An aggressive systemic mastocytosis preceded by ovarian dysgerminoma
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RESEARCH ARTICLE
Open Access
An aggressive systemic mastocytosis preceded by ovarian dysgerminoma Makiko Tsutsumi1†, Hiroki Miura2†, Hidehito Inagaki1, Yasuko Shinkai1, Asuka Kato1,3, Takema Kato1, Susumu Hamada-Tsutsumi4, Makito Tanaka2, Kazuko Kudo2, Tetsushi Yoshikawa2 and Hiroki Kurahashi1*
Abstract Background: Aggressive systemic mastocytosis (ASM) is a rare malignant disease characterized by disordered mast cell accumulation in various organs. We here describe a female ASM patient with a previous history of ovarian dysgerminoma. Methods: Molecular cytogenomic analyses were performed to elucidate an etiological link between the ASM and dysgerminoma of the patient. Results: This patient was affected by ovarian dysgerminoma which was treated by chemotherapy and surgical resection. Having subsequently been in complete remission for 2 years, she developed symptoms of ASM. A somatic D816A mutation in the KIT gene was detected in her bone marrow, which facilitated the diagnosis of ASM. Unexpectedly, this KIT D816A variant was also detected in the prior ovarian dysgerminoma sample. Whole-exome sequencing allowed us to identify a somatic nonsense mutation of the TP53 gene in the bone marrow, but not in the dysgerminoma. Microarray analysis of the patient’s bone marrow revealed a copy-number-neutral loss of heterozygosity at the TP53 locus, suggestive of the homozygous nonsense mutation in the TP53 gene. In addition, the loss of heterozygosity at the TP53 locus was also detected in the dysgerminoma. Conclusions: These results indicated that either the mast cells causing the ASM in this case had originated from the preceding ovarian dysgerminoma as a clonal evolution of a residual tumor cell, which acquired the TP53 mutation, or that both tumors developed from a common cancer stem cell carrying the KIT D816A variation. Keywords: Aggressive systemic mastocytosis, KIT, Dysgerminoma, Germ cell tumor, TP53, Loss of heterozygosity
Background ASM is one of the advanced forms of systemic mastocytosis (SM) with a poor prognosis. In this disorder, clonal mast cells become abnormally accumulated in the skin, lymph nodes, liver, gastrointestinal tract and bone marrow (BM) where they are activated and release mediators such as histamine, tryptase and cytokines that then cause organ damage [1–3]. The prevalence of ASM is 0.09 per * Correspondence: [email protected] † Makiko Tsutsumi and Hiroki Miura contributed equally to this work. 1 Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan Full list of author information is available at the end of the article
100,000, and the median age at diagnosis is over 60 years. ASM is quite rare in pediatric population [4–6]. The D816V mutation in KIT is frequently found in the tumor cells of SM patients and is an important part of the established diagnostic criteria for ASM. In addition to KIT variations, somatic mutations in other genes also occur in ASM that facilitate tu
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