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An aggressive systemic mastocytosis preceded by ovarian dysgerminoma.

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.

SUBMITTER: Tsutsumi M

PROVIDER: S-EPMC7693501 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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An aggressive systemic mastocytosis preceded by ovarian dysgerminoma.

Tsutsumi Makiko M Miura Hiroki H Inagaki Hidehito H Shinkai Yasuko Y Kato Asuka A Kato Takema T Hamada-Tsutsumi Susumu S Tanaka Makito M Kudo Kazuko K Yoshikawa Tetsushi T Kurahashi Hiroki H

BMC cancer 20201127 1

<h4>Background</h4>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.<h4>Methods</h4>Molecular cytogenomic analyses were performed to elucidate an etiological link between the ASM and dysgerminoma of the patient.<h4>Results</h4>This patient was affected by ovarian dysgerminoma which was treated by chemotherapy and surgical re ...[more]

PMID: 33246418

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Project description:Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KITD816V mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KITD816V. Midostaurin, a broad spectrum TKI with activity against KITD816V, has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KITD816V as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KITD816V. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KITD816V mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.

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An aggressive systemic mastocytosis preceded by ovarian dysgerminoma.

Publications

An aggressive systemic mastocytosis preceded by ovarian dysgerminoma.

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