining and recovery of PCR products separated on polyacrylamide gels (1994) Biotechniques, 17, pp. 915-918Smith, M.A., Rubinstein, L., Ungerleider, R.S., Therapy-related acute myeloid leukemia following treatment with epipodophyllotoxins: Estimating the risks (1994) Medicine Pediatrics Oncology, 23, pp. 86-98Tates, A.D., Van Dam, F.J., Natarajan, A.T., Zwinderman, A.H., Osanto, S., Frequencies of HPRT mutants and micronuclei in lymphocytes of cancer patients under chemotherapy: A prospective study (1994) Mutation Research, 307, pp. 293-307Tewey, K.M., Rowe, T.C., Yang, L., Halligan, B.D., Liu, L.F., Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II (1984) Science, 226, pp. 466-468Tucker, M.A., Meadows, A.T., Boice, J.D., Stovall, M., Oberlin, O., Stone, B.J., Birch, J., Fraumeni J.F., Jr., Leukemia after therapy with alkylating agents for childhood cancer (1987) Journal of the National Cancer Institute, 78, pp. 459-464Van Leeuwen, F.E., Klokman, W.J., Hagenbeek Noyon, R., Van Den Belt-Dusebout, A.W., Van Kerkhoff, E.H., Van Heerde, P., Somers, R., Second cancer risk following Hodgkin's disease: A 20-year follow-up study (1994) Journal of Clinical Oncology, 12, pp. 312-325Van Leeuwen, F.E., Klokman, W.J., Van't Veer, M.B., Hagenbeek, A., Krol, A.D.G., Vetter, U.A.O., Schaapveld, M., Aleman, B.M.P., Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood (2000) Journal of Clinical Oncology, 18, pp. 487-497Waldmann, T.A., The arrangement of immunoglobulin and T cell receptor genes in human lymphoproliferative disorders (1987) Advances in Immunology, 40, pp. 247-231Wolden, S.L., Lambron, K.R., Cleary, S.F., Tate, D.J., Donaldson, S.S., Second cancers following pediatric Hodgkin's disease (1998) Journal of Clinical Oncology, 16, pp. 536-544