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[Cancer Research 61, 2542-2546, March 15, 2001]
© 2001 American Association for Cancer Research

Epidemiology and Prevention

Transplacental Chemical Exposure and Risk of Infant Leukemia with MLL Gene Fusion1

Freda E. Alexander2, Sherry L. Patheal, Andrea Biondi, Silvia Brandalise, Maria-Elena Cabrera, Li C. Chan, Zhu Chen, Giuseppe Cimino, Jose-Carlos Cordoba, Long-Jun Gu, Hany Hussein, Eiichi Ishii, Azza M. Kamel, Silvia Labra, Isis Q. Magalhães, Shuki Mizutani, Eleni Petridou, Maria Pombo de Oliveira, Patrick Yuen, Joseph L. Wiemels and Mel F. Greaves

Department of Public Health Science, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom [F. E. A., S. L. P.]; Clinica Pediatrica, Università Milano, Ospedale S. Gerardo, 20052 Monza, Italy [A. B.]; Centro Infantil de Investigações Hematológicas D. Boldrini, Rua Dr. Gabriel Porto, 1270, Barão Geraldo, CEP 13 083 210 Campinas, Sau Paulo, Brazil [S. B.]; Haematology Section, University of Chile, Hospital del Salvador, Santiago, Chile [M-E. C., S. L.]; Department of Pathology, University of Hong Kong, Queen Mary Hospital Compound, Hong Kong [L. C. C.]; Shanghai Institution of Hematology, Shanghai Second Medical University, Shanghai, China [Z. C.]; Department of Cellular Biotechnology and Hematology, University ‘La Sapienza’ of Rome, Rome, Italy [G. C.]; Hospital de Apoio Brasilia, Unidade de Onco-Hematologia Pediatrica, SGAIN Q.4, CEP 72 620 000-Brasilia, Brazil [J-C. C., I. Q. M.]; Department of Pediatric Hematology/Oncology, Xinhua Hospital/Shanghai Children’s Medical Centre, Shanghai Second Medical University, Shanghai, China [L-J. G.]; Department of Pediatric Oncology, National Cancer Institute, Cairo University, Kasr El Eini St, Fum El-Khalig, Cairo, Egypt [H. H.]; Division of Pediatrics, Hamanomachi Hospital 3-5-27 Maizuru, Chuo-ku Fukuoka 810-8539, Japan [E. I.]; Department of Clinical Pathology, National Cancer Institute, Cairo University, Kasr El Eini St, Fum El-Khalig, Cairo, Egypt [A. M. K.]; Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [S. M.]; Department of Hygiene and Epidemiology, University of Athens, School of Medicine, 11527 Athens, Greece [E. P.]; Instituto Nacional de Cancer, Praca Cruz Vermelha, 7o. andar, Laboratorio de Marcadores Celulares-Hematologia Clinica, CEP 20230-130, Rio de Janeiro, Brazil [M. P. d. O.]; Department of Paediatrics, The Chinese University, Hong Kong [P. Y.]; and Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, United Kingdom [J. L. W., M. F. G.]

Infant acute leukemia (IAL) frequently involves breakage and recombination of the MLL gene with one of several potential partner genes. These gene fusions arise in utero and are similar to those found in leukemias secondary to chemotherapy with inhibitors of topoisomerase II (topo-II). This has led to the hypothesis that in utero exposures to chemicals may cause IAL via an effect on topo-II. We report a pilot case-control study of IAL across different countries and ethnic groups. Cases (n = 136) were population-based in most centers. Controls (n = 266) were selected from inpatients and outpatients at hospitals serving the same populations. MLL rearrangement status was derived by Southern blot analysis, and maternal exposure data were obtained by interviews using a structured questionnaire.

Apart from the use of cigarettes and alcohol, very few mothers reported exposure to known topo-II inhibitors. Significant case-control differences were apparent for ingestion of several groups of drugs, including herbal medicines and drugs classified as "DNA-damaging," and for exposure to pesticides with the last two being largely attributable, respectively, to one nonsteroidal anti-inflammatory drug, dipyrone, and mosquitocidals (including Baygon). Elevated odds ratios were observed for MLL+ve (but not MLL-ve) leukemias (2.31 for DNA-damaging drugs, P = 0.03; 5.84 for dipyrone, P = 0.001; and 9.68 for mosquitocidals, P = 0.003). Although it is unclear at present whether these particular exposures operate via an effect on topo-II, the data suggest that specific chemical exposures of the fetus during pregnancy may cause MLL gene fusions. Given the widespread use of dipyrone, Baygon, and other carbamate-based insecticides in certain settings, confirmation of these apparent associations is urgently required.




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