A Patient with TP53 Germline Mutation Developed Bowen’s Disease and Myelodysplastic Syndrome with Myelofibrosis after Chemotherapy against Ovarian Cancer

4th Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
Internal Medicine (Impact Factor: 0.9). 06/2005; 44(5):490-5. DOI: 10.2169/internalmedicine.44.490
Source: PubMed


Here we report a case of myelodysplastic syndrome (MDS) with myelofibrosis associated with Bowen's disease. A female patient had undergone an operation and chemotherapy for ovarian cancer when she was 65 years old, and she developed MDS at the age of 70 years old. PCR-single strand conformation polymorphism (SSCP) analysis of peripheral blood mononuclear cells, a Bowen's disease lesion, and normal skin showed an abnormal peak in TP53 exon5. Direct sequencing revealed that they all had missense mutation in codon 175 (G to A) of arginine switched to histidine, suggesting a germline mutation of TP53. It was speculated that p53 function was lost by TP53 germline mutation with the loss of a wild type allele induced by the chemotherapy against ovarian cancer, leading to the development of MDS. No therapeutic effects of low dose melphalan or cyclosporine A on MDS were observed, however one month of 30 mg/day prednisolone administration induced a hematological response.

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    • "hat TP53 germline mutations confer an increased risk of therapy - related neoplasms . Subsequent reports described the occurrence of t - MNs in singular cases with deleterious TP53 germ - line mutations but no consistent asso - ciation has been reported to date ( Dockhorn - Dworniczak et al . , 1996 ; Felix et al . , 1996 ; Hisada et al . , 1998 ; Kuribayashi et al . , 2005 ; Talwalkar et al . , 2010 ) . NF1 , Costello - , LEOPARD - and Noonan syndrome are developmental disorders with increased cancer and leu - kaemia risk that are associated with germline mutations in genes of the RAS - MAPK pathway ( Lauchle et al . , 2006 ; Zebisch et al . , 2007 ; Denayer et al . , 2008 ) . Single patients with NF1 who"
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    ABSTRACT: The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing. To apply whole-genome sequencing to a patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANT: Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer (negative for BRCA1 and BRCA2 mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping. Structural variants, copy number alterations, single-nucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. RESULTS; Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome. Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.
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