p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.
OBJECTIVE
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.


METHODS
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.
Leonard
Debra G B
DG
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Travis
Lois B
LB
Addya
Kathakali
K
Dores
Graca M
GM
Holowaty
Eric J
EJ
Bergfeldt
Kjell
K
Malkin
David
D
Kohler
Betsy A
BA
Lynch
Charles F
CF
Wiklund
Tom
T
Stovall
Marilyn
M
Hall
Per
P
Pukkala
Eero
E
Slater
Diana J
DJ
Felix
Carolyn A
CA
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001483:Base Sequence; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000532:radiotherapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin