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p53 Mutations in Leukemia and Myelodysplastic Syndrome after Ovarian Cancer¹

Department of Pathology and Laboratory Medicine [D. G. B. L.], Molecular Diagnostic Core Facility, University of Pennsylvania Cancer Center [D. G. B. L., K. A.], Division of Oncology, The Children’s Hospital of Philadelphia [D. J. S., C. A. F.], and Department of Pediatrics [C. A. F.], University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Division of Cancer Epidemiology and Genetics [L. B. T., G. M. D.] and Division of Cancer Prevention [G. M. D.], National Cancer Institute, Bethesda, MD 20892; Cancer Care Ontario, Toronto, Ontario, M5G 2L7 Canada [E. J. H.]; Karolinska University Hospital, Karolinska Institute, SE–177 77 Stockholm, Sweden [K. B., P. H.]; Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, MG5 1X8 Canada [D. M.]; New Jersey Department of Health and Senior Services, Trenton, New Jersey 08625 [B. A. K.]; Department of Epidemiology, University of Iowa, Iowa City, Iowa 52242 [C. F. L.]; Helsinki University Central Hospital, FIN–00290 Helsinki, Finland [T. W.]; The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [M. S.]; and Finnish Cancer Registry, The Institute for Statistical and Epidemiological Cancer Research, FIN–00170 Helsinki, Finland [E. P.]

Purpose: Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used.

Experimental Design: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing.

Results: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion.

Conclusions: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.

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